Book Biomaterials and Medical Devices

Advanced Structured Materials
Ferdiansyah Mahyudin
HendraHermawan Editors
Biomaterials
and Medical
Devices
A Perspective from an Emerging
Country
Volume 58
Series editors
Andreas chsner, Southport Queensland, Australia
Lucas F.M. da Silva, Porto, Portugal
Holm Altenbach, Magdeburg, Germany
More information about this series at http://www.springer.com/series/8611
Ferdiansyah Mahyudin Hendra Hermawan

Editors
Biomaterials and Medical

Devices
A Perspective from an Emerging Country
123
Editors
Ferdiansyah Mahyudin Hendra Hermawan
Dr. Soetomo Hospital CHU de Quebec Research Center
Airlangga University Laval University
Surabaya Quebec City
Indonesia Canada
ISSN 1869-8433 ISSN 1869-8441 (electronic)

ISBN 978-3-319-14844-1 ISBN 978-3-319-14845-8 (eBook)
DOI 10.1007/978-3-319-14845-8
Library of Congress Control Number: 2016930548
Springer International Publishing Switzerland 2016

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To
Amlie and Maka (Hermawan)
Dhila and Hani (Mahyudin)
And our beloved country Indonesia
Preface
In September 2012, about two hundred Indonesian scientists working in the bio-
materials eld gathered at the rst national symposium on biomaterials hosted by
Bogor Agricultural University in Bogor, Indonesia. A year later, the Indonesian
Biomaterials Society1 was ofcially launched. One of the strong wishes of this
newly born society was to publish a book as a way to introduce and disseminate the
works of Indonesian biomaterials scientists worldwide. After facing some chal-
lenges during the publication process, we nally present this book, Biomaterials
and Medical Devices: A Perspective from An Emerging Country.
The book covers the current development and future direction of biomaterials
and medical devices in Indonesia, including the government policies and directives.
In particular, it highlights the unique needs of Indonesian healthcare service, the
abundant potential for natural resource for biomaterials, and the challenge for
medical devices development. Indonesia, with its 255 million population, 900
billion USD of GDP with 5 % annual growth, and 72 years of life expectancy is an
emerging country having great economic potential. The government has launched a
new pro-public universal healthcare program, which at one point stimulates the
development of biomaterials aiming for national independency on producing
medical devices. The book is written by selected Indonesian experts from aca-
demics, clinics, and government agencies. It should be viewed as a reference for
researchers directing their research, for industries developing and marketing their
products, and for the government setting new policies. The perspectives and the
lessons learned from Indonesia could be then adopted for the development of
biomaterials and medical devices in other emerging countries facing similar
challenges.
1
Indonesian Biomaterials Society (Masyarakat Biomaterial Indonesia), is an independent
not-for-prot professional society having an orientation toward the development of science and
technology of biomaterials and medical devices in Indonesia. Further information can be found at:
http://biomaterial.or.id.
vii
viii Preface
We start the books coverage with the chapter Structure and Properties of
Biomaterials which introduces the structure and properties of biomaterials as an
opening to understand the science and technology of biomaterials. Chapter
Naturally Derived Biomaterials and Its Processing covers biomaterials processing
with special focus on various unconventional methods for synthesizing natural
biomaterials, where its sources are abundant in Indonesia. The biocompatibility
issues of biomaterials that include cytotoxicity, genotoxicity, in vitro and in vivo
models, and some biocompatibility data extracted from many cases in Indonesia is
presented in chapter Biocompatibility Issues of Biomaterials. It is followed by the
chapter Animal Study and Pre-clinical Trials of Biomaterials reviews the animal
study and clinical trials of biomaterials, which include animal models for bioma-
terial research, ethics, care and use, implantation study and monitoring, and
experiences on animal study of medical implants in Indonesia. Chapter
Bioadhesion of Biomaterials covers the bioadhesion aspect of biomaterials as one
of the fundamental sciences to understand implanthost interaction. Chapter
Degradable Biomaterials for Temporary Medical Implants describes degradable
biomaterials as a new generation of materials for temporarily needed medical
devices, which may nd its suitability for lowering the overall cost of implant
surgical procedures. Chapter Biomaterials in Orthopaedics covers biomaterials
for orthopedic applications with special focus on the most common surgical
intervention and type of implants used in Indonesia. Meanwhile, biomaterials in
dentistry are covered in the chapter Biomaterials in Dentistry including its current
state and development in Indonesia. Chapter Tissue Bank and Tissue Engineering
covers tissue bank and tissue engineering with the latest status of its institute in
Indonesia. And nally, the chapter Indonesian Perspective on Biomaterials and
Medical Devices concludes the book with a general overview of the Indonesian
Government policies and directives on biomaterials and medical devices, and the
challenge and opportunity for the development of biomaterials in Indonesia.
We acknowledge Prof. Andreas chsner of Grifth University, Australia, an
editor at Springer, who has facilitated the publication process of this book with the
publisher. We sincerely thank all the authors, and the people around them, for their
commitment and tireless efforts in writing their chapters to nally realize our book.
We will continue to collaborate and keep our synergy in answering the Indonesian
healthcare challenges via research and development of effective and low-cost
biomaterials and medical devices. Hopefully, this book inspires more scientists in
Indonesia and other emerging countries to proudly present their high quality works
at the international stage and be the champions beyond their native niche
(Indonesian proverb: tidak cuma jago kandang).
Ferdiansyah Mahyudin
Hendra Hermawan
Contents
Structure and Properties of Biomaterials . . . . . . . . . . . . . . . . . . . . . . . 1

Sulistioso Giat Sukaryo, Agung Purnama and Hendra Hermawan
Naturally Derived Biomaterials and Its Processing . . . . . . . . . . . . . . . . 23
Raden Dadan Ramdan, Bambang Sunendar and Hendra Hermawan
Biocompatibility Issues of Biomaterials . . . . . . . . . . . . . . . . . . . . . . . . 41
Widowati Siswomihardjo
Animal Study and Pre-clinical Trials of Biomaterials . . . . . . . . . . . . . . 67
Deni Noviana, Sri Estuningsih and Mokhamad Fakhrul Ulum
Bioadhesion of Biomaterials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Siti Sunarintyas
Degradable Biomaterials for Temporary Medical Implants . . . . . . . . . . 127
Ahmad Kafrawi Nasution and Hendra Hermawan
Biomaterials in Orthopaedics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Ferdiansyah Mahyudin, Lukas Widhiyanto and Hendra Hermawan
Biomaterials in Dentistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Margareta Rinastiti
Tissue Bank and Tissue Engineering . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Ferdiansyah Mahyudin and Heri Suroto
Indonesian Perspective on Biomaterials and Medical Devices . . . . . . . . 235
Ferdiansyah Mahyudin, Sulistioso Giat Sukaryo,
Widowati Siswomihardjo and Hendra Hermawan
ix
Editors and Contributors
About the Editors
Ferdiansyah Mahyudin is lecturer and head of the

Department of Orthopaedics and Traumatology,
Faculty of Medicine, Airlangga University (Universitas
Airlangga or Unair),2 Indonesia, as well as orthopedic
surgeon (musculoskeletal oncology consultant) at Dr.
Soetomo General Hospital in Surabaya. He completed
his MD at Sebelas Maret University, orthopedic surgery
training, and Ph.D. (2010) at Unair and Diploma on
tissue bank (2001) at National University of Singapore.
His research interests include orthopedic implants,
oncology, tissue bank, and stem cells. He is the chair-
man of the Indonesian Musculoskeletal Tumor Society.
e-mail: ortopedi@rad.net.id or ferdyortho@yahoo.com.
Hendra Hermawan is assistant professor at the

Department of Materials Engineering with joint
appointment at the Axis of Regenerative Medicine,
CHU de Qubec Research Center, Laval University,
Canada. He received his BS and MS from Institute of
Technology of Bandung (Institut Teknologi Bandung
or ITB),3 Indonesia, and Ph.D. (2009) from Laval
University. He spent 6 years of industrial postdoc
and academic works in Europe and Asia before
joining the present afliation in 2014. His research
2
More about Universitas Airlangga: www.unair.ac.id.
3
More about Institut Teknologi Bandung: www.itb.ac.id.
xi
xii Editors and Contributors
interest focuses on metals for biomedical applications. He serves as an

editorial board member of Journal of Orthopaedic Translation (Elsevier). e-mail:
hendra.hermawan@gmn.ulaval.ca.
About the Contributors
Sri Estuningsih is a veterinarian and lecturer at the Faculty of Veterinary

Medicine (FVM), Bogor Agricultural University (Institut Pertanian Bogor or
IPB),4 Indonesia. She obtained her DVM and MS from IPB, and Ph.D. (2001) from
IPB-Justus Liebig Universitt, Germany (Sandwich Program). Her research interest
focuses on veterinary pathology including immunosuppression and radiation.
e-mail: estu@ipb.ac.id
Ahmad Kafrawi Nasution is lecturer at the Department of Mechanical
Engineering, Muhammadiyah University of Riau, Indonesia. He completed his BS
at Bung Hatta University, MS at ITB, and Ph.D. (2016) at University of
Technology of Malaysia (UTM), Malaysia. He has a broad expertise which ranges
between metallurgy, failure analysis, and metal welding. e-mail:
ucokafrawi@gmail.com
Deni Noviana is a veterinarian and full professor in Surgery and Radiology,
FVM IPB. He accomplished his DVM at IPB and Ph.D. (2004) at Yamaguchi
University, Japan. His expertise lies in diagnostic imaging, echocardiography,
ultrasonography, and radiology. He is the executive director of the FVM IPB
Animal Teaching Hospital. e-mail: deni@ipb.ac.id
Agung Purnama is an NSERC postdoctoral fellow at Politecnico di Milano.
He received his BS from ITB and Ph.D. (2014) from Laval University. He
has developed a cross-disciplinary expertise comprising materials engineering,
electrochemistry, cardiology, tissue engineering, and molecular biology. e-mail:
agung.purnama.1@ulaval.ca
Raden Dadan Ramdan is lecturer at the Department of Materials Engineering,
ITB. He completed his BS at ITB, MS at UTM, and Ph.D. (2009) at Kobe
University, Japan. His research interests include phase-eld simulation, surface
treatment, and coating for biomaterials, especially the coating of hydroxyapatite on
titanium alloy by high-velocity oxy-fuel processes. e-mail: dadan@material.itb.ac.id
Margareta Rinastiti is lecturer at the Faculty of Dentistry, Gadjah Mada
University (Universitas Gadjah Mada or UGM),5 Indonesia. She completed her
DDS, MS, and Specialist in Conservative Dentistry at UGM and Ph.D.
(2010) at University of Groningen, Netherlands. Her research interests include
4
More about Institut Pertanian Bogor: www.ipb.ac.id.
5
More about Universitas Gadjah Mada: www.ugm.ac.id.
Editors and Contributors xiii
conservative dentistry, minimally invasive dentistry, and composite materials.

e-mail: rinastiti@ugm.ac.id
Widowati Siswomihardjo is dentist and full professor at the Faculty of Dentistry,
also coordinator of the Department of Biomedical Engineering, School of Graduate
Studies, UGM. After nishing her Ph.D. (1999) at Unair, she did a postdoc at
University of Melbourne, Australia. Her major interest is in the biocompatibility of
biomaterials where she collaborates closely with the Faculty of Dentistry,
University of Hong Kong. She is one of the leaders in the Indonesian national
medical devices projects. e-mail: widowati@ugm.ac.id
Sulistioso Giat Sukaryo is researcher in the Center of Science and Technology for
Advanced Materials, National Nuclear Energy Agency of Indonesia (Badan Tenaga
Atom Nasional or BATAN).6 He completed his BS and MS at ITB. His research
interest focuses on materials for medical implants ranging from metals, polymers,
ceramics to composites, and degradable biomaterials. He utilizes various nuclear
techniques for microstructure characterization and mechanical properties
improvement of polymers. e-mail: giat_s@batan.go.id
Siti Sunarintyas is lecturer at the Faculty of Dentistry with joint afliation with the
Department of Biomedical Engineering, School of Graduate Studies, UGM. She
obtained her BS from UGM, and MS and Ph.D. (2002) from Unair. Her research
interests include adhesive materials and bers for biomedical applications. e-mail:
sunarintyassiti@ugm.ac.id
Bambang Sunendar is full professor at the Department of Engineering Physics,
ITB. He received his BS from ITB, and MS and Ph.D. (2001) from Keio
University, Japan. His research interests are advance material synthesis, biomate-
rial, controlled release, and surface modication. He is the head of the advanced
materials processing laboratory in ITB and a member of the National Research
Council of Indonesia. e-mail: purwa@tf.itb.ac.id
Heri Suroto is lecturer at the Department of Orthopaedics and Traumatology,
Faculty of Medicine, Unair, and orthopedic surgeon (hand and microsurgery con-
sultant) at Dr. Soetomo General Hospital. He obtained his MD, orthopedic surgery
training and Ph.D. (2011) from Unair. He is the director of the Regenerative
Medicine and Stem Cell Center in Surabaya and focuses his research on naturally
derived biomaterial, nerve tissue engineering, tendon tissue engineering, and bra-
chial plexus injury. e-mail: hsuroto2000@yahoo.com
Mokhamad Fakhrul Ulum is a veterinarian and lecturer at the FVM IPB. He
received both his DVM and MS from IPB and Ph.D. (2016) from UTM. He has
developed multidisciplinary expertise comprising in vitro and in vivo testing of
biomaterials, biomedical imaging, microfluidics, analytical biochemistry, and
applied diagnostics. e-mail: ulum@ipb.ac.id
6
More about Badan Tenaga Atom Nasional: www.batan.go.id.
xiv Editors and Contributors
Lukas Widhiyanto is lecturer at the Department of Orthopaedics and

Traumatology, Faculty of Medicine, Unair, and orthopaedic surgeon at
Dr. Soetomo General Hospital. He completed his MD and orthopaedic surgery
training at Unair (1999), fellowship in Spine surgery at Samsung Medical Center,
Korea (2013), and Dokkyo Medical University Hospital, Japan (2015). e-mail:
lukas-w@fk.unair.ac.id
Structure and Properties of Biomaterials
Sulistioso Giat Sukaryo, Agung Purnama and Hendra Hermawan
Abstract Biomaterials are materials from which medical devices are made. Based
on their chemical composition, they can be polymers, metals, ceramics or com-
posites. Metals are still the most used biomaterials mostly due to their superior
mechanical properties and can be found in orthopedic, cardiovascular and dental
implants. However, many type of implants can only work properly when polymers
or ceramics are also used in pair with metals such as in total knee or hip arthro-
plasties. Nowadays, biomaterials are no longer seen as inert substances supporting
or replacing dysfunctional tissues or organs. They are now required to promote the
healing process and self-disintegrate once the process is completed. All the efforts
in searching ideal biomaterials are paid to improve the wellness and health of
human beings. This chapter is intended to give a brief introduction to the structure
and property of biomaterials.
Keywords Biomaterials Ceramic Metal Polymer Property Structure
1 Introduction
In general understanding, biomaterials is dened as any substance, other than a

drug, synthetic or natural in origin, which can be used for any period of time, which
augments or replaces any tissue, organ, or function of the body, in order to maintain
or improve the quality of life of an individu (Dee et al. 2003). The use of bio-
materials in the modern age was prominent during the World War II following the
S.G. Sukaryo (&)

National Nuclear Energy Agency of Indonesia, Tangerang Selatan, Indonesia
e-mail: giat_s@batan.go.id
A. Purnama H. Hermawan (&)
Laval University, Quebec City, Canada
e-mail: hendra.hermawan@gmn.ulaval.ca
A. Purnama
e-mail: agung.purnama.1@ulaval.ca
Springer International Publishing Switzerland 2016 1

F. Mahyudin and H. Hermawan (eds.), Biomaterials and Medical Devices,
Advanced Structured Materials 58, DOI 10.1007/978-3-319-14845-8_1
2 S.G. Sukaryo et al.
need to treat wounded soldiers. Since then, the concept of biomaterials has evolved
considerably.
The development of biomaterials involves various disciplines of science. It
engages multidisciplinary elds including material science and engineering, med-
ical science, biophysics, chemistry and biology. Biomaterials are now mostly
developed under the research in material science and engineering. Metal and alloys,
polymer, ceramics and composites are vastly explored and characterized in the
effort to nd specic properties that match the requirements of a particular bio-
material (Ratner et al. 2013). The development of biomaterials is directed by
medical science as the user of biomaterials. It gives information of what devices
need to be developed together with their physical, mechanical, chemical, and
biological characteristics. The development of biomaterials is also supported by
biophysics studying the compliance of biomaterials and conducting physical
properties testing such as, magnetic properties, electrical properties, phase analysis
and heat properties. Moreover, the development of biomaterials are strongly related
to the eld of chemistry suggesting the nature of elemental reactivity useful for
predicting the behavior of biomaterials towards their surroundings. Chemistry also
provides important idea on surface functionalization and coating of biomaterials.
The interaction of cross-disciplinary expertise supporting biomaterials is presented
in Fig. 1.
The translation of biomaterials from bench (laboratory) to bed (patient) requires
a long and rigorous process. Starting from the formulation of specic needs, the
synthesis of materials, design and manufacture of prostheses and clinical testing to
pass all requirements determined by regulatory agencies such as the United States
Food and Drug Administration (FDA) or European conformity (CE) agency
(Vallet-Reg 2010). The proposed biomaterials will be either granted Premarket
Approval (PMA) if substantially similar to one used before (the me too devices),
or have to go through a series of guided biocompatibility assessments. Figure 2
shows the general path of the biomaterials and implants development.
Fig. 1 Diagram of multidisciplinary contribution to biomaterials

Structure and Properties of Biomaterials 3
Fig. 2 A biomaterials development path from basic science to clinical applications. Adapted from
(Ratner et al. 2013)
The early generation of biomaterials was designed to be inert, hence providing

only physical support with minimum requirement of compatibility. Nowadays, the
concept of biomaterials has shifted signicantly. Biomaterials are now seen as
active substances, not only inert, that support the healing process of an injured
tissue. They come in various forms such as a complex hybrid of composites or
metals coated with different polymers. Usually, a single material goes for a specic
application. In the early development of biomaterials, there was a limited concern
about how a material would interact with human body since they were considered
inert. However, as the demand for biomaterials kept increasing, the development of
non-inert biomaterials added a new layer of complexity. Consequently, the need of
a systematic study to assess the compatibility of various materials become impor-
tant, permitting a standardized assessment to compare new biomaterials with the
previously existing ones. The term of biocompatibility was then introduced in the
eld. Biocompatibility refers to the ability of a material to perform a particular
function within living tissues followed by appropriate host responses, minimum
inflammatory and toxicity reactions both locally and systematically (Ratner et al.
2013). It is thus a complex function of materials, design, applications, host
responses, etc. Biological properties of biomaterials refers to the biocompatibility
and can be determined using in vitro and in vivo test systems. However, both
approaches are limited to the results obtained from models, which are not com-
pletely represent the human system.
Biomaterials consist of metals, polymers, ceramics, and composites. Each
material possess a unique building block, which determines their biological and
mechanical properties. While biological properties are mainly influenced by the
surface property of materials, mechanical properties play signicant role in satis-
fying the structural requirements of specic biomaterials or implants. Therefore,
this chapter serves as a brief introduction to biomaterials focused on the materials
structure and their mechanical properties.
2 Metals
Metals are exploited as biomaterials mainly due to their superior mechanical

properties. They have been widely used in various forms of implants providing the
required mechanical strength and corrosion resistance. They account for 70 %
implants including orthopaedic: knee joint, total hip joint, bone plates, fracture
xation wires, pins, screws, and plates; cardiovascular: articial heart valves,
vascular stents, and pacemaker leads (Niinomi et al. 2012). Figure 3 shows two
coronary stents as example of implant made of metal. Although pure metals are
widely used, alloys provide improved strength and corrosion resistance. The main
criteria in choosing metals and alloys for biomedical applications are biocompati-
bility, appropriate mechanical properties, good corrosion resistance in body fluid,
durable and cost effectivity (Dee et al. 2003).
2.1 Structure and Properties
Metals consist of metallic bonds in which free electrons circulating among the
atoms. The circulating electrons provide the transfer of electrical charge and ther-
mal conductivity. The movements of free electrons act as the binding force to hold
the positive metal ions together. The strong binding by a close-packed-atomic
arrangement results in high specic gravity and high melting points of most metals.
Since the metallic bond is essentially unidirectional, the position of the metal ions
can be altered without destroying the crystal structure resulting a plastic deformable
solid (Callister and Rethwisch 2014). Atomic structure of metals resembles blocks
of atoms which is ambulatory to each other. When stress is applied, these blocks are
displaced until the yield stress is reached and large blocks of atoms slip and pass
Fig. 3 Photograph of
coronary stents (before and
after expansion) made of
stainless steel as an example
of metal implant (Courtesy of
Biosensors International,
Singapore)
Fig. 4 Illustration of two crystal structures: a HCP, and b FCC
Table 1 General applications of metals as biomaterials

Alloy type Applications
Stainless Joint replacements (hip, knee), bone plate, xation, dental implant, tooth
steels xation, heart valve, stents, spinal instruments, screws, dental root implant,
pacer, fracture plates, hip nails, shoulder prosthesis
Co-Cr alloys Total hip and knee joint replacement, bone plate, xation, screws, dental root
implant, pacer, and suture, orthopedic prosthesis, mini boneplates, surgical
tools, dental implants, stents
Ti and its Total hip and knee joint replacement, dental implants, tooth xation, screws,
alloys suture, parts for orthodontic surgery, bone plate, screws, articial heart valves
and heart pacemakers, stents, cochlear replacement
each other. The plane along which movement occurs is called the slip plane. Slip
plane movement depends on density of the atom in the slip plane, and depends of
the crystal system in the metal. Two different crystal systems: face-centered cubic
(FCC) and hexagonal close-packed (HCP) structures are shown in Fig. 4.
Considering the number of the slip plane, FCC has higher density of slip plane than
other crystal systems and thus more ductile.
Chemical composition is one of the basic ingredients or characteristics of metals
which determines the formed microstructure and phases, thus their properties such
as physical and mechanical properties. For instance, the addition of aluminum
(Al) and vanadium (V) into pure titanium (Ti), to form the Ti-6Al-4 V alloy, greatly
increases the tensile strength of Ti. Metallurgical state is another characteristic that
determine mechanical properties, for example annealed condition offers better
ductility than that of cold worked. Finally, metal processing also affects their
microstructure and properties. For example, cast metal implants usually possess
lower strength than those made by forging. Up to now, the three most used metals
for implants are stainless steels (notably the 316L type), cobalt-chromium (Co-Cr)
alloys and Ti alloys (Niinomi et al. 2012). Table 1 lists common applications of
metals as biomaterials and Table 2 shows the properties of some metallic
biomaterials.
Table 2 Properties of some metallic biomaterials

Material Alloying composition Density E YS UTS
(wt%) (g/cm3) (GPa) (MPa) (MPa) (%)
SS316L max 0.03 C; 1315 Ni; 1719 7.96 205 190 490 40
Cr; 2.253 Mo; balance Fe 210
CoCrMo max 0.5 Ni; 2730 Cr; 57 Mo; 8.4 227 450 655 8
balance Co
Ti grade 4 max 0.4 O; max 0.5 Fe; balance 4.5 105 483 550 15
Ti
Ti6Al4V 5.56.5 Al; 3.54.5 V; balance 4.4 110 760 825 8
Ti 795 860 10
Ti6Al7Nb 5.56.5 Al; 6.57.5 Nb; balance 4.52 110 800 900 10
Ti
Ti35Nb5Ta7Zr 35.3 Nb; 5.1 Ta; 7.1 Zr; balance 5.85 55 530 590 21
(TNTZ) Ti
NiTi 54.557 Ni; balance Ti 6.45 20 50 755 10
110 800 960 15
TiNb 40 Nb; balance Ti 6.73 69 616 1421 37.3
Note E = elastic modulus, YS = yield strength, UTS = ultimate tensile strength, = elongation.
Data compiled from: ASTM F67, ASTM F75, ASTM F136, ASTM F138, ASTM F139, ASTM
F1295, ASTM F2063 and (Long and Rack 1998; Calin et al. 2014; Davidson et al. 1994; Navarro
et al. 2008; Taarea and Bakhtiyarov 2004)
2.2 Stainless Steels
Austenitic stainless steels were rst used for implants in 1936, as fracture xation
and joint replacement and have scored the longest record of practical use ever since
(Jaimes et al. 2010; Niinomi et al. 2012). The advancement in steel rening and
alloying technology elevated the grade of 18-8 type stainless steel to the widely
known AISI 316L (SS316L), which is highly recommended for implant applica-
tions since quite long time (Smethurst 1981).
Although the 316L type has adequate physical and mechanical properties and
wide availability in various shapes and sizes, some works were done to improve its
biocompatibility. Electrochemical observation on Fe-Cr-Ni alloys found that the
body environment contributed to some changes in the composition and structure of
the passive layer formed on the surface, such as Cr2O3 (Jaimes et al. 2010). These
changes make the passive layer susceptible to localized corrosion and stress cor-
rosion cracking (Talha et al. 2013). Molibdenum (Mo) contributes to stabilize the
passive lm and improve the corrosion resistance in chloride solution. However, the
breakdown of passive layer allows the release of metal ions contained in the metals,
such as nickel (Ni) and Cr ions. Ni ion is potentially harmful to the human body and
may cause allergic reactions in tissues and also toxicity (Niinomi et al. 2012). Given
the potential detrimental effect of Ni on the human body, experts recommended to
limit its content in stainless steel for medical applications. In 1992, a new steel,
ASTM F1586 (ISO5832-9) was introduced as an orthopedic implant material.
This Ni-free alloy contains a high nitrogen (N) and manganese (Mn) to stabilize the
austenitic structure of stainless steel and to improve mechanical properties, corro-
sion resistance and biocompatibility (Talha et al. 2013).
2.3 Co-Cr Alloys
Co-Cr alloys are characterized by their high corrosion and wear resistances (Yan et al.
2007). They have been widely used for articial knee joints, articial hip joints and
dental applications (Patel et al. 2012). These alloys can be processed via several
routes including casting, forging, and powder metallurgy. The most used and com-
mercially available alloys are Co-28Cr-6Mo (ASTM F75) for casting version whereas
forging versions are named as ASTM F90, ASTM F562, ASTM F799 and ASTM
F1537. Further improvement on their wear and corrosion resistance can be achieved
by heat treatment and hard surface coating, such as by using laser and electron beam
that produces non-equilibrium microstructures via rapid heating and cooling of the
surface (Walker et al. 2013).
Heat treatments and modication of elemental content could change the
microstructure and alter the electrochemical and mechanical properties of the
Co-Cr-Mo alloy. However, cast Co-Cr-Mo alloys have coarse grain and micro
porosity and brittle phase (HCP) formed along the interdendritic region which
deteriorates their mechanical properties. Therefore, phase (FCC) should suppress
the phase in order to increase ductility of the Co-Cr-Mo alloys. Adding N sta-
bilizes the phase and inhibits the phase similar to what happened in the FeCr
system (Lee et al. 2011).
In recent years, the reliability of the mechanical properties of these alloys such as
tensile strength and fatigue properties has increased considerably through advances
in alloy design and optimization of the deformation process. This reliability
becomes so important because of the increasing life expectancy of patients after
articial knee joint or articial hip joint surgeries. Currently, joint replacement
surgery is not only performed in elderly but also in younger patients. Thus, the
ability to engage in sports and tness activities after undergoing surgery becomes a
major challenge to the failure of articial joints (Mitsunobu et al. 2014).
It is generally agreed that the important factors affecting the longevity of
orthopedic implants are the release of metal ions from the implants and the for-
mation of debris which provokes tissue inflammation, bone loss and implant
loosening. About 2030 % of implant material loss were caused by the combined
action of wear and corrosion known as tribocorrosion (Doni et al. 2013). This
mechanically-assisted electrochemical process constitutes a major concern in the
clinical aspects of metal implants. Recent in vivo studies showed that metal ions
and particles are separated due to the friction on Co-Cr-Mo implant and further
caused damage to the soft tissue (Walker et al. 2013).
2.4 Ti and Its Alloys
Originally, Ti and its alloys are developed as an aircraft structural materials, but the
current research and development of these alloys is also directed toward biomedical
applications by reducing the elastic modulus and improving the biological prop-
erties (Calin et al. 2014). Ti and its alloys show excellent corrosion resistance and
high strength to weight ratio compared to stainless steels and Co-Cr alloys. A stable
and coherent Ti oxide (TiO2) thin lm is formed on Ti surface providing superior
corrosion resistance. Ti is an allotropic metal where between room temperature and
882 C forms -phase with HCP structure and above that it transforms to -phase
with body-centered cubic (BCC) structure (Brandes and Brook 1992). Pure Ti
cannot be hardened by heat treatment therefore must be alloyed with other elements
to grow precipitates in the single phase matrix. Moreover, they are very attractive
implant materials because of their high strength to weight ratio and better bio-
compatibility compared to other metallic biomaterials. The most known Ti alloy,
the Ti-6Al-4V, is considered as having excellent tensile strength and pitting cor-
rosion resistance. When alloyed with Ni, Ti-Ni alloy or better known as Nitinol,
possesses shape memory effect which is another interesting property used for
example in dental restoration wiring. Ti is featured by its light weight, with density
only 4.5 g/cm3, compared to 7.9 g/cm3 for 316L stainless steel and 8.3 g/cm3 for
cast Co-Cr-Mo alloys (Brandes and Brook 1992). Ti and its alloys for medical
applications were covered in ASTM standards F67, F136 and F2063.
Ti and its alloys are grouped into: type, + type with elastic modulus of
110120 GPa, and type with elastic modulus of 60-85 GPa (Niinomi et al. 2012).
However, the elastic modulus values are still too high compared to those of human
bone, 1030 GPa (Calin et al. 2014). This difference can hinder load transfer
between implant and the surrounding bone, known as stress shielding effect. This
effect can lead to implant loosening due to the poor bone growth around the implant
or the need for revision surgery (Rack and Qazi 2006). Concerns over stress
shielding have led to the development of Ti alloys with lower elastic modulus.
Alloying with tantalum (Ta), zirconium (Zr), silver (Ag), platinum (Pt), Al, tin (Sn),
copper (Cu) and boron (B) improves super-elastic behavior of Ti alloys, whereas
adding oxygen (O) or N gives similar effect to Ni-free Ti alloys (Niinomi et al.
2012). Lately, addition of indium (In) into Ti-Nb alloy remarkably decreases the
elastic modulus (Calin et al. 2014). Single crystal texture of TNTZ alloy possess
elastic modulus as low as 35 GPa (Niinomi et al. 2012).
2.5 Other Metallic Biomaterials
Precious metals and alloys such as gold (Au), Ag and Pt and their alloys are mostly
known in dentistry due to their good castability, ductility and resistance to corrosion.
Dental alloys such as Au-Ag-Cu system, Au-Ag-Cu with the addition of zinc (Zn) and
tin known as dental solder, and AuPt-Pd system used for porcelain-fused-to-metal
for teeth repairs (John 2000).
Ta and amorphous alloys are among other metals used for implants. The excellent
X-ray visibility and low magnetic susceptibility of Ta, makes it often used for X-ray
marker on stents. Porous Ta, which can be made by using high power lasers, has been
proposed for orthopedic implants claiming a better tissue acceptance (Balla et al.
2010). Amorphous alloys show interesting properties compared to its crystalline
counterparts whereas they exhibit a higher corrosion resistance, wear resistance, tensile
strength and fatigue strength. Amorphous alloys like that of Zr-based (Wang et al.
2011) with its low Youngs modulus is prospective for miniaturizing metal implants.
3 Polymers
A polymer is a macromolecule composed of many repeated subunits. It has a broad

range of properties and play an essential role in our current daily life. Polymers range
from synthetic plastics such as poly(styrene) to natural biopolymers such as DNA
and proteins. Due to a large molecular mass relative to small molecule compounds, it
produces unique physical properties, including toughness, viscoelasticity, and a
tendency to form amorphous structures rather than crystals. Thanks to these features,
polymers have been widely used as substitute materials to metals. Figure 5 shows a
set of total knee replacement implants as an example of implant with part made of
polymers. The articulating surface is made of ultra high molecular weight poly
(ethylene) (UHMWPE) as its has low coefcient of friction, good chemical resis-
tance, resistance to environmental stress cracking, high notched impact strength and
high energy absorption at high stress rates. However, wear is considered as one of
the major problems that shorten the life of an UHMWPE articial knee joint and
produce debris that is responsible for osteolysis (Brach del Prever et al. 2009).
Fig. 5 A set of total knee replacement implants and its xation (Courtesy of Dr. Soetomo General
Hospital, Surabaya)
3.1 Chain Structure
Both natural and synthetic polymers are created via polymerization of many small
molecules (monomers) forming a chain structure. Based on its chain structure,
polymers are classied as linear, branch, cross-link and network, as seen in Fig. 6.
Chemical bonds in a polymer consist of primary and secondary bonds. The primary
bonds involve two atoms sharing electrons hence called covalent bonds. The sec-
ondary bonds include van der Waals forces, hydrogen and ionic bonds. Primary
bonds are 10100 times stronger when compared to secondary bonds. (Callister and
Rethwisch 2014). The average length of the polymer chain can be seen from the
molecular weight of a polymer which is essentially the sum of the weight of its
monomer.
The cross-linking structure can be formed by a number of techniques, including
high energy radiation. The advantages of radiation processing include the absent of
any chemical residues as no chemical additives are requires to initiate the reactions,
applicable at all temperatures, can be targeted on specic area or surface only, and it
offers a combination of synthesis/modication of materials with sterilization
(Darwis et al. 2015). Nuclear radiation, such as -ray generated from Co60, pro-
duces free radicals which lead to break down of chain and cross-linking formation
between adjacent molecules. The dose of radiation is one of the most important
parameters where its increase makes crystallinity decreases and drops signicantly
at 100150 kGy (Lewis 2001). This radiation technique has been applied to
cross-link UHMWPE to control the degree of crystallinity thus increase its
mechanical properties and prevent wear.
Unlike metals, polymers in general are amorphous and they are not crystalline in
nature. However, polymers can be engineered so that its structure can have crys-
talline regions, both in the process of synthesis and deformation (Callister and
Fig. 6 Types of polymers chains: linear (1), branch (2), cross-link (3), and network (4)
Fig. 7 Illustration of semi

crystalline structure of
polymers
Rethwisch 2014). The magnitude of the crystalline regions within a polymer is

expressed as degree of crystallinity. It influences mechanical properties such as
stiffness, hardness, and ductility; and physical properties such as optical and density
of the polymers. The degree of crystallinity can be engineered by controlling
process parameters such as the rate of solidication, although obtaining 100 %
value is rather difcult. Polymers with branched chain structure have a lower degree
of crystallinity when compared with unbranched structures. The structure of chain
that contains mixture of amorphous and crystalline is called semi crystalline
structure. As illustrated in Fig. 7, semi crystalline polymers possess crystalline
region where chains are aligned and amorphous regions where chains are rather
forming network.
3.2 Thermal and Mechanical Properties
Based on its thermal properties, polymers are divided into: (1) thermoplastic which
is soft and viscous when it is heated up and become hard and rigid when it is cooled
down, and this process can be done repeatedly; (2) thermoset which melts when
rst heated and then hardens permanently when cooled, but when it is heated again,
the polymer will be destroyed. Thermoplastic polymers are mostly soft and very
ductile due to its linear, branch and cross-link structures. While thermoset is typ-
ically harder and rigid due to its three dimensional network (Callister and
Rethwisch 2014). The summary of thermoplastic and thermoset properties are listed
in Table 3.
The term mechanical properties is commonly used to denote stress-strain rela-
tionship for polymer systems which unlike metals these relationships depend not
only on temperature but also time dependence. The mechanical properties of
Table 3 Comparison of thermoplastic and thermoset polymers

Thermoplastic Thermoset
Few cross-linking More cross-linking (1050 % of mers)
Ductile Hard and brittle
Soften with heating Not soften with heating
Examples: poly(ethylene), poly(propylene), Examples: vulcanized rubber, epoxies,
poly(carbonate), poly(styrene) polyester resin, phenolic resin
Fig. 8 The influence of temperature to the tensile behavior of poly(methyl methacrylate)

(Carswell and Nason 1944)
polymers depend on the strain rate, temperature, and environmental conditions.

They can be brittle, plastic and highly elastic (elastomeric or rubber-like). Their
tensile strengths are orders of magnitude smaller than those of metals, but elon-
gation can be up to 1000 % in some cases. It has been long-known that mechanical
properties change dramatically with temperature, going from glass-like brittle
behavior at low temperatures to a rubber-like behavior at high temperatures (Fig. 8).
The solid state deformation of polymers is time-dependent and nonlinear. It
resembles some combination of elastic and viscous responses, known as vis-
coelastic behavior. An immediate consequence of the viscoelasticity of polymers is
that their deformations under stress are time dependent. Different to the deformation
on metals where the end point of elastic deformation is either fracture or plastic
flow, imposed mechanical stress on polymers results into strain that increases with
time (i.e. polymer creep). When a constant deformation is imposed, the induced
stress will relax with time (stress relaxation) (Ward and Sweeney 2012).
Table 4 Mechanical properties of some polymers (Kalpakjian 2008)

Material UTS (MPa) E (GPa) Poissons ratio
Acrylonitrile butadiene styrene 2855 1.42.8
Acetal 5570 1.43.5
Acrylic 4075 1.43.5
Cellulosic 1048 0.41.4
Expoxy 35140 3.517
Flurocarbon 748 0.72 0.460.48
Nylon 5583 1.42.8 0.320.40
Phenolic 2870 2.821
Poly(carbonate) 5570 2.53 0.38
Poly(ester) 55 2 0.38
Poly(ethylene) 740 0.10.14 0.46
Poly(propylene) 2035 0.71.2
Poly(stirene) 1483 1.44 0.35
Poly(vinyl chloride) 755 0.0144
Note UTS = ultimate tensile strength, E = Youngs modulus
Generally, decreasing the strain rate has the same influence on the strain-strength
characteristics as increasing the temperature where the material becomes softer and
more ductile. The strength of polymers can be increased by increasing molecular
weight, cross-linking and crystallinity which all makes the secondary bonding
enhanced as the molecular chains are closely packed and parallel. Similar to strain
hardening in metals, pre-deformation by drawing increases strength by orienting the
molecular chains. While for undrawn polymers, heating increases the tensile
modulus and yield strength, and reduces the ductilityopposite of what happens in
metals (Landel and Nielsen 1993). Mechanical properties of some polymers are
listed in the Table 4.
3.3 Examples of Most Used Polymeric Biomaterials
Polyurethanes are one of the most commonly used materials for blood contacting
medical devices due to their superior bio- and blood-compatibility. They are used as
catheters, heart valves, total articial heart, and articial blood vessels. They pos-
sess superior durability, elasticity, elastomer-like character, fatigue resistance, and
compliance (Zdrahala and Zdrahala 1999). Large family of polyurethanes provides
extensive structure and property diversity with the common characteristic of ure-
thane linkages along the large molecular chains. Generally, urethane linkages are
formed by the reaction of isocyanates and alcohols accompanied with the formation
of various bonds such as allophanate, biuret, acylurea, and disocyanurate leading to
further branching and crosslinking thus affecting their physical and chemical
properties as well as their biocompatibility (Burke and Hasirci 2004). In their early
development, polyurethanes were obtained by the reaction of diisocyanates and
glycols applied as rigid foams, adhesives, resins, elastomers, and coatings.
However, their application as medical devices was limited to the degradation and
calcication. For this reason, polyurethanes are often derived from polyether which
provides great number of linkage determining the properties of polyurethanes. This
new type of polyurethanes are virtually insensitive to hydrolysis thus very stable in
the physiological environment (Zdrahala and Zdrahala 1999).
The shift in biomaterials paradigm from biostable to bioactive has led the
development of biodegradable polymers. Polymers are now expected to help the
body to repair and regenerate the damage tissues through the degradation process.
They are widely applied as a platform in the biomedical technologies such as tissue
engineering, regenerative medicine, gene therapy, controlled drug delivery and
nanotechnology (Middleton and Tipton 2000). One of the most common
biodegradable polymers in biomedical application is polylactides. They exist in two
optically active forms: L-lactide and D-lactide. The former is naturally occurring
isomer, a building block of poly(L-lactide) (PLLA) with the degree of crystallinity
around 37 % (Maurus and Kaeding 2004). PLLA possesses good tensile strength,
low extension, and high modulus (around 4.8 GPa) making it ideal biomaterial for
load bearing applications such as orthopaedic xation devices (Leinonen et al.
2002). The degradation rate of PLLA depends on the degree of polymer crystallinity
as well as the porosity of the matrix. High molecular weight PLLA degrades between
2 and 5.6 years total resorption in vivo. PLLA is known to loose its strength after
6-months of hydrolization eventhough there is no signicant changes in mass occur
for extensively long period of time (Miller et al. 1977). For this reason, glycolides or
D-lactide are often added as copolymers allowing superior property modulation.
Poly (DL-lactide) is an amorphous polymer due to the random distribution of L- and
D-lactide units. Hence, it shows lower strength (around 1.9 GPa) compared to poly
(L-lactide) and it losses its strength within 12 months when hydrolyzed and
undergoes complete mass loss within 1216 months (Middleton and Tipton 1998).
4 Ceramics
4.1 Bonding and Structure
Ceramics are compounds between metallic and non-metallic elements and they are
composed of more than one elements such as silica (SiO2) and alumina (Al2O3).
Ceramics bonding is partially or totally ionic bonding, covalent bonding, or com-
bination of both. This bonding is tighter compared to metallic bonding (Callister
and Rethwisch 2014). The interatomic bonding in ceramics results in long range of
three-dimensional crystalline structure. Most ceramics have polygranular
microstructure while some are amorphous, similar with structure of metallic alloys.
Fig. 9 The illustration of sliding in ceramics
The characteristics of ceramics is determined by the characteristics of its

microstructure, including the size of the grain, porosity, type and phase distribution
in each particles (Carter and Norton 2007; Narayan et al. 2015). This microstructure
can be manipulated through thermal processing techniques.
In contrast to metallic bonding, the electron in ionic and covalent bonds of
ceramics are localized between the constituent ion/atoms. Consequently, ceramics
are insulator to electrical and thermal. However, ions with the same electric charge
repel each other, therefore moving the plane of atoms is difcult. The planes of
atom cannot slide before they slip past one another making ceramics as hard and
brittle material, as illustrated in Fig. 9.
4.2 Processing and Properties of Ceramics
Ceramics are often fabricated by mixing ne particles with water and an organic
binder then pressed them into one mold. They are subsequently heated or sintered at
high temperature. This process densities the particles through evaporation and
condensation. Similar to casting of metallic alloy, microstructure of ceramic
depends on the variables of the processed. For example, strength is determined by
both of the size of the grain and porosity. Grain size can be controlled by the initial
size of the particles where it will increase during the process while the porosity will
decrease (Carter and Norton 2007; Narayan et al. 2015).
Ceramics typically characterized with little creep, limited plastic deformation
and are sensitive to the presence of cracks or other defect. These are the reason why
ceramics have low tensile strength compared to the compressive strength (Hollinger
2006). Although ceramics and glasses have good resistance to corrosion, they are
susceptible to other forms of degradation when exposed to physiological environ-
ment such as in body fluids. The mechanism and rate of degradation depend on the
specic types of ceramics. In alumina, the degradation may cause a preferential

dissolution of impurities resulting cracks propagation, which subsequently leads to
fracture (Narayan et al. 2015).
In general, ceramics biomaterials (bioceramics) are expected to possess desirable
mechanical properties and biocompatibility. Calcium-phosphate is one of the most
important family for bioceramic materials. It is mainly applied for hard tissue repair
due to their similarity to the minerals in natural bone as well as their excellent
biocompatibility and bioactivity (Sakka et al. 2012). They are established materials
for augmentation of bone defects. Moreover, calcium-phosphates such as hydrox-
yapatite, fluorapatite, tricalcium phosphate have been used for medical and dental
applications (Hollinger 2006). Unfortunately, they possess relatively poor tensile
and shears properties. In practice, the strength of the calcium phosphate is lower
than that of bone and teeth (Ratner et al. 2004). In addition to their inherent
brittleness, their application is restricted to non-load bearing defects or pure com-
pression loading. Common applications include the treatment of maxilla-facial
defects or deformities, cranio facial repair, and augmentation of spine and tibial
plateau. Tricalcium-phosphate is one of the most important family members and it
is widely used as bone substitute materials due to their chemical similarity to that of
mammalian bone and teeth. However, it is considered to be brittle and it has poor
fatigue resistance hence it is not suitable for many load-bearing applications (3
5 MPa). Its poor mechanical behaviour is even more evident when applied as highly
porous ceramics. For this, metal oxides ceramics such as alumina (Al2O3) and
titania (TiO2) have been explored as bioceramic components of tricalcium phos-
phate (Sakka et al. 2012).
The formation of bone-like apatite layer is the main requirement for calcium-
phosphate materials to be bioactive and bond to living bone. Calcium-phosphate
possesses the ability to attract osteoblast and osteoclasts (Thamaraiselvi and
Rajeswari 2004). Within in vitro model, human and animal osteoblast cells anchor to
the material surface within 2 h incubation period and their proliferation depends on
their microstructure. When implanted in an osseous site, bone bioactive materials such
as hydroxyapatite provides an ideal environment for cellular interaction and colo-
nialization by osteoblast cells. This leads to a tissue response called osteoinduction in
which bone grows on and bonds to the implants (LeGeros 1993). A vast experiment
has been conducted extensively to improve the properties and performance of
calcium-phosphate based implants. In physiological solution, hydroxyapatite shows
more stability compared to tricalcium-phosphate as it has lower solubility. However,
the application of tricalcium-phosphate as a bone substitute has received considerable
attention due to its remarkable biocompatibility within living bodies when replacing
hard tissues and its biodegradable properties. Consequently, tricalcium-phosphate has
been used as bone graft substitutes in many surgical elds such as orthopaedic and
dental surgeries (Elliott 1994).
4.3 Type of Bioceramics and Their Use
Bioceramics are used to repair or replace defects in tooth or bone, to coat metallic
biomaterials and to reinforce composites. They are used mostly in orthopedic
implants such as components for arthroplasty joints with superior durability com-
pared to metals, substitutes of bone grafts, and as osteoconductive coating (Park and
Lakes 2007). Bioceramics are classied into: bioinert, bioactive and bioresorbable.
Bioinert ceramics generates minimal response in the body. Their chemical and
physical are not altered when placed in human body (Saenz et al. 1999). Typically,
these materials have a high compression strength and resistance. Alumina (Al2O3),
zirconia (ZrO2) and pyrolytic carbon are some examples of bioinert ceramics.
Figure 10 shows dental implant made of zirconia as example of implant made of
ceramics. Bioactive ceramics will react (i.e. chemically bond) with the living tissue.
Typically, they are characterized with good osteoconduction properties but have
lower mechanical strength compared to bioinert counterparts. Meanwhile, biore-
sorbable ceramics can be absorbed in the body and replace the tissue. They possess
good osteoconductivity although the interface between the ceramic and the bones is
relatively unstable (Hollinger 2006). Examples of bioresorbable ceramics are -
tricalcium phosphate, hydroxyapatite, carbonate, calcium carbonate (Hench and
Wilson 1993).
One particularity of bioceramics (including bioglass) is its osteoconductive
properties due to chemical similarity with the main mineral in bone, especially
calcium phosphate (CaP) compound such as hydroxyapatite (Ca10(PO4)6(OH)2).
Therefore, CaP is widely used as coating on metallic biomaterials for bone implants.
Table 5 lists different CaP compounds with different ratio of calcium to phosphate.
Fig. 10 Examples of dental implants made of bioceramics (Courtesy of Faculty of Dentistry,

UGM)
Table 5 Calcium phosphate with different Ca/P ratio (Saenz et al. 1999)
Name Ca/P ratio Chemical formula
Monocalcium phosphate monohydrate 0.5 Ca(H2PO4)2H2O
Monocalcium phosphate anhydrate 0.5 Ca(H2PO4)2
Dicalcium phosphate dehydrate (brushite) 1.0 CaHPO42H2O
Dicalcium phosphate anhydrate (monetite) 1.0 CaHPO4
Octacalcium phosphate 1.33 Ca8(HPO4)2(PO4)45H2O
-tricalcium phosphate 1.5 -Ca3(PO4)2
-tricalcium phosphate 1.5 -Ca3(PO4)2
Amorphous calcium phosphate 1.22.2 Cax(PO4)ynH2O
Calcium-decient hydroxyapatite 1.51.67 Ca10-x(HPO4)x(PO4)6-x(OH)2-x
[0 < x < 1]
Hydroxyapatite 1.67 Ca10(PO4)6(OH)2
Tetracalcium phosphate 2.0 Ca4(PO4)2O
5 Composites
Composites are combination of two different types of material or more without

reaction occurs between the respective elements (Callister and Rethwisch 2014).
The structure and properties of the composites depend on the structure of each
constituent forming the composite and at the same time on their combination.
Composites materials is designed to provide improved mechanical properties or to
create materials with functional and structural properties at the same time. For
instance, in polymers-ceramics composite, polymer can act as the matrix and
ceramics act as its ller (reinforcement). The properties of these composite will be
ductile, yet hard, without a change in their respective structure (Chawla 2012).
Composites are considerably attractive materials for orthopedic application since
they are modiable to have good biocompatibility, reliable mechanical properties,
biodegradability and ability to bond with the bone (Hollinger 2006). Secondary
reinforcing phase (i.e. bers and ceramic particles) can be added making them as
hard as cortical bone and improving the bone-bonding activity. A combination of
polymers and drug compounds has been applied for soft-tissue treatment as wound
dressings, which consists of polymer bers lled with medication to support the
healing process. In this case, polymer bers provide structural matrix while the
medication serves as a functional material (Park and Lakes 2007).
In metal-matrix composites, the metal acts as matrix and ceramics act as ller. In
the application of biodegradable metal for bone fracture xation, Fe or Mg is
combined with CaP particles as ller. The CaP acts as the functional material that
would promote the growth of new bone cells while the metal will be the structural
material in bone xation (Ulum et al. 2014). Another example of composites
includes the mixture of magnetite (Fe2O3), hydroxyapatite (HA), and hydroxy-
propyl-methyl-cellulose (HPMC). The mixture is intended for the treatment of
osteoporosis and cancer therapy. Magnetite generates heat when radiated within
electromagnetic eld and thus applied to kill cancer cells through hyperthermia
process (Iwasaki et al. 2013). When the mixture is injected into the bone, HA and
HPMC form gel-like structure providing matrix to magnetite (Sakka et al. 2012).
6 Summary
Biomaterials are aimed to improve the quality of life. Its requirement has been
evolved signicantly from inert materials to bioactive materials providing support
for the tissue healing process. Biomaterials extends from polymers, metals,
ceramics, and composites. They are selectively chosen according to their unique
properties in order to meet the desired requirements for a particular application.
Nowadays, metals are still widely used as biomaterials due to their superior
mechanical properties and their workability. Metallic bonds provide by free cir-
culating electrons which confer metals as good electric and thermal conductors.
Metals are often alloyed in order to modify their microstructures adjusting the
desired properties. They are widely used for making load bearing implants in
orthopedic, cardiovascular and dental applications. Similarly, polymers have been
applied as biomaterials due to their workability and wide selection of mechanical
properties due to their modiable structure. Polymers are lightweight and relatively
inexpensive. Their polyvalent applications including articial knee joint, tibial tray,
surgical sutures, coating materials and drug carriers. When it comes to superior
durability, ceramics stand out from other type of biomaterials. This property is
attributely related to the solid mixture of metallic and non-metallic elements bound
together in both covalent and ionic bonds. Paired with good osteoconductivity,
ceramics are used for arthroplasty joints, substitute of bone graft, and osteocon-
ductive coating material. Newer generation of biomaterials incorporates both
structural and functional properties together in a single material. This so called
composite is formed by mixing two or more different types of material. The
properties of composite materials depend on the constituents materials. Metals,
polymers, and ceramics have been incorporated to form different composites for
various biomaterial applications ranging from bone fracture xation to hyperther-
mia treatment for cancer therapy.
The development of biomaterials is now at the same pace as the research for
drug discovery. Biomaterials are no longer seen as inert materials supporting
dysfunctional tissues or organs. They are now required to promote the healing
process and self-disintegrate once the process has been completed. Moreover,
specic desired properties for particular application are on the hunt through engi-
neering process in an accelerated pace. All the effort is paid to improve the wellness
and health of human beings.
Acknowledgment We acknowledge the nancial supports from Indonesian Ministry of Research,

Technology and Higher Education (SGS), CHU de Qubec Research Center (HH), and Natural
Science and Engineering Research Council (AP).
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Naturally Derived Biomaterials and Its
Processing
Raden Dadan Ramdan, Bambang Sunendar

and Hendra Hermawan
Abstract The rich Indonesian biodiversity has been viewed as an innite resource
of naturally inspired and derived biomaterials. The utilization of these natural
materials for biomaterial applications necessitates additional steps to the currently
established conventional synthesis methods. Some of these steps have been suc-
cessfully developed at a lab scale with suitable controlling parameters resulting into
an optimum overall synthesis processes. Further optimization and ne tuning on the
parameters are required to translate the innovation into a commercialization. More
efforts from biomaterial researchers and a supportive policy from the Government
are essentially needed to foster the development of biomaterial and its applied
technology resulting into low-cost yet effective medical devices to support the
national health care program. This chapter concentrates its discussion on selected
naturally derived biomaterials, their sources and their processing which have been
developed in Indonesia. These include synthesis of hydroxyapatite from coral, land
snail and egg shells via precipitation reaction, sol-gel, hydrothermal and biomimetic
methods, new synthesis of membrane and encapsulation using template derived
from a flower plant, and synthesis of zirconia for dental restoration.
Keywords Biomaterials Biomimetic Coral Natural Precipitation Sol-gel
R.D. Ramdan (&) B. Sunendar

Institute of Technology of Bandung, Bandung, Indonesia
e-mail: dadan@material.itb.ac.id
B. Sunendar
e-mail: purwa@tf.itb.ac.id
H. Hermawan (&)
CHU de Quebec Research Center, Laval University, Quebec City, Canada

24 R.D. Ramdan et al.
1 Introduction
In one denition, a biomaterial is any substance (other than a drug) or combination

of substances synthetic or natural in origin, which can be used any time, as a whole
or as a part of a system which treats, augments, or replaces any tissue, organ or
function of the body (Von Recum and Laberge 1995). By this denition, natural
products can be applied as biomaterials of natural in origin which its historical use
dates back to 3000 BC when the ancient Egyptians used sutures made from animal
sinew, coconut shells, wood and ivory to repair injured skulls and replace teeth
(Ratner et al. 2004). Theoretically, any material natural or man made can be a
biomaterial as long as it serves the stated medical and surgical purposes for ulti-
mately safely implantation in or on the human body. Nature has provided a range of
materials (mainly polymers and minerals) with remarkable functional properties.
Natural was dened as something that is present in or produced by nature and not
articial or man made, and most often the denition is assumed to mean something
good or pure (Fratzl 2007). Among the advantages of using natural materials for
implants is that they are similar or familiar (biomimetics) to materials in the body
systems.
Indonesia is the largest archipelagic country in the world having undeniable
richness in species and ecosystems from its more than 17,000 islands with large
rainforest, 87,000 km2 of coral reefs and 24,000 km2 of mangrove areas. The
archipelago (Fig. 1) is the heart of the Coral Triangle, the global hotspot for marine
life and the worlds richest coral species biodiversity. In June 2010, a group of
seven international research institutions has founded the Indonesian Biodiversity
Research Center (IBRC) with headquarter located in Bali. The Center aims to
promote biodiversity stewardship in Indonesia through collaborative research and
educational programs, to increase biodiversity research in Indonesian scientic
communities, and to build lasting research networks between Indonesian and US
research centers. The Indonesian Ministry of the Environment estimates that more
than half of Indonesias species are still unrecorded while there is still much to be
discovered.
In this chapter, we concentrate our discussion on selected naturally derived
ceramic biomaterials, their sources and their synthesis or processing which required
additional steps rather than the conventional processes for synthetic origin. Special
attention is given to natural biomaterials and processes developed in Indonesia.
These include, among all, synthesis of hydroxyapatite (HAp) from coral, land snail
and egg shells via precipitation reaction, sol-gel, hydrothermal and biomimetic
methods, new synthesis of membrane and encapsulation using template derived
from a flower plant, and synthesis of zirconia from abundant raw materials found in
Indonesia for dental restoration.
Naturally Derived Biomaterials and Its Processing 25
Fig. 1 The Indonesian archipelago (Google)
2 Natural Source of Ceramic Biomaterials
Ceramic biomaterials (bioceramics) have been used as active biomaterials for

promoting regeneration of tissues, healing of traumatic disease, or restoring phys-
iological functions. They found the applications in dental restorations, lling of
bony defects, rebuilding bone at facial, cranial and other parts (Hench 1991).
Bioceramics are mostly produced from synthetic raw materials, but natural sources
are also available such as corals and shells which are found abundant in many
places in Indonesia.
2.1 Corals
Due to its porous nature and high content of calcium carbonate, coral and its derived
HAp have been used as bone grafts, spinal fusion, bone ller and orbital implants
since 30 years ago with proven biocompatibilty and resorbability (Guillenium et al.
1987; Ige et al. 2012). Its porous structure is a range similar to that of cancellous
bone (150500 m) and thus makes it ideal for ingrowth of blood vessels
(Ben-Nissan 2003). Apart of their exoskeleton structure, coral grafts can act as a
carrier for growth factors thus improving their osteoinductivity or osteogenicity
(Louisia et al. 1999). The use of coral derived bone graft prevents the transmission of
human immunodeciency virus, hepatitis B, hepatitis C and other similar diseases
(Suzina et al. 2005). There are many commercial brands of coralline HAp available
in the market since decade ago, such as Biocoral, Pro-osteon and Interpore (Damien
and Revell 2004). Figure 2 shows example of bone graft produced from coral.
Fig. 2 a Porite coral, b chemically treated pieces of coral, c coralline HAp bone graft
Production of bone grafts from natural coral for medical applications, such as
orthopaedic and cranio-maxillo-facial surgeries, needs a set of rigorous protocols of
preparation and purication. As part of conservation efforts, only dead coral from
Poratidae family (Porites or Goniopora species) is usually harvested as raw
materials for the production of coralline HAp (Damien and Revell 2004). The coral
material is cut into smaller pieces (blocks and granules) then chemically treated
followed by freeze drying and radiosterilized before subjected to a series of bio-
compatibility tests (Suzina et al. 2005). There are several techniques widely utilized
to synthesis HAp directly from corals, including hydrothermal and microwave
processes, and sol-gel coating (Balzsi et al. 2007).
In a simple hydrothermal method, the coral is subjected to a temperature of 900 C
to decompose all carbonate phases and remove all organic materials. The preheated
coral, calcium carbonate, is then converted into HAp by chemical exchange reaction
with diammonium phosphate resulting in pure coralline HAp powders with both
aragonite and calcite phases (Sivakumar et al. 1996). Under a controlled
hydrothermal exchange process, a mix product of calcite (CaCO3) and -tricalcium
phosphate (-TCP) can be derived from coral sand grains with retaining porous
structures, making them suitable as bone scaffolds (Chou et al. 2007). The use of a
mineraliser (KH2PO4) can accelerate the exchange process and eliminate the for-
mation of intermediary phases, while without the mineraliser, aragonite is converted
at high temperature and pressure into calcite, which was subsequently converted to
-TCP and nally to HAp. The use of mineralizer gives a better retention of the
original structure of the coral such as the pore interconnectivity (Xu et al. 2001).
2.2 Shells
Numerous shells are found in nature and some of them have been evaluated for
possible biomaterials. As an example, cockle shell which has almost similar mineral
composition to that of coral suggesting its potential to be used as a material for
orthopaedic applications (Awang-Hazmi et al. 2007). The nature of the mollusc
Fig. 3 a Achatina fulica snail, b its shell, c HAp powders
shell, in-terms of both mineral composition and porous structure, makes it an ideal
bioceramic materials candidate with exceptional mechanical properties (Rodrguez-
Navarro et al. 2006). Apart of marine mollusc, there are thousands of land snail
species, including helix aspersa, helix pomatia and achatina fulica which can be
easily found in Indonesia. Their shell is rich in calcium carbonate thus can be used
as a source for bioceramic production. Figure 3 shows images of achatina fulica, its
shell and HAp powders.
In view of utilizing the abundant source (and waste product) of land snail shells,
various Ca-phosphates powders, specically monetite, fluorapatite, have been
produced from helix pomatia shells via a simple economical method. The empty
shells were washed, dried, crushed and ball milled to obtain 100 m size powders,
then stirred at 80 C while reacted with drops of H3PO4 for 8 h. The liquid part was
then evaporated in an incubator at 100 C for 24 h to nally collect the
Ca-phosphates powders (Kel et al. 2012). Another HAp synthesis can be done from
achatina fulica shells by a reflux method. It is started with drying and milling the
shells to obtain powders continued by deproteinization in basic solution, followed
by reflux in weak acid solution and ended by heat treatment and gelatinization.
3 Synthesis of Naturally Derived Bioceramics
3.1 Hydroxyapatite Powders
One important bioceramics that is progressively developed by many researchers is

HAp, Ca10(PO4)6(OH)2, a bioceramic material with chemical composition similar
to that of mineral in bone and tooth. It has excellent biocompatibility and can be
directly attached to the bone and does not pose toxicity. In addition, apatite
structure accommodates ion exchange by substituting hydroxyl ion (OH) with
other ion. Therefore it can also be used for lter application, such as for sorption of
bivalent metal (Ro et al. 2006).
Based on its chemical composition, one of the requirements for the synthesis of
HAp is by providing calcium donor which can be taken from natural resources. It is
expected that by taking calcium donor from natural resources, we can decrease the
cost of HAp production. There are many potential raw materials for calcium donor,
one of them is achatina fulica shells which are provided in the huge amount in
Indonesia. Another natural resource material for calcium donor that is provided in
the huge amount in Indonesia is egg shells. Egg shell contains 50.2 % calcium,
12 % magnesium and 21 % natrium (Freire et al. 2000) thus is highly prospected as
calcium donor for the synthesis of HAp. However, there is limited study reported on
the synthesis of calcium from these natural resources. Both shells are commonly
treated as waste product, therefore, synthesis of calcium from this natural sources
can support the green environment program in the country.
Calcium from achatina fulica shell is provided in the form of two types of
calcium carbonate (CaCO3): aragonite and calcite. Aragonite and calcite has similar
composition but different crystal structure. The former is easier to be dissolved in
sea water and is considered as metastable structure. Therefore, if both of these
carbonates exist in the same shell, it is preferable to have calcite at the outer while
aragonite at the inner of the shell. However, since the outer shell is normally coated
with a protein namely periostracum, the dissolution of this calcium sources can be
avoided.
One pertinence method for HAp synthesis from achatina fulica shells is the
reflux method. It is considered as the development of distillation method and
involves the condentation of vapors that is followed with returning of condensate to
the origin system. This reflux method is started with drying the shell that is fol-
lowed with milling to obtain the appropriate raw materials size. This step is very
important, because ne particles are required for optimum interface reaction during
reflux process. Therefore after milling process, shieving for ltering the appropriate
size of the shell powder is required. After that deproteinization is performed by base
solution and followed with reflux in weak acid solution. The last step is heat treatment
and gelatinization. Heat treatment is important step in reflux method and influences the
morphology, crystallinity and surface area of the particles (Khalid et al. 2013).
Figure 4 shows the flow chart of HAp synthesis from achatina fulica shells.
On the other hand, one option to synthesize HAp from egg shell as calcium
donor is by solution combustion method. This method is one of chemical approach
for the fabrication of nanomaterials by mixing the oxidizer and fuel and heating up
this mixing and ended with calcination of the heated powder. In the beginning, egg
shell solution is made with HNO3 and is followed by mixing the solution with
phosphate and other solution (i.e. acid or base). Result of these steps is a transparent
gel of HAp. The last step is heat treatment of HAp gel to transform it into powders.
In the solution combustion method, common parameters to be optimized are the
fuel type, the fuel to oxidizer ratio and initial furnace temperature (Ghosh et al.
2011). Different fuel type might affect on the morphology of the product, whereas
Fig. 4 Flow chart of HAp synthesis from achatina fulica shells
Fig. 5 Flow chart of HAp synthesis from egg shells
different fuel to oxidizer ratio affect the heating temperature and in turn lead to
agglomeration of the product. On the other hand, initial temperature has signicant
effect on the existence of unburnt layer of the synthesan during the process.
Figure 5 shows the flow chart of HAp synthesis from egg shell.
3.2 Hydroxyapatite Membranes
Among the important biomaterial membranes is scaffold membrane which is

essential for many biological activities. This membrane also important element for
the bone transplantation and normally in order to increase the performance of the
membrane for this purpose, other materials is required for the growth initiation of
new cell, such as by HAp membrane. As in the case of HAp synthesis, it is
important to provide raw material for its production in the huge amount in nature, to
keep sustainability of production as well as to support the green environment
program. Additional important reason related with membrane scaffold application is
the egg shell has complex structures that consist of protein bers, porous structure
and connected each other. This raw material is also provided in a huge amount and
therefore progressively developed as template for anorganic materials growth.
One of the method to grow HAp membrane utilizing egg membrane as the
template is by biomimetic method, a method that imitates model, system or element
in nature. In biomimetic synthesis, synthesis of target molecule through a series of
reaction and requires intermediate structure. In this case, HAp is the target molecule
whereas the egg membrane is the intermediate structure. HAp source can be pre-
pared from SBF solution, where egg membranes are immersed for certain period
and through it HAp membranes grow. SBF is a solution with similar chemical
composition and concentration to human blood plasma with other condition such as
pH and temperature are also kept identical with this plasma. The solution releases
calcium and phosphate during immersion of egg membrane and induces the for-
mation of HAp on the egg membrane. The growth of HAp on the membrane is
indicated by the increase of ber diameter that becomes in order of several
micrometres.
Normally, more HAp grows on the egg shell as a function of immersion period
in the SBF solution. Several important parameters that affect the formation of HAp
membrane by biomimetic method are pre-treatment, heat treatment and template.
Among important pre-treatment that accelerate the formation of HAp is by NaOH
treatment (Miyazaki et al. 2002). For the case of egg membrane, immersion of egg
membrane in NaOH solution increases the porosity size of the membrane. On the
other hand, the membrane template might influence the mechanism of formation of
the apatite (Sun et al. 2006).
Another way to synthesize HAp membrane is by mixing alginate-chitosan as the
membrane template and followed with the growth of HAp on the membrane.
Alginate is a substance extracted from seaweed and refer to alginic acid and its
derivatives. For the alginate extraction, seaweed is dissolved in a hot solution of
sodium carbonate for hours resulting into dissolved sodium alginate and undis-
solved substance (cellulose) that is subsequently removed. Chitosan is a biobased
polymer and produced by deacetylation of chitin. The source of this material is
exoskeleton of crustacean, such as crabs and shrimps. This material is biodegrad-
able and biocompatible in nature and can be synthesized into various type of
morphology such as membranes, sponges, gels, scaffolds, microparticles,
nanoparticles and nanobers (Anitha et al. 2014). Chitosan has potentiality for
various applications such as drug delivery and tissue engineering. Alginate and
chitosan have opposite charges, with positive for chitosan and negative for alginate.
Therefore, mixing of these substances might create a stable structure with a strong
chemical bonding and can produce a membrane template relatively fast with con-
trollable porosities.
For membrane template applications, it should be considered that the membrane
has interconnected porosity in order to support cell migration, gas diffusion,
nutrition and other functions. The growth of HAp on alginate-chitosan membrane
template will increase biocompatibility of the membrane, and therefore improve cell
adhesion, the growth and formation of new tissue. As has been explained previ-
ously, HAp can be made from SBF solution, such as the famous Kokubo solution
(Kokubo et al. 2004). This solution is acellular solution with inorganic ion con-
centration approaching the extracellular solution in human body. The solution can
be prepared by dissolving NaCl, NaHCO3, KCl, K2HPO43H2O, MgCl26H2O,
CaCl2 and Na2SO4 in distilled water, whereas pH of this solution kept at 7.4 and
temperature at 36.5 C (Hayakawa et al. 2000). By this method, immersion time
might affect degree of crystallinity of the product, whereas pH of the solution
influences the kinetic of HAp formation.
Another potential raw material for HAp membrane template is hibiscus tiliaceus,
a species of flowering tree which is commonly found in Indonesia. HAp membrane
synthesis from this source is started by cleaning the hibiscus tiliaceus raw material,
which is then heated at certain temperature (such as 500700 C) for several hours
in order to create active carbon membrane support. HAp formed on this membrane
by impregnation the membrane in the SBF solution, in the similar way as the case
of egg shell and alginate-chitosan membrane previously explained.
4 Other Naturally Derived Biomaterials Processes
4.1 Micro-Capsules
Controlled release of drug in the textile application has been progressively devel-
oped in recent years for the purpose of skin care and medication. Coating is the
method implemented for this application with a controllable release kinetics by the
number of layers in the system (Martin et al. 2013). In addition, initial surface
condition of textile ber should be considered related with incorporation of drug
and its release kinetic (Labay et al. 2014). For the purpose of skin care and wound
prevention, textile lubrication should also be considered in order to reduce friction
against the skin (Gerhardt et al. 2013).
Recently for the controlled released application, textile is coated with
micro-capsule that contain active compound. Micro-capsule is a product of
encapsulation, where one compound, either in the form of solid, liquid or gas, is
wrapped by other compound such as thin lm of polymer (Jackson et al. 1991).
Commonly, active compound such as drug is wrapped inside the capsule (shell
material). Active compound is released through porosities on micro-capsule, which
can be due to differences in pH, osmosis pressure, temperature and air pressure. The
release can also be due to mechanical loading and self reaction of the active
compound, which is a function of time.
Silica is one of raw materials that can be used for micro-capsule due to its
biocompatibility characteristics. One of the methods to produce micro-capsule from
silica is by mixing emulsion and sol-gel. In this method, three main stages should
be performed: precursor preparation, emulsication of precursor and solidication
of micro-capsule. As an example, precursor for silica micro-capsule can be made
from tetraethyl orthosilicate (TEOS), HCl, dan tetrahydroxybenzophenone (THBP)
solutions that are emulsied in siklohexane with the addition of sorbitan monos-
tearate (span 60) as surfactant. HCl is used as acid catalyst whereas THBP is active
compound to be encapsulated. The volume of TEOs precursor and the rate of
emulsication have signicant effect on the morphology and micro-capsule particle
size. In addition, increasing TEO concentration might increase the particle size. On
the other hand, the addition of surfactant has signicant effect on the morphology of
silica particle product. Emulsication step will produce micro droplet that in turn is
solidied by sol gel reaction. The nal product of these processes is encapsulation
active compound in the micro-capsule.
One potential application of micro-capsule in drug delivery is for hyperthermia

cancer therapy. At this method, cancer tissue is heated within 4445 C, temper-
ature at which cancer cell can be destroyed with minimum damage to the normal
tissue. For this purpose chemotherapy active substance is attached on nanomagnetic
particle and encapsulated by micro-capsule. One requirement for nano-magnetic
particle for this application is sufcient biocompatibility. Therefore for this purpose,
this nano-magnetic particle is encapsulated with polymer that has sufcient bio-
compatibility and biodegradability. As an example is producing nano-magnetic
particle from NiCl26H2O precursor and encapsulated with alginate and chitosan
shell.
For drug delivery applications, core-shell structure of micro-capsule offer variety
of advantages in the released controlled of the active substances. One of the famous
methods for producing miro-capsule with core-shell structure is by sol-gel method
through Stober route utilizing silica template. Stober route process was found in
1968 and obtained by series of reaction between silica precursors with alcohol and
water as well as alkali catalyst, which were used to produce homogeneous silica
particle in the size of micro-capsule (Stober et al. 1968). In certain case, in order to
increase the homogeneity of the silica particle, dispersion particle such as chitosan
is added. Chitosan has excellent biocompatibility and increases the absorption of
drug and has been applied in various applications such as tissue engineering, drug
delivery system, encapsulation and wound healing.
There are various methods to produce micro-capsule such as polymer encap-
sulating bioactive antioxidant by electrospinning method in the food industries
(Fernandez 2009). Another method is electrostatic dry powder coating which can be
used in the production of drugs in the pharmaceutical industry, with the particle
cores lower than 1 mm (Szafran 2012). In order to coat membranes on the active
particles or catalyst and produce micro/mesoporous structure (Membrane
Encapsulated Catalysts or MECs), fluidized bed lm coating is viewed as a
potential method. As an example of this method is by lm coating of spherical
zeolite particles with a suspension of nano-alumina in hydroxylpropyl cellulose
(HPC) to create MECs (Capece 2011).
In addition to the above method, microfluidic technique is a method to encap-
sulate living cell. Example of micro-capsule for this purpose is alginate hydrogel
microparticles which is obtained from double-emulsion template that is produced
using microcapillary device (Martinez et al. 2012). Another method is the pres-
surized carbon dioxide anti-solvent co-precipitation process. As an example of this
method is the encapsulation of propolis in the micro-capsule of water soluble poly
(ethylene glycol) or PEG (Yang et al. 2014). In addition, another encapsulation in
the food industry area is encapsulation of antioxidant and aromas which is usually
exist in oil and easily oxidized such as the encapsulation of vegetable oil in powder
of maltodextrin and acacia gum by spray drying method (Fuchs et al. 2006).
Fig. 6 Production process of bioactive glass material
4.2 Bioactive Glass for Cancer Treatment
Another important development in biomaterials is bioactive glass for cancer cell

detection with the help of Magnetic Resonance Imaging (MRI) apparatus. Bioactive
glass such as -Fe2O3 can be used for cancer cell detection due to its paramagnetic
characteristics that will be detected by MRI. Bioactive glass is made of raw glass
materials such as SiO2, CaO, Na2O dan P2O5 and are added with Fe2O3. Heating
these compounds up to their melting temperatures produces calcium ferrite
(CaFe4O7) and -Fe2O3 as bioactive glass ceramic. The process is relatively simple
without the need for high-tech apparatus and nano size particles.
There are several steps used to produce bioactive glass starting from mixing raw
materials as mentioned above. The mixing composition is then heated up to liquid
state and then followed with fast cooling outside the furnace to obtain glass state of
the mixing. The next step is milling to produce ne particles of bioactive glass and
followed with two stages of heat treatment. The rst step of heat treatment is for the
nucleation of bioactive glass and the next step is for the growth of the glass, where
it is expected that Fe2O3 crystallizes become -Fe2O3. Heat treatment can be per-
formed near the glass transition temperature in an oxidizing atmosphere (Eun-Tae
Kang et al. 2013). Figure 6 shows the process step to produce bioactive glass
material. In the case of laboratory work, for the purpose of simulating the released
of -Fe2O3 in the body fluid, the resulted bioactive glass materials is immersed for
certain period in SBF. After this immersion, the weight loss of bioactive glass is
measured to indicate the released of the glass. During its application, it is expected
that the body fluid carries the glass on the cancer cell then covering the cell, by
which it can be detected under the MRI. Immersion in the SBF solution can also be
used for detecting the biocompatibility of the glass which is indicated by the
formation of bioapatite on the glass surface for the bioactive materials.
4.3 Dental Biomaterials
One of the challenge in dental biomaterials is improving the biocompatibility and

mechanical property of composite resin. HAp as previously described has excellent
biocompatibility but its mechanical property is considered insufcient for com-
posite resin dental application. Therefore, HAp is mixed with other materials such
as zirconia-alumina-silica to form a composite of HAp-zirconia-alumina-silica thus
can be used as ller in the composite resin dental restoration.
The above composite is synthesized started from preparing each component.

Zirconia is prepared from zirconium chloride precursor with isopropyl alcohol as
solvent, while alumina is from aluminum nitrate nano-hydrate precursor with
aquadest as solvent. Silica is synthesized from tetraethyl orthosilicate (TEOS)
precursor with aquadest as solvent. Each precursor is mixed using a template such
as acacia mangium pulp, then stirred at a controlled pH, aged for hours up to days,
cleaned and dried. The last step of this synthesis is sintering with variation
temperature and holding time. For the case of HAp, similar process is applied
with different precursor, such as (NH4)2PO4 precursor and aqua dm as solvent.
These three components are mixed with coupling agent (i.e. mixing of
trimethoxypropylsilane and chitosan) to increase the adhesion of ller with polymer
dental restoration matrix. The last step is mixing the llers with coupling agent and
dental restoration matrix. Figure 7 shows the step of production of dental restoration
material.
There are several important parameters affecting the quality of ller material
particles such as concentration and type of coupling agent, pH of mixing colloid
and crystallinity of the composite substances. The addition of coupling agent, such
as chitosan induces a better binding between ller materials and the matrix.
Crystallinity of the composite substances signicantly affects the mechanical
properties of the ller composite, such as hardness, compressive strength, elastic
modulus and stiffness. While pH and composite concentration signicantly affect
the resulted particle size and in turn affect the mechanical properties of the com-
posite particles.
Related to the material resources in Indonesia, zirconia is provided in a huge
quantity. However it is still rarely developed for biomaterials purpose due to lack of
research on this material. In addition for the perfect application of this material as
biomaterial it is preferable to mix with other materials as stabilizer, such as Y2O3,
CaO, MgO, La2O3, and CeO in order to increase the mechanical properties of the
material. The result of these composite mixing can also be used for ller in dental
restoration applications.
One of the methods to produce nano-particle zirconia with stabilizer such as
MgO is by sol-gel method. Zircona can be taken from ZrCl4, while MgO source is
MgSO4 with aquadest as the solvent. In order to increase particle distribution, other
substances such as chitosan can be added. The mixture is then aged and dried,
followed by calcination process. The last step is homogenization of the powder by
mortar milling or ultrasonic homogenizer. Figure 8 shows the step of process to
produce nano-particle zirconia with stabilizer. Among important parameters that
Fig. 7 Production steps of dental restoration material

Fig. 8 Production steps of nano-particle zirconia with stabilizer
affect the quality of nano-particle zirconia are calcination temperature, particle

distribution and stabilizer composition. Calcination temperature should be deter-
mined in order to obtain appropriate particle size, whereas particle distribution is
important for the homogeneity mechanical properties. Stabilizer composition affects
the particle size of zirconia composite and in turn determines the mechanical
properties as well.
4.4 Surface Treatment
Various metals with excellent oxidation resistance such as titanium alloy have been
used as implant materials. Additional surface treatment and coating are often
applied on its surface to further improve its biocompatibility. Among them are
sol-gel and thermal spray methods with HAp, carbon, titania and hydrogel titanate
as the coating materials.
For the HAp coating, one of new potential thermal spray methods is
high-velocity oxy fuel (HVOF) process (Ramdan 2014). The method is expected to
give better degree of crystallinity of HAp and increase the bonding strength with the
metal surface (Lima 2005; Gaona 2007). Intermediate layers such as titania and
carbon nanotube, are often used to facilitate this bonding. In order to coat HAp on
metal implant by HVOF method, a careful surface preparation is required. A series
of grinding, polishing or sand blasting is normally performed in order to create flat
surface with sufcient roughness to allow a good mechanical interlocking. The
oxide layer on titanium alloy should be removed to enhance adhesion property. This
can be done by chemical etching that also gives additional contour on the metal
surface. Apart of the surface preparation, the precursor for coating, HAp powders,
should have sufcient flow ability in dry condition.
HAp coating with HVOF process is very fast and can be accomplished in 10 s.
Therefore no diffusion of HAp will take place into the metal substrate leaving the
possible bonding mechanism only for mechanical interlocking. In order to increase
the bonding strength between HAp and the metal substrate, post-annealing treat-
ment can be performed subsequently. This additional treatment might induce a
diffusion of HAp into the metal substrate. Figure 9 shows one optional of HAp
coating on the metal substrate by HVOF process.
Fig. 9 Flow chart of HAp coating on metal substrate by HVOF method
Another surface treatment to increase biocompatibility of metal implant is by

coating with carbon layer. It can be done by dip coat the metal in a carbon sus-
pension. Before the process, as in the case of HVOF coating, several substrate
preparation should be done such as grinding, ultrasonic cleaning and an optional
immersion in a coupling agent such as chitosan that enhances the adhesion of
carbon layer on the metal surface. After that, coating is performed by dipping the
metal substrate into the carbon suspension followed by drying. The last step is
sintering the coated sample in order to create adhesion between the substrate and
carbon. The carbon coated metal surface will allow an easier growth of HAp during
biomimetic process in SBF compared to non-coated metal. Figure 10 shows a flow
chart of HAp coating by biomimetic process with carbon as intermediate layer.
Another pre-treatment that can be done to enhance HAp biomimetic coating
process is by introducing hydrogel titanate intermediate layer through alkali treat-
ment. For the alkali treatment, metal substrate is immersed in NaOH solution to
produce hydrogel titanate (HTiO3nH2O) that is obtained from the reaction
between TiO2 and hydroxyl ion from NaOH. After the immersion process, the
metal is heat treated to dehydrate the hydrogel titanate and form a stable sodium
titanate (Na2Ti6O13). Heat treatment can also induce better bioactivity of the alkali
treated layer (Lu et al. 2012). After that, immersion in SBF is performed to grow
HAp layer on the treated metal surface. Figure 11 shows a flow chart of biomimetic
coating of HAp with substrate preparation by alkali treatment.
Fig. 10 Flow chart of biomimetic coating of HAp on metal substrate with pre-treatment by
dipping in the carbon suspension
Fig. 11 Flow chart of HAp biomimetic coating on metal substrate with pre-treatment by alkali
treatment
5 Perspective
The undoubtful rich Indonesian biodiversity, both its rainforests and coral reefs, has
been viewed as the unlimited source of naturally inspired and derived biomaterials.
The authors view on utilization of this biodiversity is not as the source for
industrial exploitation of biomaterials synthesis, but rather for learning from the
Nature in nding useful biomaterials for the benet of humanity. This biodiversity
must be used wisely and intelligently. It must be conserved. The tragic rapid loss of
Indonesias biologically wealthy rainforests and the increase of threatened native
mammals and the destructive exploitation of coral reefs must be prevented.
The utilization of natural resource materials, which are specic yet abundantly
available in Indonesia, for biomaterial applications necessitates additional steps to
the currently established conventional synthesis methods. These steps have been
successfully developed at a lab scale with suitable controlling parameters resulting
into the optimum overall synthesis processes. Further optimization and ne tuning
on the parameters are required to translate the innovation into a commercial scale.
More efforts from biomaterial researchers and a supportive policy from the
Government are essentially needed to foster the development of biomaterial and its
applied technology resulting into low-cost yet effective medical devices to support
the national health care program.
Acknowledgment The authors acknowledge the support from the Indonesian Ministry of
Research, Technology and Higher Education (RDR, BS) and the CHU de Qubec Research Center
(HH).
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Biocompatibility Issues of Biomaterials
Widowati Siswomihardjo
Abstract The history of biomaterials started with gold and ivory, when these
materials were used by the Egyptians and Romans before the twentieth century.
Biomaterial is dened as any non-vital materials used in medical devices, intended
to interact with biological systems. An important property that differentiates a
biomaterial from other material is its biocompatibility. It is a term that is referred to
as the appropriate host response to biomaterials. The understanding of biocom-
patibility is becoming an interdisciplinary study, since the biocompatibility of
biomaterials is a critical issue in limiting device longevity and functionality.
Biocompatibility is a multifactorial property, and it can be illustrated as a dynamic
and an ongoing process. Some materials, such as amalgam, acrylic resin, and
bis-GMA have been used for years in dentistry. On the other hand controversies
still arise to debate the biocompatibility of those materials. Measuring the bio-
compatibility of a material is very complex. It is based on three levels of tests. Since
there is no guarantee that a material is 100 % safe, all regulations and standards are
related to the risk and safety of the materials. It is a challenge for biomaterials
scientists to provide biomaterials with good biocompatibility that are able to serve
for the best result of medical treatments. Gadjah Mada University as a leading
university in Indonesia pays a great interest in the eld of research. Some studies in
developing local biomaterials and medical devices conducted by researchers of
Gadjah Mada University are presented in this chapter.
Keywords Biomaterials biocompatibility biological response
W. Siswomihardjo (&)
Gadjah Mada University, Yogyakarta, Indonesia
e-mail: widowati@ugm.ac.id

42 W. Siswomihardjo
1 Introduction
In the history of human life, the rst biomaterials used were gold and ivory. These
materials were used by the Egyptians and Romans who lived along time before the
twentieth century. Biomaterials are dened as non vital materials used in medical
devices, intended to interact with biological systems. In the last few years the
biocompatibility of biomaterials has been developing into a complex and com-
prehensive study. Medical treatments are related very much with the use of bio-
materials, whereas all materials are poison, and nothing is without poisononly
the dose permits something not to be poisonousas stated by Paracelsus, the
father of toxicology. Biocompatibility is a term which is extensively used in
materials scienceit is the ability of a material to elicit an appropriate biological
response in a given application in the body. Biocompatibility of a material can be
illustrated as a multifactorial property, with a dynamic and ongoing process. Of the
biological responses to materials, toxicity test is the rst screening test used for
almost all materials. Nowadays using humans as research subjects without previous
tests of the biocompatibility of the developed material is considered unethical. The
understanding of the biocompatibility of materials is not only important for clinical
practitioners but also manufacturers who are responsible for providing safe mate-
rials on the market. This chapter describes the basic concept of biocompatibility of
biomaterials and illustrates it with some research in developing new materials
conducted especially in Indonesia.
2 Biocompatibility of Biomaterials
The study of biomaterials is a wide-ranging eld, covering aspects of biology,

medicine, engineering and materials science (Temenoff and Mikos 2008). At the
beginning of the twenty rst century, biomaterials are widely used throughout
medicine, dentistry and also biotechnology. Previously the word biomaterial was
not used, as the forms of biomaterials today were not yet in existence (Ratner et al.
2004). In the history of human life, the rst biomaterials used were gold and ivory
for the replacements of bone defects, and these materials were used by the
Egyptians and Romans who lived along time before the twentieth century (Bergman
and Stumpf 2013). Biomaterials are dened as any non-vital materials used in
medical devices, intended to interact with biological systems (Schmalz and
Arenholt-Bindslev 2009). Materials that are inserted into the human body are thus
referred to as biomaterials and include ceramic, polymers, metals and composites.
One of the major concerns of biomaterial scientists is the biological response to the
chosen material, since it will determine the biocompatibility (Temenoff and Mikos
2008). The clinical success of a biomaterial depends on many properties of the
material. The most important property that differentiates a biomaterial from other
material is its ability to exist in contact with tissues of the human body without
Biocompatibility Issues of Biomaterials 43
causing any harm to the body (Williams 2008). Biomaterials serve to restore health,
function and esthetic appearance of patients. To fulll these objectives, biomaterials
are designed to work intimately with their hosts (Tang 2014).
All materials intended for the application in human body, will initiate tissue
responses when implanted into the living tissues (Anderson 2001). When a material
is inserted into living tissue, interaction with the surrounding biological system will
occur and produce biological response (Wataha 2001). Biocompatibility is a term
that is used extensively in the science of biomaterials. It describes the relative
ability of a material to elicit an appropriate biological responses in a given appli-
cation in the body (Sakaguchi and Powers 2012). Biocompatibility is referred to as
the appropriate host response to biomaterials (Tang 2014).
Many implants conducted prior to 1950 did not succeed, due to a poor under-
standing about the biocompatibility of biomaterials (Ratner et al. 2004). In the last
few years, the biocompatibility of biomaterials has been growing into an increas-
ingly sophisticated and complex eld of study. The understanding of biocompati-
bility is becoming an interdisciplinary study that draws on knowledge from biology,
materials science, biomechanics, engineering as well as aspects of clinical practice
and the specic condition of the host. It can be said that to test new materials prior
to clinical use is quite recent, but the historical use of the biocompatibility of
biomaterials extends back to the time of Hippocrates. The biocompatibility of
biomaterials becomes a critical issue in limiting device longevity and functionality
(Onuki and Bhardwaj 2008). Nowadays using humans as research subjects in
developing new materials without preliminary testings on the biological properties
of the new material is considered as unethical (Anusavice 2003). As no biomaterial
is absolutely save and free from any potential risk of harm, biocompatibility testings
are listed as rst priority in developing new biomaterials. The main purpose of
biocompatibility testings is to protect the safety of not only the patients but also the
clinical staff and laboratory technicians (Temenoff and Mikos 2008). Since the way
in which the mutually acceptable co-existence of biomaterials and tissues is
developed, has been of great interest for many years to many biomaterials scientists
(Williams 2008).
Related with the denition of the biocompatibility of materials, it can be
understood that a single material may not be biologically acceptable in all appli-
cations (Sakaguchi and Powers 2012). For example, a material that clinically is
acceptable as a root canal sealer may not be acceptable as a dental implant (Fig. 1).
In the case of a bone implant, the requirement for a biocompatible material is that
the material should integrate with the bone (Fig. 2). In this condition the appropriate
biological response for the implant material is what we call osseointegration.
Whereas materials for root canal sealer, the expectation is that the material will not
initiate inflammation, and thus osseointegration is not the appropriate biologic
property. Whether a material is biocompatible or not for a specic function, depends
much on the clinical and physical function for which the material will be used. It also
depends on the biological response that will be required from the material
(Sakaguchi and Powers 2012). Thus, in choosing a material, it is important to rst
clearly dene the purpose for which the material will be used.
44 W. Siswomihardjo
Fig. 1 Illustrations for a fully lled root canal with biocompatible sealer where it lls the apical
and lateral canal and a non compatible sealer which is not able to ll the accessories canals
Fig. 2 Illustration of osseintegration between a metal implant and the alveolar bone
Another example is the biocompatibility of the impression material (Fig. 3).

There are many kinds of impression materials, such as alginate, agar, ZOE and
silicon. Some concerns about the biological response of impression material is the
potential for inflammation and causing hypersensitivity. A biocompatibility prob-
lem might happen when some of the materials are trapped in the patients gingival
sulcus (Fig. 4). A foreign body of impression material is known to elicit gingival
inflammation, which might also disturb the tooth preparation (Anusavice et al.
2013). Therefore, it is important to clean the gingival sulcus directly after taking the
impression to minimize the possibility of hypersensitivity.
Fig. 3 Alginate impression material (Courtesy of Faculty of Dentistry, UGM)
Fig. 4 Possible entrapment of impression material in the sulcus gingivalis
3 Factors and Nature of Biocompatibility
The traditional concept of biocompatibility is understood as a lack of signicant

adverse reaction between material and the oral tissues (Browne 1988).
Unfortunately, nowadays it is recognized that there are only few materials that do
not elicit a signicant interaction with the host tissues (Browne 1994). Based on
that fact, an updated concept of biocompatibility becomes the ability of materials to
induce an appropriate and also an advantageous host response during its intended
clinical usage (Murray et al. 2007).
46 W. Siswomihardjo
Biocompatibility is a multifactorial property (Fig. 5) which will interact with its

surrounding environment. The biological response of the material will alter if there
are changes occured in host condition or the material itself (Sakaguchi and Powers
2012). The biocompatibility of a material is not stable nor absolute (Wataha 2001)
and also very individual; it can be said to be like color (Fig. 6). A materials color
depends on the character of the light source, how the light interacts with the
material, and how the observer interprets the reflected light. In this sense a mate-
rials color depends on its environment, similar to the biocompatibility of materials
(Sakaguchi and Powers 2012).
Fig. 5 Biocompatibility as a multifactorial property
Fig. 6 The biocompatibility

of material is like the color
reflection of material that
depends on the interaction of
material with light and
observers interpretation of
the reflected light
Factors that influence the occurence of biological response of biomaterials

(Wataha 2001; Sakaguchi and Powers 2012; Anusavice 2003; Anusavice et al.
2013) are as listed below:
1. The chemical nature of the materials components
2. The physical nature of the materials component
3. The types and locations of patient tissues that will be exposed to the material
4. The duration of the exposure
5. The surface characteristics of the material
6. The amount and nature of substances eluted from the material
7. The forces and conditions placed on the material
8. The physical function for which the material will be used
9. The design of the device
The biocompatibility of a material can be illustrated as a dynamic, and an
ongoing process. A material device that is today placed in the body as biocom-
patible, may not be biocompatible in the future. The general condition of the host
may alter through exposure to diseases or aging. On the other side, the materials
device itself may change through corrosion or fatigue, or the loads placed on the
material may change through alterations in the occlusion or diet. The interaction
among host, materials function and materials properties (Fig. 7) will continue over
time (Wataha 2001). Some materials device may develop complications, the
adverse interactions of host with the material, or vice versa. Complications occur
mostly as a consequence of biomaterial and tissue interactions (Ratner et al. 2004).
Any material device that is placed in the body can cause local or systemic bio-
logical responses. These two responses are influenced by the components that might
be released from the material. The nature, severity and location of these effects are
determined by the distribution of the released components (Anusavice et al. 2013).
Local biological responses might be influenced by: (1) the ability of material com-
ponents to be distributed to these sites, (2) the concentration of the material com-
ponents, and (3) the exposure times of those components which may occur from
seconds even to years (Anusavice 2003). Similar to a local biological response, the
systemic side effect from the components of materials are also a function of the
Fig. 7 The interaction among

host, materials function and
materials properties
48 W. Siswomihardjo
distribution of those components released from the materials. Local toxicity or a local
biological response is based on the chemical interaction between a toxic component
and biologically relevant molecules (Schmalz and Arenholt-Bindslev 2009). The
systemic biological response depends on: (1) the duration and concentration of the
exposure of the released components, (2) the excretion rate of the components, and
(3) the site of the exposure.
4 Biocompatibility of Selected Biomaterials
4.1 Amalgam
One of the most interesting issue related with clinical dentistry today, is the use of
amalgam as restorative material. It is the most important lling material in the
history of dental materials, as it has been used continuously for almost 200 years to
reconstruct decayed teeth (Soni et al. 2012). In many countries, dental amalgam is
still of great importance as restorative material. However, it is a fact that the overall
use of dental amalgam is decreasing, due to its content of mercury, known as a toxic
substance.
The amalgam used today are mostly based on the formulation which is published
by G.V. Black in 1895. Modications of the basic formulation were subsequently
introduced in the early 1960s (Anusavice et al. 2013). Amalgam is an alloy which
contains mercury as one of its components. Mercury is liquid at room temperature
and it can be alloyed with solid metals (Anusavice 2003). Amalgam alloys contains
predominantly silver and tin. It may also contain concentrations of other compo-
nents such as copper, zinc, gold and mercury. To produce dental amalgam, mercury
is mixed with the powder of the amalgam alloy.
The amount of alloy and mercury to be used can be described as the
mercury/alloy ratio, which signies the number of parts by weight of mercury
divided by the number of parts of alloy to be used for the particular technique. The
mercury content is about 50 % by weight and that for spherical alloys is 42 % by
weight (Anusavice et al. 2013). Free mercury (Hg) is known to be a cause of
contact dermatitis and mercury vapor is about ten times more toxic than lead on
human neurons and with synergistic toxicity to other metals (Mutter 2011). Cell
culture tests have demonstrated the toxicity of the free Hg in dental amalgams. With
the addition of copper (Cu), dental amalgams have become toxic to cells in culture, but
low-Cu amalgams do not inhibit cell growth (Mallineni et al. 2013). High-Cu amal-
gams cause severe reactions when in direct contact with the tissue (Lawrence et al.
1972). Dental amalgam when handled correctly, it has a high durability (Schmalz and
Arenholt-Bindslev 2009).
Oral amalgam pigmentations or amalgam tattoos (Fig. 8) are relatively common
clinical lesions caused by unintended deposition or displacement of amalgam
particles into the oral soft tissue during dental operative or surgical treatments
Fig. 8 a Amalgam lling;

b amalgam tatoo, a
discoloration of the gingival
mucosa (Courtesy of Faculty
of Dentistry, UGM)
(Schmalz and Arenholt-Bindslev 2009). Amalgam tattoos are harmless and asymp-
tomatic. Seen as discoloration of the gingival or buccal membrane, nowadays the
prevalence of amalgam tattoos remains high as the general population continues to
have existing amalgam llings replaced by the newer composite llings (Lundin et al.
2013).
A review article on the biocompatibility of dental amalgams (Ucar and Brantley
2011) stated that: (1) mercury released from dental amalgam restorations does not
contribute to systemic disease or systemic toxicological effects, (2) allergic reac-
tions to mercury from dental amalgam restorations have been demonstrated, but
these are very rare. While the general public remains concerned about amalgam
llings (Fig. 9) as they contain 50 % mercury (Pleva 1994), they are nevertheless
widely used due to the fact that they have not been found to cause disease or
harmful effects (Duplinsky and Cicchetti 2012). This controversy means that dental
professionals around the world continue to debate the potential risk of dental
amalgam to our health (Schmalz and Arenholt-Bindslev 2009). For decades, the
dental professions have sought aesthetic restorative materials to replace the tradi-
tional amalgam alloy for stress-bearing restorations (Mallineni et al. 2013).
4.2 Acrylic Resin
The use of polymers have revolutionized the biomedical industry ever since their
discovery. Many prostheses made from polymers have been in use for the last three
decades (Bhola et al. 2010). Since the mid of 1940s, polymethyl methacrylate
(PMMA) has become the most common material for the fabrication of denture
50 W. Siswomihardjo
Fig. 9 a Amalgam
restoration; b toxic reaction of
buccal mucosa close to the
restoration (Courtesy of
Faculty of Dentistry, UGM)
bases. Most resin systems used in dentistry as denture bases are based on methyl
methacrylates (MMA) (Gautam et al. 2012). Around ninety-eight percent of all
denture bases are still constructed from methyl methacrylate (Phillip 1989). Its
color, optical properties, and dimensional characteristics remain stable under nor-
mal intraoral conditions, and its physical-mechanical properties have proven to be
adequate for dental applications (Anusavice et al. 2013).
Polymerization is the chemical reaction in which monomers of a low molecular
weight are converted into chains of polymers with a high molecular weight. Recent
years have seen controversy emerge regarding the possible complications and
negative side effects from the use of acrylic resin denture bases. Despite its satis-
factory aesthetic properties and, ease of processing, PMMA denture bases have the
potential to elicit irritation, inflammation or allergic reaction in the oral mucosa
(Ozen et al. 2006). Many in vitro and in vivo experiments were conducted on
acrylic based resins or on their leached components, and results showed them to
have cytotoxic effects (Gautam et al. 2012). A study conducted by Pradeep and
Sreekumar (2012) proved that monomer MMA is indeed cytotoxic even in very low
concentrations. Atoxic compound which exists in the chemical composition as
monomer, can cause allergies in dental laboratory staff and denture wearers prior
and after the polymerization (Lassila et al. 2001). Regarding leaching components
from PMMA, two aspects are of particular importancethe monomer polymer
ratio and the residual monomer concentration (Gautam et al. 2012). Polymethyl
methacrylate is one of the most widely used polymer for denture bases, but dentists
and laboratory staff should be very careful in handling the acrylic resin. Techniques
should be employed to reduce exposure to MMA in order to reduce the risks
(Fig. 10) of possible complications (Leggat and Kedjarune 2003).
Denture stomatitis has been found to be a common problem related with denture
bases. Candida albicans is a normal commensal in the oral cavity. There is always a
risk of the development of Candida associated denture stomatitis (CADS) for
patients who are wearing denture (Bhat et al. 2013). Candida albicans is not only
able to adhere to the mucous surfaces, but may also stick to the acrylic resins
(Fig. 11) of dental prostheses (Salerno et al. 2011).
Fig. 10 a Allergic reaction to MMA in denture base material; b same patient after substitution of
MMA containing denture base material with polycarbonate material (Courtesy of Faculty of
Dentistry, UGM)
Fig. 11 a Healthy mucosa of the upper jaw; b mucosa with denture stomatitis caused by infection
with Candida albicans (Courtesy of Faculty of Dentistry, UGM)
4.3 Titanium
Metal alloys are important materials as replacement of non-functional parts of the

body, but unfortunately many alloys are prone to corrosion (Singh and Dahotre
2007). Since the 1960s, titanium has become a very popular metallic biomaterial
52 W. Siswomihardjo
because of its excellent properties for many medical applications. Both titanium and
titanium alloys, based on their physical, chemical and biological properties, appear
to be suitable for implants and prostheses (Ozcan and Hammerle 2012).
Many practioners accepted titanium to be relatively inert substance with minimal
side effects (Lugowwski et al. 2000). It is generally considered as a safe metal to
use in implantation but on the other hand some studies have suggested that par-
ticular titanium might cause health problems (Fig. 12), or produce further side
effects such as dark staining in the tissue around the titanium (Frisken et al. 2002).
Fig. 12 Complication caused by: a titanium metal plate; b, c orthopaedic plate (Courtesy of Dr.
Sardjito General Hospital, Yogyakarta)
The exact mechanism for titanium release is not clear, but some reports have shown
that ionization of all metals occurs to some extent and titanium may be released in
relatively large concentrations into surrounding tissues (Woodman et al. 1984).
A biocompatible titanium base which is alloy suitable for bone implant should meet
at least these requirements (Mehta 2015): (1) potentially toxic elements should be
avoided completely, (2) elements that may have potential toxicological problems,
should be used only in minimal amounts, (3) the alloy should have high corrosion
resistance, (4) the alloy should have at least low modulus, high strength, be smooth
and notched fatigue strength, (5) the alloy should have good workability and
ductility. Factors that can influence the failures and complications that might occur
when using metal implants, (1) the skill of the operator, (2) condition of patient, and
(3) anatomic (Chee and Jivraj 2007).
4.4 Bisphenol a Glycol Dimethacrylate (bis-GMA)
During the rst half of the twentieth century, silicates were the only tooth-colored
aesthetic materials available for cavity restoration. Although silicates release
fluoride, they are no longer used for permanent teeth because they become severely
eroded within a few years. Since the early 1970s, resin-based composite systems
have become the material of choice for direct aesthetic (Fig. 13) anterior restora-
tions (Anusavice 2003).
In dentistry, resin composites have been used with increasing frequency as
restorative materials as a result of the demand for both aesthetic restorations and
concerns over the adverse effects of mercury from amalgam (Sweeney et al. 2012).
There are three major structural components in resin-based composite: matrix, ller
and coupling agents (Anusavice et al. 2013). Current dental resin systems are
Fig. 13 Composite resins as direct aesthetic restoratios: a before; b after restoration (Courtesy of
Faculty of Dentistry, UGM)
54 W. Siswomihardjo
generally based on dimethacrylate monomers. Several restorative materials avail-

able on the market contain the monomer bis-GMA (Kostoryz et al. 1999).
Composite resins are extensively used in dentistry due to their aesthetic and
good physical and mechanical properties (Tuan Rahmi et al. 2012). The develop-
ment of ber-reinforced composite (FRC) has served the dentists the possibility of
fabricating restorations with an excellent appearance (Zhang and Matinlinna 2012).
Next to that, FRC provides a metal-free tooth restorations for single and multiple
teeth replacement (Garoushi et al. 2011).
Although the physical properties of resin composites are constantly being
improved, result of in vivo studies have shown that their use is often related with
necrosis or irritation of the pulp or the adjacent periodontium (Nalcaci et al. 2006).
This cytotoxicity is the result of residual uncured monomer (Sideridou et al.
Sideridou et al. 2004), indeed bis-GMA has been found to be cytotoxic in many cell
culture systems (Wataha et al. 1994).
5 Concept of Assessing Biocompatibility
The increasing use of biomaterials in clinical medicine to replace failing organ

function has heightened the need to apply relevant tests to study the safety of
materials of new medical devices (Kirkpatrick et al. 2005). One of the important
prerequisites for the clinical usefulness of biomaterials is a high level of biocom-
patibility (van Tienhoven et al. 2006). All biomaterials used in human beings have
to be tested for their biocompatibility before dening their clinical performance
(Illeperuma et al. 2012). Biocompatibility of a biomaterial refers to the extent to
which the material does not have toxic or harmful effects on biological system
(Keong and Halim 2009). The use of biomaterials may result in damage to various
tissues. Therefor measuring the biocompatibility of a material is very complex,
involving a number of steps to test interactions between the material and its sur-
rounding tissues. Historically, new materials were simply tested in humans to assess
their biocompatibility. However, current materials must be extensively screened for
biocompatibility before they are used in humans (Sakaguchi and Powers 2012). The
assessment of the biocompatibility of a material is a very complicated procedure
that may involve several biological tests, tests of physical and mechanical prop-
erties and also risk-benet analysis (Wataha 2001). Even if the risk of damage
caused by a new material is considered to be acceptable, it has to be understood that
some people may get problems based on specic conditions. In other words, it is
related to the problem of individual compatibility (Schmalz and Arenholt-Bindslev
2009). Biocompatibility of material is measured based on three levels of tests:
(1) in vitro, (2) in vivo, (3) clinical tests (Table 1).
Table 1 Advantages and disadvantages of biocompatibility tests (Sakaguchi and Powers 2012)
Tests Advantages Disadvantages
In vitro Quick to perform Relevance to in vivo is
Least expensive questionable
Can be standardized
Good experimental control
Excellence for mechanisms interaction
In vivo Allow complex systemic interactions Relevance to use is questionable
Response more comprehensive than in vitro Expensive
tests Time consuming
More relevant than in vitro tests Difcult to control
Difcult to interpret
Legal and ethical concerns
Clinical Relevance to use of material is assured Very expensive
Very time consuming
Can be difcult to control
Difcult to interpret and quantify
Major legal and ethical issues
5.1 In Vitro Test
In vitro test is the initial step to evaluate the harmful effects of new materials that
may occur (Illeperuma et al. 2012). It is dened as an experiment that is performed
in test tubes, cell-culture dishes, or outside of a living organism. These experiments
need the placement of a material or a component of a material in contact with a cell,
enzyme or any other isolated biological system. Based on the objectives, in vitro
tests can be divided into those that measure the cytotoxicity or cell growth and
those that measure the effect on the genetic material in a cell (Craig and Powers
2002). The advantages of in vitro tests are their being experimentally controllable,
fast, and relatively simple and there is no need to consider about the ethical and
legal issues. The primary disadvantage is their questionable relevance to the use of
the material for human (Wataha 2001). It is important to understand, that since
in vitro tests are performed outside of living organism, the interactions that create
biological response in the body are not present.
5.2 In Vivo Test
The animal test or in vivo tests for biocompatibility are different than in vitro tests
because the tested material will be placed into an animal. For example, the material
may be implanted into a mouse or placed into the tooth cavity of a rat (Wataha
2001). In vivo tests are distinct from clinical tests, in that the material is not placed
in the animal with regards to its nal use. The use of an animal allows the inter-
action between host and material to occur. The biological responses in animal tests
56 W. Siswomihardjo
are more comprehensive and relevant than in vitro tests. Nevertheless, the relevance
of these tests is still unclear, especially in estimating the appropriateness of an
animal to represent a human (Craig and Powers 2002). The perspectives that should
be considered in the in vivo assessment (Anderson 2001):
1. Involving the utilization of the tests to determine the general biocompatibility of
the newly developed materials for which some knowledge will be necessary for
further research
2. Regarding the test of medical devices focuses on the biocompatibility of the
nal product, that is the medical device and its component materials in the
condition in which it is implanted.
5.3 Clinical Test
Clinical tests are experiments conducted in clinical research, it can be performed in

animals or in human volunteers. It is mandatory especially for materials that are
considered to be of high risk (Anusavice et al. 2013). Such studies are mainly
designed to clarify specic questions about new treatments or interventions
including the use of new materials. The tests require that the developed material
should be placed in a situation identical to its intended clinical use. The importance
of clinical tests for predicting biocompatibility because they imitate the clinical use
of the material in all aspects, including duration, location, and the placement
technique. Clinical tests are the gold standard in predicting biocompatibility as the
result will provide a denitive answer as to whether a material is biocompatible and
clinically useful or not (Craig and Powers 2002). Details and protocols on clinical
tests are provided completely in ISO standards, such as ISO 14971 (Anusavice et al.
2013). However, clinical tests have many complications and problems, next to that
these trials can be quite costly. The tests are very time consuming, extremely
difcult to control, difcult to interpret, quite expensive, and are legally and ethi-
cally very complex (Wataha 2001). Finally decision for market clearance is then
approved by many sides, such as manufacturers, governmental agencies or private
organizations (Anusavice et al. 2013).
5.4 Cytotoxicity Test
Among the many biological responses to materials, toxicity was the earliest response
studied. Now that biocompatibility testings has evolved signicantly, the rst
screening test used for almost all new developed material is the cytotoxicity test. It is a
test that assesses the toxicity of a material by measuring the cell number or growth after
exposure to a material (Craig and Powers 2002). Two types of cells can be used for the
in vitro assays, the primary and the continuous cells. Fibroblasts are very common for
conducting cytotoxicity tests especially for dental materials, since they are in close
proximity with many restorative materials in the oral cavity (Moharamzadeh et al.
2007). Some assays have been developed to test the cytotoxicity of materials.
A commonly used method is the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl
tetrazolium bromide) and the tryphan blue dye exclusion assay. The dye exclusion
assay in that the tryphan blue is a vital stain used to selectively color dead cells blue
based on the principle that viable (live) cells actively pump out the dye by efflux
mechanism, whereas dead cells do not. The MTT test will measure the viability of cells
based on the metabolic activity (Chintalwar et al. 2012). If the cell is able to reduce the
MTT, the resulting formazan is blue and insoluble and deposits in the cell. The amount
offormazan formed is proportional to the enzymatic activity (Craig and Powers 2002).
In many countries, materials for medical devices are subjected to legal regula-
tions. Since there is no guarantee that a material is 100 % safe (Wataha 2001), all
regulations and standards are related to the risk and safety (covering biocompati-
bility) of the materials (Table 2). To assess the biocompatibility of materials,
Table 2 ISO 10993 a standard which governs the use of materials

ISO Standard Title
ISO 109931: 2003 Evaluation and testing within a risk management process
ISO 109932: 2006 Animal welfare requirements
ISO 109933: 2003 Tests for genotoxicity, carcinogenicity and reproductive toxicity
ISO 109934: 2002 Selection of tests for integrations with blood
ISO 109935: 1999 Tests for in vitro cytotoxicity
ISO 109936: 2007 Tests for local effects after implantation
ISO 109937: 1995 Ethylene oxide sterilization residuals
ISO 109939: 1999 Framework for identication and quantication of potential degradation
products
ISO 1099310: 2002 Tests for irritations and delayed type hypersensitivity
ISO 1099311: 2006 Tests for systemic toxicity
ISO 1099312: 2002 Sample preparation and reference materials
ISO 1099313: 1998 Identication and quantication of degradation products from polymeric
medical devices
ISO 1099314: 2001 Identication and quantication of degradation products from ceramics
ISO 1099315: 2000 Identication and quantication of degradation products from metals and
alloys
ISO 1099316: 1997 Toxicokinetic study design for degradation products and leachables
ISO 1099317: 2002 Establishment of allowable limits for leachable substances
ISO 1099318: 2005 Chemical characterization of materials
ISO 1099319: 2006 Physicochemical morphological and topographical characterization of
materials
ISO 1099320: 2006 Principles and methods for immunotoxicological testing of medical devices
58 W. Siswomihardjo
distinctions have been drawn from the standards (Schmalz and Arenholt-Bindslev
2009):
1. Horizontal standards are valid for all medical devices
2. Semihorizontal standards are valid for groups of products
3. Vertical standards are valid for individual materials.
6 Development of New Biomaterials in Indonesia
Gadjah Mada University (Universitas Gadjah Mada or UGM) in Yogyakarta,

Indonesia is a leading and the oldest university in the country. Within its eighteen
faculties, researchers are collaborating to develop new biomaterials through inter-
disciplinary studies funded by the Government. The following are examples of
local biomaterials and medical devices which have been developed by UGM and its
partners.
6.1 Orthopaedic Metal Plates
The enormous need of orthopaedic implants such as osteosynthesis plates is difcult

to fulll in developing countries like Indonesia (Dewo et al. 2008). A heavy
earthquake with a magnitude of 6.3 on the Richter scale, struck the Indonesian
island Java in the early morning of May 27, 2006. The earthquake caused 5,782
deaths and 36,299 people were injured. While the tsunami of 26 December 2004 in
Aceh caused 186,983 deaths and injured 125,000 people (Dewo et al. 2008).
Earthquake and tsunami casualties were mainly suffering from musculoskeletal
injuries, especially fractures. Osteosynthesis plates are used in orthopaedic trauma
surgeries to provide xation and positioning of a fractured bone (Dewo et al. 2012).
Unfortunately for such large numbers of causalities there were not enough bone
plates in the local hospitals. The lack of bone plates were caused by: (1) all bone
plates are imported, means they are very expensive, (2) donated bone plates from
overseas were very late in their arrival, (3) local suppliers did not have enough bone
plates in stock. In order to overcome the shortage of surgical implants, implants can
be re-used after appropriate cleaning (Magetsari et al. 2006). Another alternative is
utilization of local products, because locally produced bone plates are much cheaper
and can be obtained faster than from abroad. Mechanical properties of Indonesian
made osteosynthesis plates have shown to be improved by the application of sur-
face mechanical attrition treatment (SMAT), as they become comparable to the
mechanical strength of the standard plates (Dewo et al. 2008, 2015).
Fig. 14 A package of GAMA-CHA developed by UGM (ID P 0036890)
6.2 Bone Grafts
For bone substitution purposes, bio-inspired design is a very important key to

induce new bone formation within physiological condition. In this sense, hard
tissue is regarded as carbonate-substituted hydroxyapatite (CHA) because carbonate
is one of the most abundant impurity ions and its content is about 48 wt%
(Barraletet et al. 2000; Landi et al. 2005). This is the reason for the extensive
development of CHA for the last decade (Ana et al. 2010; Sunarso et al. 2013).
Researchers at UGM have been successful in developing and fabricating human
bone apatite or CHA composite as reliable construct scaffold for bone substitution.
It is now in the process of translating this from the laboratory onto the market, in
collaboration with an Indonesian pharmaceutical company managed by the uni-
versity holding company (Fig. 14).
6.3 Ventriculoperitoneal Shunts
Insertion of a shunting device for the treatment of hydrocephalus patients has

become a routine surgical procedure in neurosurgical practice. However, shunt
60 W. Siswomihardjo
Fig. 15 Ventriculoperitoneal shunt with semilunar valve system for hydrocephalus child
complications are frequent problem for pediatric neurosurgical service, most of

which are mechanical complications and infection (Scott 1990). To overcome these
problems a neurosurgeon from the Faculty of Medicine at UGM has designed a
semilunar slit valve shunt and a free mobile cylindrical antisiphon valve. It is
proved that the semilunar valve shunt has the ability to maintain a normally neg-
ative intracranial pressure for children in sitting position. The semilunar valve shunt
(Fig. 15) has more advantages especially in the mechanism of opening and closing
of the valve, compared to other valve designs (Sudiharto 2002).
6.4 Bone Substitutes
Palatoschisis is a birth defect in human and animals. It is caused by a failure of the

elevation, apposition or fusion of the lateral palatine processes, resulting in the
persistence of a slit-like opening between the oral and nasal cavities (van den
Berghe et al. 2010). Data from Dr. Sardjito General Hospital in Yogyakarta illus-
trates a signicant number of palatoschizis patients, with 85 cases in 2013.
Palatoschizis (Fig. 16) is a serious esthetic and functional problem that causes
difculty in chewing, swallowing and also speaking. Since there is no synthetic
material for bone substitute, to reconstruct the roof of the oral cavity, plastic surgery
can take place or a denture combined with an obturator can be fabricated
(Dandekeri et al. 2012).
Dentistry and orthopaedic applications deal a lot with hydroxyapatite (HAp) due
to its good biocompatibility, osteoconductivity, and the bone-bonding properties
(Simon et al. 2005). HAp has been studied for several years as bone substitute
Fig. 16 a Palatoschizis patient reconstructed with; b denture combined and with; c obturator
(Courtesy of Faculty of Dentistry, UGM)
material (Triyono et al. 2015). A team of researchers from UGM proved that local
gypsum, from the area of Tasikmalaya Indonesia was synthesized into HAp by
microwave-hydrothermal method (Pujiyanto et al. 2006). Based on this research, it
can be showed that the sintering process at the temperature of 1450 C did not
signicantly effect on the cytotoxicity properties of local HAp powder (Pujiyanto
et al. 2013). Pure HAp has chemical composition, biological and crystallographic
properties which are highly similar to bone and teeth (Herliansyah et al. 2006).
Bulk HAp exhibits poor mechanical properties, therefore there is a need to
improve its mechanical properties (Wang et al. 2004). Zirconia (Fig. 17) is one of
the important llers that has been used to increase the strength of many ceramics
(Nayak et al. 2008). In bone surgery zirconia has shown very wide applications
(Quan et al. 2008). One of the major drawbacks in the use of biomaterials is the
occurence of biomaterial-centred infections (Gottonbos 2001). It is proven that local
HAp with 20 % zirconia has been an effective concentration in inhibiting the
growth of S. epidermidis (Siswomihardjo et al. 2012).
Fig. 17 SEM images of: a HAp structure; b HAp with zirconia ll in the pores
62 W. Siswomihardjo
7 Perspective
The biocompatibility of biomaterials has developed into a very complex discipline

of materials science, since the term biocompatibility has an important role with
respect to the safety of materials. In the last decade there is a rush in new products
of materials. On the other hand there is a high percentage of occurence in the
adverse reactions to materials, not only to patients but medical personnel as well. It
has understood that there are various ways in which materials and tissues can
interact to each others which will result in a specic biological response. It is then
becoming a challenge for biomaterials scientists to search for strategies how to
improve the biocompatibility of biomaterials, with nal goal provide biomaterials
that are able to serve for the best performance of medical devices.
Acknowledgement My special thanks goes to my colleagues P. Sudiharto, H. Dedy Kusuma, B.

Primario Wicaksono, MG. Widiastuti, Punto Dewo, Ika Dewi Ana, H. Agung Pribadi, Purnomo
and Y. Novian Paramarthanto who supported me with pictures, references, suggestions and fruitful
discussions in completing this chapter.
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Animal Study and Pre-clinical Trials
of Biomaterials
Deni Noviana, Sri Estuningsih and Mokhamad Fakhrul Ulum
Abstract An in vivo study is one of the most important steps in the process of
translating biomaterials to clinical applications. It is mostly conducted to conrm
in vitro results before going further to clinical trials. Appropriate use of animal
models in the in vivo studies of biomaterials and medical devices is mandatory and
should meet the approved regulations and ethics as dened by both local and
international regulatory bodies. These studies involve the use of various approaches
and protocols in order to know the body responses both local and systemic and to
nd out the short- and long-term responses of the body toward the implanted
biomaterials or devices. This chapter describes complete procedures and practices
of in vivo studies starting from selection of appropriate animal model,
pre-implantation, surgical procedure and post-implantation, and monitoring of
material-host responses. Some experiences of in vivo studies done by Indonesian
researchers and the development of new implants are also presented.
Keywords Biomaterials Biocompatibility Animal testing
1 Introduction
The use of animal models in the in vivo testing phase is unavoidable in order to
meet the achievement of product security for human being. Various kind of animal
models used in the research must be treated appropriately in accordance with the
rules and regulations of animal welfare and eligibility nationally and internationally.
The consideration of an appropriate animal model and the preparation procedure,
D. Noviana (&) S. Estuningsih M.F. Ulum

Bogor Agricultural University, Bogor, Indonesia
e-mail: deni@ipb.ac.id
S. Estuningsih
e-mail: estu@ipb.ac.id
M.F. Ulum
e-mail: ulum@ipb.ac.id

68 D. Noviana et al.
implantation, monitoring of the bio-information result of animal response during

and after the implantation is discussed in this chapter. This chapter also presents
various experiences of in vivo study done by Indonesian researchers, the devel-
opment of biomaterial implant in order to meet the national biomedical product for
the independence of nation.
Animal models are animals chosen representatively for biocompatibility testing
of a material developed for human beings (Pearce et al. 2007; Shanks et al. 2009).
Biomaterial that has been proven safe in vitro does not necessarily show a good
response when it tested in vivo in the form of implantation in animal models. The
stages of in vivo testing using animal models in the research of biomaterial
development become unavoidable matters. Various kinds of animal models which
are appropriate to use in the research must be treated morally and ethically well in
order to get the more representative response that has good validity to the appli-
cation that supports human tissue recovery (Grimm 2014; Shanks et al. 2009). The
animal models used in the research must be ruled which is appropriate to the
eligibility and welfare of animals internationally, and the local regulation of a
country (Beauchamp and Childress 2001; Marie 2005). These clauses are made as
the reference; therefore, the treatment given to the animals does not harm either to
the animals or the result of the research itself. Implant is a need in the medical eld
which can improve the quality of human health, however, the implant remains
categorized as a foreign object that will be responded by the immune system.
Therefore, the study of the body response to the implants is an absolute must done
before they are applied to humans.
This chapter focuses on animals model for biomaterial research, ethics, care and
use, implantation study and monitoring, and experiences on animal study of
medical implants in Indonesia. The consideration of an appropriate model animal
selection and preparation procedure of animal suitability, animal uniformity,
implantation process until the monitoring of animal during and post implantation is
discussed in this chapter. This last chapter also presents various experiences and
in vivo study done by Indonesian researchers in order to develop the biomaterial
implantation so that the independence of the nation in the need of fullment of
national biomedical products can be reached.
2 Animal Model for Biomaterials Research
2.1 Common Animal Models
Animal models are commonly used in biomedical research especially for validating
results of in vitro testing (Muschler et al. 2009; Pearce et al. 2007) before appli-
cation to human. They are used due to a similarity of the organ function and organ
system owned by human body (Shanks et al. 2009). The response showed by
animal model towards the therapy or treatment and certain diseases is like the
Animal Study and Pre-clinical Trials of Biomaterials 69
response showed by human body (McGonigle and Ruggeri 2014). Animal models
have a shorter life span compared to human body. Moreover, they have a faster
metabolic rate so that the analysis of long-term implantation response can be pre-
dicted better. Types of animal models used in the research are mostly rodent ani-
mals (9598 %), like mice and rats, while the rests are other species (about 25 %),
such as rabbits, small ruminants, dogs and other species (Harkness et al. 2013). The
reaction and effect occurring in implantation and its influence in the process of
tissue recovery was examined deeply, and the results showed a good reaction for
the human.
2.2 Appropriate Animal Models
Appropriate animal models are the main factors in in vivo test (Mardas et al. 2014).
The suitability of animal models in terms of functionality and application of bio-
logical response generated after the implantation into the main target in the research
(Table 1). The selection of appropriate animal models in the test process keeps
developing along with the development and modication of biomaterial implants in
orthopedic and dentistry (Pearce et al. 2007). Some of animal models that are
commonly used in in vivo material test in orthopedic and dentistry implants are
small-size animals (Mapara et al. 2012), for example mice (Freilich et al. 2008;
Yang et al. 2011), rats (Piccinini et al. 2014) and rabbits (Mapara et al. 2012).
Whereas large animals (Gardel et al. 2013; Pearce et al. 2007), like sheep (Ulum et al.
2014a), goat (Li et al. 2007), dog (Baas 2008), and pig (Ruehe et al. 2009) are also
used in in vivo test. Large animals have loading functionality and bone structure
which are similar to human beings. Therefore, they are often used as animal models
(Gardel et al. 2013).
2.3 Target Achieving Bio-Information from Animal Models
Biocompatibility is the major target in the development of biomaterial implants.

The properties of biocompatibility can be analyzed by using various approach in
order to know the local response as well as the systemic response and to know the
short and long response after it implanted in animals model (Table 2). The extra-
cellular fluid in the surrounding implantation site is the sample example that can be
taken to determine the local response with the application of microdialysis system
(Keeler et al. 2014). The sampling time of extracellular fluid can be done within a
few days up to several months adjusted to the study design. Extracellular fluid can
be analyzed at various biomarkers, such as elements, biochemical elements as well
as cytokinesthe marker of either good or negative implantation biomaterial in the
body locally.
Table 1 Several example of animal models for biomedical implants

Animal Species Implantation Target analysis References
model site
Mice Balb/C Tibia bone Compatibility test Cheng et al.
(2013b); Yang
et al. (2011)
Balb/C Tail blood Biodegradation and Mueller et al.
vessel systemic distribution of (2012)
biodegradable metals
implant
Ddy Femoral Biocompatibility and Noviana et al.
muscle biodegradation of (2012b); Paramitha
Subcutaneous biodegradable metals et al. (2013)
tissue implant
C57BL/6 Femur bone Osteoconductivity of Cheng et al.
bioactive-scaffolds (2013a)
Rat Sprague-Dawley Femur bone Compatibility bone Alghamdi et al.
implants and osteoporotic (2014); Alt et al.
(2013); Lips et al.
(2014)
Mechanical properties Boerckel et al.
and integration of implant (2012); Yavari
et al. (2014)
Systemic body responses Lucke et al. (2003)
post-implantation
Tibia bone Gait load implant Piccinini et al.
integration (2014)
Implant-associated Haenle et al.
infection (2013); Lucke et al.
(2003)
Systemic body responses Panjaitan et al.
post-implantation (2014)
Calvarian Bone cement for bone Schliephake et al.
bone repair (2004)
Wistar Tibia bone Mechanical loading on Zhang et al. (2012)
peri-implant bone healing
Mandible Bone cement for bone Issa et al. (2008)
bone repair
Wistar-kyoto Calvarian Bone grafting Kneser et al.
bone (2006)
(continued)
Table 1 (continued)
model site
Rabbit New Zealand Dorsal muscle Biocompatibility Cheng et al.
white (2013b)
Femur bone Biocompatibility Sennerby et al.
(2005); Sul et al.
(2002)
Biocompatibility on Yu et al. (2012)
systemic and local tissues
response
Implant for bone Baro et al. (2002)
infection
Tibia bone Biocompatibility Sennerby et al.
(2005); Sul et al.
(2002)
Mandible Biocompatibility of bone Wang et al. (2007)
bone scaffold
Sheep Thin tailed Radia bone Biocompatibility and Ulum et al. (2014a,
sheep-Indonesia biodegradation of 2015)
biodegradable metal
implants
Tibia bone Biocompatibility and Ulum et al. (2014a,
biodegradation of 2015)
biodegradable metal
implants
Italian massese Tibia bone Autologous bioceramic Kon et al. (2000)
scaffold
Osteointegration of metal Sachse et al. (2005)
implants
Femur bone Mechanical and Giavaresi et al.
histomorphometric study (2003)
of post metal-implants
implantation
Goat Dutch milk goat Paraspinal Biological performance Li et al. (2007)
muscles
Lumbal bone Biological performance Li et al. (2007)
Spanish-goat Lumbal bone Biological study of bone Brantigan et al.
fusion post-implantation (1994)
Dog Beagle Mandible Biologic stability of Cha et al. (2010);
bone bone-implant contact Cho et al. (2013)
American hound Femur bone Revision of arthroplasty Baas (2008)
Bone allograft and Barckman (2014)
implant xation
Tibia bone Bone allograft and Barckman (2014)
implant xation
Mongrel-dog Illiac artery Patency and healing Castaeda et al.
characteristic of stents (2000)
Aorta artery Patency and healing Castaeda et al.
characteristic of stents (2000)
(continued)
Table 1 (continued)
model site
Pig Minipig Mandible Dental implant Joos et al. (2005)
bone osseointegration
Bone regeneration Ruehe et al. (2009)
Femur bone Mechanical evaluation of Pithon et al. (2013)
orthodontic implants
Miniature swine Vessels Arterial healing post Nishimura et al.
stenting (2012)
3 Ethics, Care and Use of Animals
3.1 Bioethics in Biomaterials Research
The ethical and moral in doing research are the norms applying the basic principles
of good interaction that regulate the interaction between humanas the user of
animals, and the animals that are used in the research (Beauchamp 2008; Grimm
2014; Marie 2005). There are four basic principles of bioethics as stated by
Beauchamp and Childress (2001), namely (1) the principle of respecting autonomy
(respect for autonomy), (2) the principle of doing good deed (benecence), (3) the
principle of not doing harm (non-malecence) and (4) the principle of justice
(justice). Animal models are seen as individual or group of research partners that
must be treated well according to the ethical principles. These principles serve as
the guidance in how humans (the researcher) treat the animal models used in the
research.
3.2 Principles of 3R (Three R Principle) and 5F

(Freedoms)
Declaration of Helsinki, 1964 (Rothman and Michels 2000; Bdru 2013; Holm
2013; World Medical Association 2001) mentioned a few principles that contained
the statements about the use of animals in doing research, i.e.: (1) Medical research
involving human subjects must conform to generally accepted scientic principles,
be based on a thorough knowledge of the scientic literature, other relevant sources
of information, and on adequate laboratory and, where appropriate, animal exper-
imentation; (2) Appropriate caution must be exercised in the conduct of research
which may affect the environment, and the welfare of animals used for research
must be respected.
The ethical use of animals in doing research should follow the instruction
and recommendations of international standards (Grimm 2014; Guhad 2005;
Table 2 Several example of method to achieving bio-information from animal model

Sample Access Response target of bio-information Analysis
Local Systemic Short Long
period period
Extra Microdialysis Biochemistry, elements,
cellular ELISA, biosensor,
fluid biomoleculer
Hard tissue Biopsy, Radiology, histology,
(bones) euthanasia elements,
Soft tissue Biopsy, Radiology, histology,
(muscles, microdialysis, elements, ELISA,
skin, etc.) euthanasia biomoleculer
Whole Venesection, Haematopoetic prole,
blood canulation biochemistry, elements,
ELISA, biosensor,
biomoleculer
Urine Centesis, Biochemistry, elements,
canulation, ELISA, biosensor,
pach biomoleculer
Organ Biopsy, Radiology, histology,
tissue microdialysis, elements, ELISA,
(liver, euthanasia biomoleculer
spleen,
kidney,
etc.)
Trnqvist et al. 2014). Russell and Burch (1959) were the rst people that stated the
idea of the use of animals in doing research which was expected to follow the rules
of 3 R (The three R principle). The 3 R principles are (Guhad 2005; Russell and
Burch 1959): (1) the use of experimental animals should receive attention in the
effort of nding the replacement (replacement), (2) the reduction in the number of
animal use to its limit use can be analyzed statistically (reduction), and (3) The
improvement of animal handling towards the animal is used to reduce the impact
that can be painful and stressful (renement).
The rst principle of Replacement is to avoid the use of animal as much as
possible in doing research (Guhad 2005; Reinhardt 2008; Russell and Burch 1959).
Researchers should explore the possibility of using organ culture/tissue/cell as a
substitute for the use of live animals or lower order animals, for example, replace
the use of primates to mice or rats replaced by poultry or poultry replaced by sh,
and so on. This replacement principle is basically the biological response expected
from the test. This could be represented by a given response from the replacement
animals. The second principle, Reduction, is to develop a strategy of a fewer animal
use to produce the same data adjusted to the research design (Guhad 2005; Russell
and Burch 1959). The principles covers the effort to maximize the bioinformation
obtained from an experiment without adding the number of animals or the number
of potential treatments towards the pain caused by the treatment in the research so
that the researchers can obtain the maximum benets without adding the pain and
the number of experimental animals. The third principle, Renement, is an attempt
to modify the maintenance management or procedures of research treatment so that
it can improve the animal welfare or reduce or relieve the pain and stress
(Buchanan-Smith et al. 2005; Guhad 2005; Russell and Burch 1959).
The 3R principle should be combined with 5F principle (The ve freedoms) in
the use of animals. The 5F principle tries to place the animal as an object of
research with animal welfare principle; therefore, the response given will be rep-
resentative enough, and it has a good validity towards the research result that will
be obtained (Marie 2005; Phillips 2008). The animals treated well will give best
response if it is compared to those treated badly. Inappropriate treatment will mix
up the data obtained; as a result, the data become unrepresentative anymore to the
research result. This will result in an inappropriate conclusion because the response
obtained bothers the research result.
The 5F principles are: (1) the animals are free from hunger and thirst, (2) the
animals are free from uncomfortable feeling, (3) the animals are free from pain,
trauma, and disease, (4) the animals are free from fear and long-term stress, (5) the
animals are free to express their natural behavior, which are given a room and
facility which is appropriate to the environmental enrichment and will not interfere
with the research results expected (Suckow et al. 2012).
Ensuring the animal models are free from hunger and thirst by given food
adjusted to the natural condition with a balance nutrition accordance with the needs
or research design and drinking water in adequate amounts. The feed is given
accordance with the needs and drinking water is supplied in ad libitum; moreover,
the animals can easily access them. Furthermore, the animals are free from dis-
comfort feeling which can be overcome by taking into account the needs of the
animals to a shelter or nest in accordance with the natural conditions on the size,
temperature, humidity, ventilation and lighting. The animals are free from pain,
injury, and disease that can be done through the established health programs, such
as using non-invasive technique or minimal invasive, pain-reducing medication or
consciousness, and always use a method of euthanasia in accordance with the rules
of ethical use of animals such as providing transition and adaptation to the new
environment, a new cage ofcer, a new feed, or a new procedure before the study
performed. The cage ofcers or researchers must have expertise and skill in the
handling of animals which are in line with the requirements and implementation of
research procedures. The animals used in study will be free to express their natural
behavior by providing sufcient width cage, good cage quality, and attention to
socialization, specic behavior, as well as enrichment programs. Enrichment pro-
gram is given in various forms according to the type of animals, such as a swinging
for primates, woodcarvings for rodents, and so forth.
3.3 Indonesian Regulations for Animal Use in Biomedical

Research
The ethical use of animals in research in Indonesia refers to the international

document, like The Guide for The Care and Use Laboratory Animals and
Helsinki Declaration (Garber et al. 2010; Portaluppi et al. 2010; Touitou et al.
2004). Then in Indonesia, its implementation refers the ethical code of Indonesian
veterinarian in the Articles of Association of Indonesian Veterinary Medical
Association (Chapter III Article 18, 19, 21 and 22), as well as Law of the Republic
of Indonesia No. 18, 2009 which is completed with the Law of Republic of
Indonesia No. 41, 2014 about Husbandry and Animal Health in which there are
articles (Chapter VI Article 66, Chapter VII Article 71 and 74), that have provided
signs to veterinarian, researcher, and animal user; therefore, they will not harm the
animals.
The implementation of the research using animals is supposed to involve min-
imal one skilled and experienced veterinarian to make sure that the animals are in a
good condition, healthy and prosperous. A veterinarian is a human resource that has
knowledge and skill related to animal health based on the ethical code of a vet-
erinarian and an applied legislation. The articles of Indonesian Veterinary Medical
Association in Chapter III contains ethical codes of veterinarian in Indonesia
containing some responsibilities of a veterinarian towards the patient (animal)
namely, (1) treating the patients attentively, and giving affection as the meaning for
their owner, and using all the knowledge, skill and experience to interests of the
patients, (2) helping the patients in an emergency condition and or providing a way
out if they are not able to refer to other colleagues who are able to do so, (3) with
the consent of his client, the veterinarian can perform euthanasia (mercy sleeping)
because he believes that the best acts as the way out for the patients and his clients,
(4) prioritizing the animal health and preventing disease expansion that can result in
the economic and social losses.
Related to the animal welfare, the Law of Republic of Indonesia No. 18, 2009
and its enhanced within the Law of Indonesian Republic No. 41, 2014 about
husbandry and animal welfare stated that: (1) animal handling is carried out nor-
mally and humanly without any persecution or abuse that dangers the animal,
(2) animal handling is performed by animal medical ofcers that are qualied in
terms of ethical code and they obey their vow or promise profession, (3) the use of
animal or part of animal is done under the control of veterinarian based on the
ethical and veterinarian principles by considering the animal welfare.
3.4 Animal Ethic, Care and Use Committee
The committee of animal ethics is a committee that is responsible for doing the
study of research or method of animal use in an institution (Grimm 2014; Marie
2005). This committee is appointed by the institution to make sure that every
procedure in animal use has been in line with the principle of animal welfare. The
committee of animal ethics in education and research institutions using animal in
their research and education activity in Indonesia is ruled by the decree of the
Minister of State for Research and Technology No. 108/M/Kp/IX/2004, the
Minister of Health No. 1045/Menkes/SKB/IX/2004 and the Minister of Agriculture
No. 540.1/Kpst/OT.160/9/2004 about the formation of National Bioethics
Committee and Health Research Ethics National Commissioninstitutions han-
dling bioethics and ethics problem in national level.
4 Implantation Study, Live Monitoring and Histological

Analysis
4.1 Adaptation and Clinical Health Synchronization
Animal Adaptation
Animal adaptation is an initial step that should be done by researchers before the
animals are used in a series of research. The animals need adaptation process with
the new environment which may be different from the previous one. The adaptation
should be carried out at least in a few days after their arrival because on the way to
the new place, the animals experience stress and distress (Obernier and Baldwin
2006); consequently, this influences the (physio biology) condition and the behavior
of the animals (Arts et al. 2012). The condition and environment of the new treat-
ment is supposed to be not too different from the previous condition. The animal will
adapt several factors, namely physical and chemical factors (Fox et al. 2002). The
examples of physical factor are temperature, relative humidity, air flow and its
composition, noisy level, lightning, radiation, cage and its equipment, as well as
other physical factors (Fox et al. 2002). Whereas chemical factors, like xenobiotic
(biotransformation, feed, and water), pharmaceuticals (drugs, sedation, painkillers,
euthanasia drug, antimicrobial drug, and other agents) and pheromones (Fox et al.
2002). The time needed by the animal to adapt depends on the type and strain of the
animals; like rodents need around 17 days (Obernier and Baldwin 2006).
Clinical Health Synchronization
Next, the health condition of the animal should clinically be treated the same
because Indonesia is a tropical country. Tropical area has an amazing microbe
diversity characteristic if it is compared to sub-tropical and non-tropical areas. The
uniformity of the experimental animals can be done by giving some antimicrobial
agents to them like ant parasite, antimolds well as other suitable microbe (Morris
1995). Geographical area with a different climate has various similarity of pathogen
agents; therefore, it becomes a unique challenge for the medical team to give
antibiotic use policy (Campbell et al. 2014). This treatment can be given around
Table 3 Recommendation for animal health synchronization

Time Drugs type Remark Reference
Day 02 No drugs The animals are in a resting condition (recovery) Obernier and
after transportation to adapt new environment Baldwin
Day 3 Anthelmintic Deworming part 1 (2006)
Day 48 Antibiotic Antibiotic
Day 9 Anthelmintic Deworming part 2
Day 1014 Antibiotic Antifungal or antiprotozoal
Day 1530 No drugs The animals are in a resting condition (recovery)
after the treatment of synchronization before
they are used in the next stage
couple of days until several weeks with a number of treatment, like prevention
dosage and or treatment to homogenize the health condition of experimental ani-
mals (Table 3).
4.2 Pre-implantation Treatments
Fasting treatment to several experimental animals are various. This depends on the
treatment form of implantation surgery and types of animals. Animal models in
research with the procedure of implantation surgery will not be given food before
they experience the process of anesthesia. The pre-medication and pre-anaesthesia
treatment should be given before the anesthesia to perform implantation surgery.
Pre-surgical Fasting
Pre-surgical fasting before the treatment of implantation surgery is done in order to
avoid the pulmonary aspiration coming from the remaining food in the digestive
system (Crenshaw et al. 1999; Maltby 1993). The fasting starts at 2 h before the
surgery to clear the fluid, and it takes 6 h to clear the solid from the digestive system
(Ljungqvist and Sreide 2003). Animals with compound stomach (rumen) in the
group of ruminants (sheep, goat, and cow) should fast for 2448 h before they get
anesthetized to the surgery. Animals with the type of monogastric stomach (dog,
cat, pig) should fast for 624 h. Rodents animals and rabbits (mouse, rat, genuine
pig, hamster, and rabbit) do not need to fast because this group has high metabolism
level. This group does not have gag reflex so that regurgitation will not occur
during the surgery treatment.
Pre-medication
Pre-medication is a stage before the animals get anesthetized to the surgery treat-
ment. Pre-medication is performed by giving certain medicine to prevent the
pre-infection and during the surgery (Bratzler et al. 2005; Bushnell et al. 2008).
Although infection is not unavoidable, pre-medication treatment is a good thing to
do before the surgery (Martin 1994). Generally, the medicine given is antibiotic as
prophylaxis antibiotic that is given before the surgery (Bratzler et al. 2005;
Dale et al. 2004; Morris 1995). The route of antibiotic application in pre-medication
is intravenous (iv), in which the distribution of the antibiotic in the tissue is more
optimal than that in other route that cannot predict the level and the absorption time
is longer (Martin 1994). The recommended time is minutes before the surgery is
performed. The earlier of the pre-medication given, 120180 min, the higher risk of
infection in the surgical site will be (surgical site infection) (Hawn et al. 2013). In
long duration of surgical treatment, like more than 2 h, the intravenous antibiotic
application must be repeated every 23 h once (Hawn et al. 2013; Martin 1994).
Pre-anesthesia
Pre-anaesthesia is a certain medication treatment to the animals before anesthesia
drugs given. The treatment of pre-anaesthesia medicine to the animals is intended to
give security within the anesthesia, so that the stages of anesthesia become
smoother and avoid the negative effect (Bosing et al. 2012), avoid myocardial
arrhythmias to occur (Romano et al. 2012), avoid the negative effect in the car-
diopulmonary system (Bosing et al. 2012; Langan et al. 2000; Schumacher et al.
1997), and patient risk with cardiomyopathy (Kato 2014).
The Sterilization of the Implant Material
Sterilization implant material can be done in several ways based on the material
used. Implant material should be packed with a heat-resistant material. Implant
material is corrosion resistant and made of a metal that can be sterilized in con-
junction with a surgical instrument made of metal. Sterilization material is made of
metal that can use dry-heat sterilization (oven), heat with high pressure (autoclave)
or with radiation energy of gamma rays or X-rays (Fossum 2013; Heaton 1998;
Mann et al. 2011). While material that cannot stand with heat can use ultraviolet
rays, gamma rays or X-rays. Especially for sterilization using ultraviolet light, the
implant material must be exposed directly by light with no obstacles such as
packaging because it can lead to ineffectiveness of the sterilization process.
4.3 Surgical Implantation
Anesthesia
Anesthesia is a major procedure before the process of surgery is performed on the
animal for research need. Anesthesia is an action taken to eliminate some or all of
the sensation of pain from the body as a result of the presence of drugs that suppress
the sensation of local nerves (peripheral) and central (general) (Fish et al. 2011;
Kohn et al. 1997). Anesthesia is limited to the working of the local nerve function
due to the suppression of local nerve (blockage) or the main branch of the nerve
(regional) by the drug. General anesthesia is a form of anesthesia that removes the
awareness and sensation of pain and muscle relaxation characterized by the
decreased reflexes. While surgical anesthesia is an elimination of consciousness,
sensation of pain and muscle relaxation due to the provision of one kind or
combination of drugs. This will facilitate the surgical procedure because of the loss
of pain sensation and movement of animal.
The stages of consciousness loss in the process of general anesthesia are divided
into 4 stages (Kohn et al. 1997). The initial phase is characterized by the voluntary
excitation motors, struggling and ataxia. The second stage is the stage of delirium or
involuntary excitement in which the animals start to lose consciousness and lose
voluntary control. At the end of second stage is marked by the absence of response
to sounds, unconscious and began to lose the sensation of pain. The third stage is
the stage of surgery or called anesthesia surgery that depends on the number of
doses of the drug given to suppress the central nervous system. The surgical
anesthesia itself is divided into 4 plane, namely plane 1 that is characterized by the
pain loss and muscle relaxation. Plane 1 is only appropriate to minor surgical
treatment with the procedure of non-invasive surgery. Plane 2 is characterized by
the loss of pain sensation and the muscle experience relaxation until this plane is
appropriate to whole surgical treatment (both of minor and mayor). Plane 3 is the
stage in which the animals lose their nerve reflex total (intercostals muscles). Plane
4 is the last plane from anesthesia characterized by the paralysis thoroughly from
intercostals muscles, enlarged pupils, cardiopulmonary function suppression of the
further level (severe). Stage 4 of the anesthesia is characterized by the cessation of
respiratory system and circulatory system. This stage is the beginning of death
because the respiratory and circulatory systems stop.
The selection of anesthetic agent and the appropriate dose is the key for the
success of the surgery. The details of form and type of anesthetic and analgesic
selection that t can be seen in Lumb and Jones Veterinary Anesthesia and
Analgesia (Grimm et al. 2011; Tranquilli et al. 2013). The anesthesia was given a
few minutes (1020 min) after pre-anaesthesia. Anesthesia can be administered
several routes, parenteral e.g. intra-peritoneal, intra muscular, intravenous, and
local, or per-inhalation according to the type of the surgery and the type of animals.
The dose of the drug in mild, moderate or strong conditions is adapted to the type of
surgery that will be carried out (Garcia 2013).
Analgesia
An analgesic agent that serves relieve pain (DeLeo 2006). This dosage is usually
given in conjunction with anesthesia in animals undergoing implantation surgery.
Certain surgical actions can cause pain even though the animals are in the absence
of consciousness. The pain can trigger the cytokines production that mediates
certain response, such as pain reflexes that are out of control so that it can cause
death in animals (eyler et al. 2007). Pain reflex are suppressed so that the variety
of surgical procedures can be run without the unnecessary reflex motion that can
harm the animals and surgical team. The analgesic administration is usually given
until a few days after implantation in order to suppress the effects of
pro-inflammatory cytokines (Beilin et al. 2003).
Hair Shaving and Disinfection of Surgical Area
Animals generally have hair on their body so that the shaving is done in the area of
surgical orientation and continued by the provision of disinfectant and animal
Fig. 1 The implantation of biomaterials in experimental animals. a The construction of gap in the
rat femoral bone, b the implantation of stainless steel in the rat femoral bone, c the implantation of
magnesium rod in the rat femoral bone, d the implantation of polymer membrane in the rat frontal
bone, e the implantation of silk suture head in the mice femoral muscle, f the implantation of
porous metal bone graft material with intra-medulla pin on the mice femoral bone
positioning on the operating table for surgery (Fossum 2013; Mann et al. 2011).
Disinfection of the surgical area is given by using iodine tincture or using a sterile
plastic wrap to cover the surgical area.
Implantation
Surgical implantation can be performed after the animals are completely anes-
thetized and do not feel the pain; moreover, they are in the condition of relax
(Clarke and Trim 2013). This condition can be achieved in anesthetic condition of 2
and 3 stages the surgery is done in accordance with the design of the study wanted
(Fig. 1).
The Monitoring of Anesthetized Animals
The monitoring of animals during the anesthesia is needed to be done to determine
the stage of the anesthesia process after the administration of anesthesia until the
animals awake again (recovery) (Clarke and Trim 2013; McKelvey and
Hollingshead 2003). Anesthetized condition is the condition in which the animals
are in the biological stage that is close to death. Therefore, monitoring the status of
anesthetized animal must be done continuously to ensure that the animals are in a
safe condition of stage 4 (death) from anesthesia. There are several things that
should be observed in animals, namely the system of cardiovascular system, res-
piratory system, muscle tonus and sense of vision (Table 4) (Garcia 2013).
Table 4 Animal observation

Cardiovascular Respiratory Muscle tone Eye
system system
Heart rate and Respiratory rate Jaw or limb tone Position of eye (presence
rhythm Depth of Response to painful or absence of movement)
Mucous breathing stimulus (toe or tail Size of pupil
membrane Character of pinch) Responsiveness of pupil
color breathing to light
Capillary rell Blood gases Palpebral reflex
time Hemoglobin Corneal reflex
Arterial pulse oxygen saturation Lacrimation
and pressure (SpO2)
Body
temperature
Post-implantation Monitoring
Post implantation of the animals is monitored until they are completely aware. The
post anesthesia recovery time varies depending on the type of drug used and the
surgical procedures performed (Clarke and Trim 2013). The monitoring
post-implantation should be done within 2448 h. This is important to determine
the condition of a change in behavior of animals under the normal conditions such
as eating, drinking and their activity (Garcia 2013). Stitching wounds are examined
in the form of a strong knot and the wounds are neatly closed (not open) and there is
no bleeding (Fossum 2013). During this monitoring period, antibiotics of post
implantation is given to prevent infection in the surgical area. Once recovered well,
the animals are returned to the cage maintenance for further treatment of post
implantation.
4.4 Post-implantation
Post-implantation Pain Killer (Analgesia)

Surgery causes tissue damage in animals due to the incision and implantation of
actions that cause the sensation of post-surgical pain (Walker et al. 2011). The pain
sensation is a major alarm system that inform the damage of the tissue (Sneddon et al.
2014). The provision of post implantation analgesia aims to reduce pain and suppress
the negative effects on the release of pro-inflammatory cytokines from the tissue
damaged by surgery (Beilin et al. 2003). Not all animals show the pain sensation
clearly (naked eyes) (Fitzpatrick et al. 2006). The methods for analyzing the pain of
the animals can be done with 3 approaches (Walker et al. 2011; Weary et al. 2006),
i.e. by measuring the function of the body through the measurement of food intake
and daily drink or weight, by measuring the physiological response of the body of the
blood cortisol concentration prole, and by observing changes in the behavior of
animals, like the sound produced. The preparations of anti-pain need to be given after
the implantation treatment although the sensation of the pain in each animal varies
(Nielsen et al. 2009; Tranquilli et al. 2013; Viuela-Fernndez et al. 2007). The
application of pain killer (analgesia) is intended to reduce excessive pain sensation
that causes distress to the animals after surgery (Richardson and Flecknell 2005).
Antibiotic post-implantation
The infection after surgery can be so risky in sepsis that it can increase the value of
morbidity, mortality and additional cost of treatments (Lane et al. 2010). Antibiotics
are given in accordance with the purposes, usually given for surgery that lasts for
more than 2 h and or patients receiving implant material installation.
Post-implantation antibiotics should be given to avoid infection after surgery
(Campbell et al. 2014). Generally, antibiotics of post-surgery range in 35 days
with long-acting types of antibiotics with 2 day interval or daily administration
short-acting (Tables 5 and 6) (Martin 1994).
Suture Removal
Suturing the cut functions to support the tissue so that the distance among the cuts
can be made as close as possible in order to make the wound recover well (Bennett
1988). Suturing the skin can use silk or nylon thread that can be absorbed by the
body (Altman et al. 2003; Bennett 1988; Vepari and Kaplan 2007). Monitoring on
cuts and seams should be done within 4872 h to make sure that there is no
infection and apart stitches (Fossum 2013). This sewing thread should be taken
within 35 days gradually or no later than 14 days after surgery (Fossum 2013;
Mann et al. 2011).
Table 5 Bacteriologic and pharmacokinetic criteria for biomaterials implantation

Bacteriologic Antibiotic level expected Dose
properties
Rapid and >Minimum inhibitory concentration Large single dose (23
dose-dependent (MIC) of organisms for a short period times the usual dose)
killing
Post-antibiotic
effect
No inoculum effect
(e.g.,
aminoglycosides)
Time-dependent >Minimum inhibitory concentration Single dose of a drugs
killing (MIC) of organisms Throughout the with a long half-life
surgical procedure (long-acting)
No post-antibiotic Repeated doses of a drug
effect with a short half-life
Inoculum effect (short-acting)
(e.g., -lactam
antibiotics)
Table 6 Pharmacodynamics properties of 3 types of antibiotics

Properties -lactam antibiotics Aminoglycosides Quinolones
Inoculum effect +
Post-antibiotic effect + +
Killing rate Time-dependent Dose-dependent Intermediate
Implantation Syndrome Risks

Implantation syndrome of material should be of concern in the implementation of
the material implantation. Although the mechanism of syndrome cannot be
explained well, syndrome implantation can cause things outside the desire to death
during and after implantation (De Maria et al. 2012; Donaldson et al. 2009). The
forms of syndrome were found as bone cement implantation syndrome (BCIS)
(Donaldson et al. 2009), coronary syndrome of post-stenting of heart coronary
arteries (Ferrari et al. 2005), blood clotting (Park et al. 2010), Brugada syndrome of
post cardioverter-debrillator installation in the heart (Sacher et al. 2006),
and infection that occurs after biomaterial implantation (Matsuno et al. 2006;
Reefhuis et al. 2003).
4.5 Data Monitoring
Life Monitoring
Monitoring data of pre-, peri- and post-implantation in animals can be done in
several ways, namely the method of non-invasive, minimal invasive and invasive.
Samples can be taken, like blood (Fig. 2), urine, tissue, heart and brain electricity,
body and tissue temperature, implant stability, and radiology image. Product of
response result analyte of tissue interaction with biomaterial can be accessed
through the biosensor (Wilson and Gifford 2005). The number of biological sam-
ples is adjusted to the types and size of animal. Monitoring data for histologic
examination of tissue response in the living animal can be done with biopsy of
tissue, muscle, bone and organ (Lehtonen et al. 2001). Implantation biopsy pro-
cedure follows the protocol of implantation in accordance with the type of animals
used.
Post-mortem Monitoring
Monitoring data of post-mortem is usually performed to design research that has
end-point of animal euthanasia. Some biocompatibility tests of a certain biomaterial
on the organ are used for analysis purposes of histologically systemic response of
some vital organs that can be taken partly or entirely at the end of the test. Such
actions sometimes do not enable the animals to be able to stay alive so that the
procedure of euthanasia is needed (Alper 2008). Euthanasia is a medical procedure
that removes animals soul gently and humane (Stokes 2002). Animals are eutha-
nized rst and then followed by tissue removal. The making of remaining
Fig. 2 Blood sampling in several types of animals of post implantation of biomaterial

implantation: a blood sampling of the mice was taken through the venous sinuses retroorbitalis,
b through intacardial or via the tail vein of the mice, c the blood sampling of the rabbit were taken
through venous auricalis on the ears, and d the sheep were taken through the jugular vein in the
neck
biodegradable sample or the untouched sample of the non-degradable implant is

taken to analyse for the further characteristics (Ulum et al. 2015). The local tissue,
such as muscle, bone of implantation area and the sample for systemic reaction
from inside organs can be taken for histology examination (Paramitha et al. 2013;
Ulum et al. 2014b).
4.6 Biomedical Imaging and Its Analysis in Life Animal
Biomedical Imaging
Biomedical imaging is a method that seeks to describe a variety of responses that
occur in implant, peri-implant, tissue around the implant, and other tissue in greater
distance from the implant or the so-called systemic response. Generally, the
biomedical imaging uses energy of ionizing radiation, such as X-rays, non-ionizing
radiation, like magnetic resonance and high-frequency sound waves, ultrasound
(Beard and Losh 2006; Davis 2008).
X-ray-based imaging is radiography, tomography, fluoroscopy (Davis 2008).
Since X-rays are found, the current development of radiological imaging technol-
ogy is growing very rapidly for medical diagnostic purposes as well as for advance
research world (Tempany and McNeil 2001). It is necessary to consider that the
energy of ionizing radiation causes negative effects so that imaging is only per-
formed in a short time and in certain time (Barrett et al. 2015; Dincer and Sezgin
2014). The image of bone and the implant can be analyzed properly in this imaging,
both digitally and conventionally. Radiogram implant can be analyzed by using
densitometer at illuminator (Noviana et al. 2013a; Ulum et al. 2014a). Radiogram
on illuminators can be converted into digital images by using a digital camera, and
then it can be analyzed by using software to analyze the picture, like
ImageJ. The application of ImageJ software in the analysis has been applied to
tissue response towards the metal implant that can be absorbed by the body and it
experiences the process of biodegradation (Ulum et al. 2014b).
Magnetic resonance energy-based imaging (MRI) has the ability to image soft
tissue very well and there is no ionizing radiation (Davis 2008; Hartwig et al. 2009;
Jacobson 2005). The MRI imaging was well known for certain time, and it can be
done safely to the animals (Tempany and McNeil 2001); however, there were no
effects that were encountered, namely magnetic resonance energy that can cause a
biological effect (Hartwig et al. 2009).
Imaging using high frequency of sound energy is ultrasonography
(USG) (Diederich and Hynynen 1999). The imaging that utilized USG can image
real-time; however, image taking over long time causes an increase in temperature
of surrounding tissue examination hazardous (Jacobson 2005; Teefey et al. 2004).
Ultrasound utilizing high frequency sound energy is because of the absence of
ionizing radiation; however, imaging taking a long time causes an increase in tissue
temperature around the location of dangerous examination (Liu et al. 2014; Palmeri
and Nightingale 2004). The weakness of ultrasound is in the imaging of hard tissue,
like bone, the implant and the air. The weakness has developed and can be over-
come well so that ultrasound has a diagnostic value (Shiver et al. 2005; Tchelepi
and Ralls 2009; Ulum et al. 2015).
Biomedical imaging in animals is different from that in human. Some experi-
mental animal need a series of procedures for the restraint and the handling of
animals is done before imaged. Animal preparation procedure generally needs an
anesthetic action as well as the repetition of anesthesia for imaging in a long
duration of time. The application of contrast material and the exposure of ionizing
radiation influence directly or indirectly towards the physiological function of
animals (Driehuys et al. 2008).
Animal Handling and Restraint
Handling and restraint of animals are an important step prior to the preparation of
imaging. The forms and techniques used will vary on each animal depending on the
type of research and the target data to be taken during the monitoring data.
Considering animal movement during imaging is the main thing that bothers if the
movement cause noise or inference in an image taken; therefore, the next form of
handling can be taken by giving tranquilizer, sedation or anesthesia (Hildebrandt et al.
2008). Tranquilizer, sedation and anesthesia are handling and restrain forms chemi-
cally in the experimental animals to facilitate a variety of procedures in medical
treatment and research given in accordance with certain rules (Fish et al. 2011; Muir
and Hubbell 2014).
Generally, handling and restrain technique of animals can be divided into
physical and chemical forms (Fowler 2011). Physical handling can be done by
using restrain or other tools that can make animals become cooperative during the
imaging. Sheep or goat can be handled by using clamp cage or the combination of
restrain during ultrasound imaging, brain and heart electricity image, blood sam-
pling or others. Rodent animals can also be handled by using clamp cage with a
special design adjusted to the size of their body. While chemical handling is a
treatment using tranquilizer, sedation, or anesthesia drugs depending on the image
target that will be taken (Hildebrandt et al. 2008).
Animal Preparation for Biomedical Imaging
The preparation of animals before imaging will be different. This depends on the
form of imaging that will be taken. The procedure difference depends on the
equipment types and ability in making the image wanted (Johnson et al. 2014). The
animals should fast before the process of anesthesia in order to avoid animal
movement, and the animals are given ophthalmic ointment during the process of
imaging. The preparation procedures of other animals is like the installation of
probe electrocardiograph (ECG), installation of cannula at arterious or venous
blood channels, the installation of endotracheal tube and others that can be done to
the animals. The installation of intravenous catheter for anesthesia or physiological
fluid of the body should be done for the imaging procedure about 3060 min. Small
rodents can be given intraperitoneal or subcutaneous.
Implant Imaging
Post-implantation imaging of implanted materials can be conducted in several
approaches (Davis 2008; Driehuys et al. 2008), such as radiography, tomography,
positron emission tomography (PET), single photon emission computed tomogra-
phy (SPECT), computed tomography (CT and Micro-CT), Magnetic Resonance
Imaging (MRI), Magnetic Resonance Microscopy (MRM) or ultrasonography
(USG). Analysis of any implant changes occurring can be analyzed further by using
software that is suitable to the image produced.
Radiology imaging that is available and easily had for researchers in Indonesia is
radiography and ultrasound, the conventional or digital ones. Conventional image
can be made into digital by using digital camera. Next, the digital image is pro-
cessed and analyzed further by using software, and computer can be used for the
picture. Advance radiology imaging like tomography (CT-scan) and MRI is still
limited and it is only available in hospital for human patients only. Radiography
imaging at biomaterial post-implantation can use software tool to analyze the image
like ImageJ to analyze the image prole of implant opacity and tissue from
radiogram (Fig. 3).
Besides using prole line, the analysis in radiogram density can also be done
with method that is usually used to measure the intensity of image in cell
fluorescent coloring (Gavet and Pines 2010; Potapova et al. 2011). Briefly, cell
intensities counted with corrected total cell fluorescence formula (CTCF), in which
the CTCF = Integrated Density(area of selected cell X mean fluorescence of
background readings). The result of the calculation in Arbitary unit (a.u.). From
the formulation, it can be adopted for radiogram image to become corrected total
intensity (CTI) with grey unit scale (Gray Value) by dividing the value of a.u. with
1012 and the last value is made to become absolute so that the number obtained is in
scale range of gray value that is 0256.
In the technique of imaging that uses USG, the area shaving of the animal
models in the area of imaging should be done (Fig. 4). Probe USG is attached to the
Fig. 3 Digital radiogram of several metal implant types can be found in the mice femur bone and
the analysis result is line plot prole: a, b implant stainless steel and line plot prole, c,
d iron-porous and line plot prole, e, f tantalum-porous and line plot prole, g the result analysis of
corrected total intensity (CTI) implant stainless steel, iron-porous and tantalum-porous. Asterisk
sign implant, circle bone, broken red line analysis area line plot prole using software of
ImageJ, red triangle implant analysis area, and yellow line triangle background analysis area, cor.
bone cortical bone
skin of imaging area by using ultrasound gel in order to get the best image and have
diagnostic value. Response interpretation of tissue can be describe in every change
occurring in implant and tissue around it. Sonogram produced in digital format is
then analyzed by using software to get the best image at biomaterial implant,
per-implant and tissue (Noviana et al. 2013b).
Peri-implant Imaging
What is interesting to the researchers is the reaction that happens in interface
between the implant and the tissue. Peri-implant on the implant side and tissue side
as interfaces also can be the image by previous imaging system. Several approaches
are performed by adjusting the modality from diagnostic tool that exists to access and
create the image of interface area reaction like USG (Huang et al. 2007; Nishii et al.
2012; Noviana et al. 2013b), radiodensity (Baena et al. 2013; Fonseca et al. 2006),
and histology (Sennerby et al. 2005).
Surrounding Tissue Imaging
The imaging of tissue around the implant is done to know the response that happens
in millimeter from the interface implant with the tissue. The reaction of the tissue
around the implant can be imaged by using several approaches radiologically. Soft
tissue and the internal architecture, like muscle, can be seen clearly by using USG
(Noviana et al. 2013b: Ulum et al. 2015), tomography(Coan et al. 2008; Sofka et al.
2006) and MRI-based (Botnar et al. 2004; Hermawan et al. 2010). Figure 5 shows
response image of metal post implantation of tissue that is absorbed by the body in
femur bone of rat using USG. While harder tissue image, like bone, at gold standard
still use x-ray based imaging (Fig. 3).
Systemic Tissue Imaging
The imaging of systemic tissue at organ functions can be well imaged by using
USG- (Gibbon et al. 2002; Kosonen et al. 2013; Noviana et al. 2012a) and
MRI-based (Botnar et al. 2004; Jacobson 2005). This imaging is intended to know
the indirect influence and long term installation of implant in the body.
4.7 Histological Analysis
Histology Analysis for Biomaterial Implants

Analysing the tissue related to the implant interaction can be done by using his-
tology approach (Carleton and Drury 1957; Ozawa et al. 2002; Wick 2012).
Implant planted in tissue can be processed histologically or it can be released from
the tissue adjusted to the type of embedding tissue and the target data that will be
taken. The series of tissue process starts from the preparation until the coloring and
the tissue analysis in the slide. General analysis of tissue response can be performed
by using hematoxylin-eosin coloring (HE) while special response uses stain that
depends on specic target of response wanted (McLaughlin 1983; Troyer et al.
2002).
Fig. 4 Technique of USG imaging of post implantation of sheep foot and its analysis. a The
shaving around imaging area, b USG imaging, c sonogram, d schematics gure sonogram and the
analysis of echogenicity difference along the implant of steel-bioceramic from line plot prole
that uses ImageJ software e day 14 and f 60 post-implantation. Head arrow sign the formation of
new bone around the implant, arrow time of liquefaction around the implant, red asterisk implant,
circle bone
Tissue Harvesting
Tissue of post-implantation for both biopsy and euthanasia that has been taken is
kept in the preservative solution like Buffer Normal Formaldehyde (BNF) with
10 % concentration or other solution that is suitable (Bancroft and Gamble 2008).
The tissue is kept 48 h minimal to give enough time for BNF to inltrate and
preserve the tissue. Mature tissue is marked by the inltration from BNF well and
then it is trimmed in accordance with the tissue analysis target wanted.
Fig. 5 Sonogram of biodegradable porous metallic implant at rat bone: a the long cutting at USG
imaging, b cross cutting at USG imaging. Head arrow sign cavity image lled by fluid, animal
implant, circle femur bone
Tissue Embedding
Embedding tissue can be done by using two ways, namely by using parafn (soft
embedding) (Bancroft and Gamble 2008) and polymer (hard embedding) (Willbold
and Witte 2010). Soft embedding of this tissue uses parafn in which the hard
implant (ceramic and metal) is released from the implantation tissue. Hard
embedding of tissue uses polymer in which the implant in implantation tissue is not
necessarily to be released (Cerri and Sasso-Cerri 2003; Willbold and Witte 2010).
Tissue Staining
General coloring to analyze the tissue usually uses coloring material,
hematoxylin-eosin (Carleton and Drury 1957; Page 1983). Hematoxylin gives violet
blue color in constituent elements of main cell. Eosin gives red color at cytoplasm and
cell wall. Various occurrences of cellular interaction happening at the tissue can be
generally visualized well by using this general coloring (Cerri and Sasso-Cerri 2003;
Mao et al. 2009; Pearce et al. 2007). Special coloring is intended to analyse the
specic response of cellular level or cell product (cytokin) between the implant
material and tissue (McLaughlin 1983). Special coloring works through the specic
chemical reaction between antigen and antibody targeted in the tissue. Furthermore,
special coloring is also intended to the degradation products. This can be used to know
the distribution of material in local of systemic tissue (Mueller et al. 2012). In ana-
lyzing the tissue response to implants which implanted for long periods, there will
appear chronic inflammatory response, the body forming a brous capsule composed
of connective tissue. To visualize the connective tissue well, to make it look distinct
with the surrounding tissue, Masson trichrome staining is commonly used (Kingsbury
2008). Tissue analysis of the product due to the occurrence of inflammatory cell
metabolites in response to a foreign body such as implants for tracking of various
cytokines or enzymes (metalloproteinases) using immunohistochemically methods
can be used. Likewise, the existence of specialized cells can be tracked using
immunohistochemically techniques, such as tracking macrophages, neovasculariza-
tion by tracking endothelial cells and so on (Buchwalow and Bcker 2010).
5 Experiences on Animal Study of Medical Implants

in Indonesia
Indonesia is a developing country that keep developing dynamically, one of which

is in independence business to fulll the need of biomaterial in health medical
business. Researchers from higher institutions, national research institution or small
group observers and biomaterial developer try to design and make material that is
suitable for medical biomaterial need. This is for the need of human being in Asia,
especially Indonesia itself. The result of product, prototype and sample material
development that has been designed and synthesized has been tested through
in vitro biocompatibility test.
The next stage is in vivo test in several animal models in accordance with the
aim why the products are made. The analysis performed for orthopedic with heavy
functionality burden is implant product for articial hip and joint replacement
implant. While the product for slight orthopedic burden is bone plate, bone screw,
and intra medulla implant. Furthermore, the product for almost very less burden is
craniofacial implant (plate and screw). The testing of biocompatibility at the ani-
mals with heavy burden is done at small ruminant, like sheep and goat, or pig.
While for the slight or almost no burden, the testing is performed at rodents like
mice, rats, and rabbits.
Several biomedical implants have been done in vitro and in vivo testing by some
researcher from Indonesia. The bioceramic material from egg shell as dental ller
has been tested in local dental dog. The stainless steel intramedullary implant that
developed by local industry has been tested at New Zealand White rabbits femoral
bone. The stainless steel bone plate tested at mandibular bone of Sprague Dawley
rats and New Zealand White rabbits. Tantalum bone plate implant with bioceramics
coating is done at rats femoral bone (Panjaitan et al. 2014). The newest devel-
opment of implant that can be absorbed by the body has also been done with steel-
and magnesium-based material at experimental animals, mice (Paramitha et al.
2013), rat and sheep (Ulum et al. 2015). Furthermore, testing is also performed to
polymer implant for the surgery thread suture performed at mice (Ulum et al. 2012),
eye tissue at rabbits, and craniofacial and femoral at rat (Panjaitan et al. 2014). The
result of the testing has been reported partly and the others have been processed for
publication (Table 7). Several examples of implantation process of biomaterial
implant were performed by researchers in Indonesia at some types of animals and
examples of how to analyze the radiology image (radiogram and sonogram) over
the tissue response towards biomaterial as described in Figs. 1, 2, 3, 4 and 5.
Table 7 Some experiences on animal study in Indonesia

Animal Biomaterial Materials Duration References
implants (days)
Mice Bone implant Stainless steel 316L 30 Noviana et al. (2012b);
rod Paramitha et al. (2013)
Bone implant Cr-coated 30 Noviana et al. (2012b);
rod biodegradable iron Paramitha et al. (2013)
Bone implant Biodegradable iron 30 Noviana et al. (2012b);
rod Paramitha et al. (2013)
Surgical suture Natural silk 7 Ulum et al. (2012)
Bone scaffold Biodegradable porous 30 Unpublished
iron
Bone implant Biodegradable 30 Unpublished
rod magnesium
Bone scaffold Polymer (PLGA)- 30 Unpublished
coated biodegradable
porous iron
Intramedullary Stainless steel 316L 30 Unpublished
implantrod
Rat Bone implant Porous tantalum 60 Panjaitan et al. (2014)
plat
Bone implant HAp-coated porous 60 Panjaitan et al. (2014)
plat tantalum
Craniofacial Stainless steel 316L 60 Unpublished
implantplat
Craniofacial Pericardium membrane 60 Unpublished
implant
membrane
Bone ller HAp 60 Unpublished
Bone implant Biodegradable porous 360 Unpublished
plate iron
Rabbit Intramedullary Stainless steel 316L 60 Unpublished
implantrod
Craniofacial Stainless steel 316L 60 Unpublished
implantplat
Sheep Bone implant Iron-bioceramic 70 Noviana et al. (2013a, b);
composite Ulum et al. (2013, 2014a, b,
2015)
Bone scaffold HAp-TCP 60 Unpublished
Bone cement HAp-TCP 60 Unpublished
Pig Bone implant HAp-TCP 90 Unpublished
Dog Dental ller HAp-TCP 60 Unpublished
6 Perspective
Indonesia is a developing country in various elds that continuously strive to

improve many things for the prosperity of its people, as well as in terms of the
development of biomaterial implants. Several regulations and procedures for the
provision of an animal model for the development of implants are already available
and continue to be addressed in line with the demands of international standards in
safe products for its users. Various things have presented above about the ability
and experiences of Indonesian researchers and scientists to gather a wide range of
products of the nations children were tested both in vitro and in vivo animal
testing. Tests on animals already a done deal and are able to prove the various
processes that occur in the animal body with an imaging technique capable of
imaging the things that happened between the materials with the animals body
locally and systemically.
Acknowledgements The authors acknowledge the support of Indonesian Ministry of Education

and Culture-DGHE No. 083/SP2H/PL/Dit.Litabmas/II/2015 and Indonesian-Australia Center
Small Grant in the year of 2015.
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Bioadhesion of Biomaterials
Siti Sunarintyas
Abstract Biomaterials are widely used in many kinds of medical devices. The
biomaterials used can be metal, polymer, ceramic or composites. Bioadhesion will
be occured when the medical device contact to biological surface. There are many
conditions where bioadhesion is benecial and vice versa. The implantation of
medical devices in the human body is not without risk. It is reported that implan-
table medical devices are an ideal interface for microorganisms. There are infec-
tions caused mainly by bacteria originating in the body. Some aspects influence
bioadhesion of implantable medical devices including surface topography, chemical
interaction, mechanical interaction and physiological interactions are discussed.
The understanding of such aspects hopefully governs medical practitioners in
controlling the medical devices bioadhesion process, then optimizing the desirable
bioadhesion and removing the undesirable interactions. To complete the discussion
on bioadhesion of biomaterials, it is also described some methods of bioadhesion
testing including surface roughness measurement, contact angle measurement,
surface topography evaluation and biolm formation testing. At last, a perspective
related to biomaterials used as medical devices is presented.
Keywords Bioadhesion Biomaterial Medical device
1 Introduction
The use of biomaterials has become an integral part of modern health care.
Sometimes severe trauma causes the human body to become damaged beyond
natural repair. Often, oncological surgery creates irreparable damage while the
results of wear cannot be repaired by natural processes. Irreparable damage to the
human body may not be necessarily associated with lost of function and quality of
life. Numerous biomaterial devices are available for the restoration. Biomaterials
S. Sunarintyas (&)
e-mail: sunarintyassiti@ugm.ac.id

104 S. Sunarintyas
have found applications in approximately 8,000 kinds of medical devices that have
been used in repairing skeletal systems, returning cardiovascular functionality,
replacing organs, and repairing senses. There will be bioadhesion when the bio-
materials are placed in the body. Bioadhesion is the state in which two materials, at
least one of which is biological in nature, are held together for extended periods of
time by interfacial forces. In the context of medical devices usage, the term of
bioadhesion refers to the adhesion of biomaterials to a biological tissue. The
bioadhesion interaction could be desirable or undesirable. The biological substrat
can be cells, bone, dentine, mucus, or biolm containing matrix protein and
microorganisms. The biomaterials used can be metal, polymer, ceramic, and
composites. An understanding of the bioadhesion mechanism principle of medical
devices used in the body and some aspects influence bioadhesion is important for
clinical practitioners in managing their patients. Moreover, this chapter also
describes some methods of bioadhesion evaluation. In the last part, it is discussed
about bioadhesion issues related to biomaterials used as medical devices.
2 Bioadhesion: State of the Art
Bioadhesion is said to occur when two materials, at least one of which is biological
in nature, are held together for extended periods. Bioadhesion has largely remained
well in the eld of biology referring to cellular interactions (cytoadhesion) or to
mucosal adhesion (mucoadhesion). Whether it is cell-to-cell, soft or hard tissue, or
mucosal adhesion, the phenomenon of bioadhesion involves the formation of a
bond between two biological surfaces or a biological surface and a synthetic sur-
face. Therefore, bioadhesion can be extended to include any type of adhesion
process in contact with or within the biological milieu. The term bioadhesion
includes the adhesive properties of synthetic components and the natural surfaces
(such as cells, tissue, bone, dentin, mucous). Bioadhesion could also refer to the use
of bioadhesives material to bond two surfaces together, which is relevant in drug
delivery, dental and surgical applications (Woodley 2001; Mobley et al. 2002;
Vaidyanathan and Vaidyanathan 2009). Nowadays, the wide interest in bioadhesion
research is due to its implications for the development of new biomaterials, ther-
apies and technological products.
Bioadhesive systems are reported have been used for many years in the eld of
dentistry and orthopaedics (Meuller et al. 2010; Shah and Meislin 2013) as well as
in opthalmology (Zhu et al. 2013) and for surgical application (Jeon et al. 2014).
There have been also interested in the use of bioadhesives in other areas, such as
soft tissue-based articial replacement, and controlled release systems for local
release of bioactive agents. Such applications include systems for release of drugs
in nasal cavity (Alagusundaram et al. 2010), intestinal administration (Philip and
Oman 2010), and urinary bladder application (Haupt et al. 2013).
Depending on the chemical composition of biomaterial and its function on the
biological surface involved, bioadhesion may be desirable or undesirable. Examples
Bioadhesion of Biomaterials 105
of desirable bioadhesion interactions are shown in Figs. 1 and 2. The use of dental
composite resin as lling material (Fig. 1) illustrates bioadhesion interaction
between email or dentin (biological substance) and the synthetic polymer adhesive
restorative material. The other example of desirable bioadhesion is bone cement as
a synthetic substance commonly used to hold implants in bone. Figure 2 shows the
bioadhesion of bone cement in joint replacement.
Fig. 1 Composite resin usage for lling dental cavity (Courtesy of Faculty of Dentistry, UGM)
Fig. 2 Joint replacement is xed with bone cement

106 S. Sunarintyas
The bioadhesion between materials can also be undesirable. The undesirable

interaction is commonly well known as biofouling (Palacio and Bhushan 2011).
A biolm is an aggregation of microorganisms that form on a solid substrate, which
may form during the implantation of biomaterials into the body. The formation of
biolms on both living (cells) and non living (i.e. cathethers, stents, implants)
surfaces has been identied as a cause of disease. An example of biolm formation
is plaque or calculus formation on the surface of dental composite resin lling
restoration (Fig. 3). Such biolm formation unsatises the patients as decreasing
aesthetic appearance and odor.
This chapter describes both of the desirable and undesirable bioadhesion. There
are many conditions where bioadhesion is benecial, for example: cell adhesion on
implant devices, the use of bioadhesives for surgical and dental application, and
mucoadhesion in drug delivery system. By understanding the aspects influence the
desirable and undesirable bioadhesion, the control of bioadhesion process will be
accurately and there will be ways to optimize desirable bioadhesion interaction and
prevent or remove the undesirable bioadhesion.
The undesirable bioadhesion such as biolm formation, plaque, and calculus will
also be discussed in this chapter. The understanding of such bioadhesion will
respect to infection prevention of permanent implants and devices. Moreover, the
evaluation of both desirable and undesirable bioadhesion will be described for
characterization of biomaterial. Finally, the occurance of both bioadhesion on
metal, polymer, ceramic, and composite devices will be discussed.
Fig. 3 Plaque formation on

composite resin lling stained
by disclosing solution
(Courtesy of Faculty of
Dentistry, UGM)
3 Aspects of Bioadhesion
There are two stages in the formation of bioadhesion (both desirable and unde-
sirable). The rst part is the contact stage, when two surfaces are brought together
into intimate contact and the second one is the consolidation stage, when the
adhesive interactions occur. There are several theories explaining how such inter-
actions occur based on surface wettability, molecular interpenetration, mechanical
interlocking, adsorption, fracturing of the adhesive bond, and electron transfer
across an interface (Smart 2014). The bioadhesion interaction is usually complex
and requires the application of more than one theory.
In brief, there are 4 aspects affect the bioadhesion interaction, namely: surface
topography, chemical interaction, mechanical interaction, and physiological inter-
action. Surface topography relates more to the surface roughness morphology.
Chemical interaction includes the electron transfer across the interface of materials
and adsorption processing in the surface of material. Mechanical interaction covers
surface wetting, mechanical interlocking, and macromolecular interpenetration
phenomena. Physiologic aspect includes physiologic interaction of adhesive.
Knowledge of such aspects govern clinicians permit a greater understanding of the
bioadhesion mechanism and allow the development of more effective systems that
can be used in medical therapies.
3.1 Surface Topography
Cell adhesion on synthetic biomaterials surfaces is studied due to its direct impli-
cations for the design and clinical performance of medical devices. The adhesion of
cells on biomaterials is an example that describes the importance of surface
topography of a substrate surface where the cells are cultured. There are various
studies aimed to evaluate the relationship between surface topography and cell
adhesion (Katsikogianni et al. 2008; Faeda et al. 2009; Ho-Nam et al. 2009;
Ansalme et al. 2011; Galasso et al. 2011; Crawford et al. 2012; Huang et al. 2014).
The studies of cellsubstratum interactions are often complicated by the presence of
different types of surface pattern. Among the studies, surface topographies can be
grouped into three general patterns: (i) irregular surface topography, (ii) regular
surfaces topography and (iii) hierarchical surface topography (Ho-Nam et al. 2009).
Research on Three-dimensional surface images of the nonprecious alloy
(nickel-chrome based alloy), that were taken after different surface treatments
(Faeda et al. 2009), revealed that the airborne-particle abrasion group was irregular,
while the 1000 SiC abrasive paper group showed a relatively regular surface
topography. Titanium surface topography research reports that hierarchically
structured titanium surface topography with topography-induced inherent antibac-
terial capability and excellent osteogenic activity had been constructed. Biological
evaluation of such topography revealed that antibacterial ability and excellent
108 S. Sunarintyas
Fig. 4 SEM images of hierarchically titanium surface with different scale
osteogenic activity of samples with optimized hierarchical structure was better

when compared to the control group (Huang et al. 2014). Figure 4 showed such
hierarchically titanium surface with different scale.
Researches on surface topography show that the evaluation of the surface is
measured on surface roughness (Ra). Orthopedic researches reports that surface
roughness becomes immensely studied by numerous investigators with the goal of
improving the performance of bone implants (Gittens 2011).
3.2 Chemical Interaction
There are two chemical interaction aspects which are usually discussed in bioad-
hesion process of biomaterials, namely the electron transfer across the interface of
materials and the adsorption processing. Regarding to the electron transfer there are
two interactions which are well known: primary bonds (strong bioadhesion) and
secondary forces (weaker bioadhesion). The primary bonds involve ionic, covalent,
and metallic bonds. Ionic bonds occur between atoms that have large differences in
electronegativity. Covalent bonds are formed through the sharing of valence elec-
trons, rather than complete electron transfer as for ionic bonds. Metallic bonds are
formed in two surfaces containing elements that are electropositives (Temenoff and
Mikos 2008). Secondary forces such as polar (dipole-dipole), hydrogen bonding or
van der Waals interaction (induces dipoles) also play a large role in bonding the two
surfaces. Secondary forces involve attraction between atoms that require neither
electron transfer nor electron sharing. The attraction occurs between molecules that
have a portion that is slightly positively charged and a portion that is slightly
negatively charged (Temenoff and Mikos 2008; Palacio and Bhushan 2011).
Fig. 5 Schematic of a protein adsorbing on surfaces with different net charge and polarity
Illustration on the role of surface chemistry in protein adsorption is described by

Andrade et al. (1992). It is assumed that the surface is uniform and the interaction
between protein and surface is only one type. The strength of the protein adsorption
depends on the net charge and polarity of the side of protein available for
adsorption and the composition of the substrate surface. The protein and substrate
could either be predominantly hydrophobic, positively charged, negatively charged
or neutral hydrophilic. The interaction of a neutral hydrophilic side of protein with a
surface having a similar polarity tends to lead to weak adsorption. Ionic interactions
between proteins and substrate surfaces will lead to relatively moderate adsorption.
The interaction between hydrophobic protein part and the substrate lead to strong
adsorption. Such illustration (Fig. 5) is only regarding to one interaction. However,
proteins contain complex arrangements of hydrophobic, charged and neutral
hydrophilic groups which will lead to complex combination interactions.
3.3 Physical and Mechanical Interaction
Wettability
The physical and mechanical aspects influenced bioadhesion are mostly studied
regarding to the wettability phenomenon and mechanical interlocking interaction.
Wettability studies usually involve the measurement of contact angles as the pri-
mary data, which indicates the degree of wetting when a solid and liquid interact.
Small contact angles (<90) correspond to high wettability, while large contact
angles (>90) correspond to low wettability. Illustration in Fig. 6 indicates contact
angles formed by sessile liquid drops on smooth solid surfaces. For < 90o the
110 S. Sunarintyas
Fig. 6 Contact angles of liquid drops on a solid surface
liquid wets the wall (e.g. water on glass), for > 90o the liquid does not wet the wall
(e.g. mercury on glass). Surfaces that have high contact angles and resist wetting
with water are referred to as hydrophobic (water hating). Conversely, surfaces with
low water contact angles are hydrophilic (water loving) (Bauer 2010).
Contact angle is dened as the angle formed by the intersection of the
liquid-solid interface and the liquid-vapor interface. A small contact angle is
observed when the liquid spreads on the surface, while a large contact angle is
observed when the liquid beads on the surface. More specically, a contact angle
less than 90 indicates that wetting of the surface is favorable, and the fluid will
spread over a large area on the surface; while contact angles greater than 90
generally means that wetting of the surface is unfavorable so the fluid will minimize
its contact with the surface and form a compact liquid droplet. When the contact
angle is 0, it is said that complete wetting occurs. In other condition, superhy-
drophobic surfaces show water contact angles greater than 150, showing almost no
contact between the liquid drop and the surface. Table 1 summarizes the rela-
tionship of contact angle to wettability (Bauer 2010). Moreover, contact angles are
not limited to the interface on a solid-liquid, but also to the liquid-liquid interface on
a solid. Ideally, the shape of a liquid droplet is determined by the surface tension of
the liquid. In a pure liquid, each molecule in the bulk is pulled equally in every
direction by neighboring liquid molecules, resulting in a net force of zero.
Table 1 Relationship of contact angle to wettability, cohesion, and adhesion (Bauer 2010)
Contact angle Wettability Adhesion strength Cohesion strength
=0 Perfect wetting Strong Weak
0 < < 90 High wettability Strong/weak Strong/weak
90 < < 180 Low wettability Weak Strong
= 180 Completely non-wetting Weak Strong
However, the molecules exposed at the surface do not have neighboring molecules
in all directions to provide a balanced net force. Instead, they are pulled inward by
the neighboring molecules creating an internal pressure. As a result, the liquid
contracts its surface area to maintain the lowest surface free (Snoeijer and Andreotti
2008).
It is known that small droplets and bubbles are spherical, which gives the
minimum surface area for a xed volume. The intermolecular force to contract the
surface is called surface tension. It is responsible for the shape of liquid droplets. In
practice, external forces such as gravity deform the droplet. Consequently, the
contact angle is determined by a combination of surface tension and external forces
(usually gravity). Theoretically, the contact angle is expected to be characteristic for
a given solid-liquid system in a specic environment (Snoeijer and Andreotti 2008).
Mechanical interlocking
Interfacial contact and chemical interactions are considered for the initial stages of
bioadhesion. Mechanical interlocking between two molecules of two contacting
surfaces will maintain the adhesive bond. In dentistry, mechanical interlocking
principle is well known in the application of resin composite lling to restore email
or dentin. Acid etch is used to create micropores on the surface of email or dentin so
that the adhesive resin composite material penetrate to the pores and create
mechanical interlocking interaction. The illustration of mechanical interlocking is in
Fig. 7. Tooth dentin contains tubulus that radiate from the pulp. The tubulus
dentinalis structures facilitate the penetration of resin monomers into the dentin and
their retention once the resin has been polymerized (Asmussen et al. 1991). It is
known that chemical effects play a role in the adhesion between a restoration and
Fig. 7 Mechanical
interlocking of resin
composite lling to dentin
112 S. Sunarintyas
dentin. However, the other dimension in this adhesive event is the permeation of the
adhesive into the collagen brillar network found in tooth dentin (Vaidyanathan and
Vaidyanathan 2009).
Physiologic interaction aspect
Bioadhesion can also take place through physiologic interaction. The example of
such interaction is brin tissue adhesive and lectins adhesive. Fibrin tissue adhesive
is based on the physiology of the blood coagulation process. Thrombin cleaves the
protein brinogen during clotting into smaller brin subunits, which then go
through end-to-end and side-to-side polymerization. Factor XIII is responsible for
the cross linking of the subunits into a stable brin clot in the presence of calcium
(Mobley et al. 2002).
Recently brin tissue adhesive has been used by ophthalmic surgeons as alter-
native to suture. It is reported that suturing is a time consuming task in ophthal-
mology and suture induced irritation and redness. Possible suture related
complications are postoperative wound infection and corneal graft rejection. To
prevent such complications, ophthalmic surgeons are switching to sutureless sur-
gery by tissue adhesives as brin glue (Panda et al. 2009). Fibrin tissue adhesive
has been used also in patients receiving total knee arthroplasty. Fibrin tissue
adhesive reduced blood loss in cementless total knee replacement, therefore reduce
the need for blood transfusion. In conclusion, it is said that brin tissue adhesive is
appropriate to enhance hemostasis and vessel sealing at the operative site in
cementless total knee replacement, in order to reduce blood loss after surgery and
the risk of complications (Sabatini et al. 2012).
Lectins are carbohydrate-binding proteins, macromolecules that are highly
specic for sugar moieties. Lectins perform recognition on the cellular and
molecular level and play numerous roles in biological recognition phenomena
involving cells, carbohydrates, and proteins. Lectins also mediate attachment and
binding of bacteria and viruses to their intended targets. Lectins have the ability to
bind specically to glycosylated cell membrane components. Lectins are being
investigated for their ability to transport macromolecules with implication for drug
delivery to the gastrointestinal tract (Lehr 2000).
4 Bioadhesion Testing
4.1 Surface Roughness Measurement
Finishing and polishing procedures may result in differences of surface roughness

of biomaterials, thus possibly affecting the formation and adhesion of protein
adsorbed (Eick et al. 2004). The overall effect of surface roughness is not clear.
Some reports suggest that the amount of protein adsorbed is not or very moderately
affected by the surface roughness without conformational changes of protein (Cai
et al. 2006); while other reports reveal high augmentation of the proteins adsorbed
and abrupt changes in their conformation upon adsorption (Han et al. 2003). It was
stated also that proteins with dimensions in the same order as the surface roughness
are not conformationally altered by the surface, and proteins with dimensions much
smaller or much larger change upon adsorption (Galli et al. 2002). However,
Fournier (1999) found no linear relationship between the surface roughness and
protein adsorption.
Surface roughness, also known as surface prole Ra, is a measurement of surface
nish. It is topography at a scale that might be considered texture on the surface.
Surface roughness is a quantitative calculation of the relative roughness of a linear
prole or area, expressed as a single numeric parameter (Ra). In three-dimensional
optical prolometry, roughness is usually expressed as surface area roughness (Sa).
Prole roughness (Ra) can be extracted as a line through an area. Interestingly, Sa is
also able to report average Ra through a surface by averaging several proles. In
summary, proling techniques tend to be more accurate, area techniques tend to be
fast (Vanburger and Raja 1990).
Optical prolometer and stylus prolometer are suitable for measuring most
surface roughness applications. Atomic force microscopes (AFM) and electron
scanning microscopes (SEM, TEM) have higher resolution and are typically used
for asperity measurements, but can be destructive of the surface, depending on the
materials. Recently, it is reported that a technique for the measurement of roughness
using ber-optics has been developed (North and Agarwal 2009). Another new
method of surface roughness measurement using microcomputer-based vision
system has been reported (Luk 1989). The computer is used to analyze the pattern
of scattered light from the surface to derive a roughness parameter. The parameters
are obtained for a number of tool-steel samples which are ground to different
roughnesses. A correlation curve is established by plotting the roughness parame-
ters against the corresponding average surface roughness readings obtained from a
stylus instrument. Similar correlation curves are produced for different materials
such as brass and copper.
4.2 Contact Angle Measurement
Contact angle value is an important parameter to predict the wettability properties

of the materials. The wettability properties of the surface are an important parameter
to predict the capability of microbial adsorption and colonization on the biomaterial
surface in biologic environment. Previous studies reported that protein was
adsorbed on high (hydrophobic) and low (hydrophilic) energy surface during the
biolm pellicle formation. However, pellicle on low-energy surface (hydrophobic)
was thicker and more loosely bound. Moreover, the surface area of plaque accu-
mulation is less on low-energy (hydrophobic) surface than on high-energy (hy-
drophilic) surfaces (Andrade et al. 1992; Katsikogianni et al. 2008; Mikhail et al.
2013).
114 S. Sunarintyas
There are various techniques used to measure contact angles. The techniques
include the telescope-goniometer method, the Wilhelmy balance method, and the
modern developed drop shape method. Most of the techniques can be classied into
two main groups: the direct optical method and the indirect force method. Notably,
studies of small droplets on solid surfaces allow wetting theories to be tested to the
nanometer scale, bringing new insight to contact angle phenomena and wetting
behaviour.
The most widely used contact angle measurement method is the conventional
telescope-goniometer method. The measurement is based on direct measurement of
the tangent angle at three-phase contact point on a sessile drop prole (Yuan and Lee
2013). Over the years, modications of the equipment have been made to improve the
accuracy and precision. A camera can be integrated to take picture of the drop prole
so as to measure the contact angle (Smithwich 1988). The use of high magnications
enables a detailed evaluation of the intersection prole (Kwok et al. 1996).
The advantageous of direct optical method is on its simplicity. It is only used
small amounts of liquid and small surface substrates in the measurement. On the
other hand, there is a relatively higher risk of impurities due to the small size of the
liquid and substrate. As for accuracy and reproducibility, the measurement relies on
the consistency of the operator in the assignment of the tangent line, which can lead
to signicant error and inconsistency between multiple users. The limitation of
direct goniometer method is the measurement of small contact angles (below 20)
cannot be accurately measured due to the uncertainty of assigning a tangent line
when the droplet prole is almost flat. Moreover, the imaging device only focuses
on the largest meridian section of the sessile drop, which means the prole image
reflects only the contact angle at the point in which the meredian plane intersects the
three-phase line (Kwok et al. 1996). Despite all of the issues, the conventional
goniometer method is considered as the most convenient method if high accuracy is
not needed.
The Wilhelmy balance method is a widely used technique that indirectly mea-
sures contact angle on a solid sample. The Wilhelmy balance technique is an
indirect force method. It has several advantages over conventional optical methods.
First, the task of measuring an angle is reduced to the measurements of weight and
length, which can be performed with high accuracy and without subjectivity.
Second, the measured force at any given depth of immersion is already an averaged
value. Although this feature does not help determine the heterogeneity, it does
automatically give a more accurate contact angle value that reflects the property of
the entire sample. In addition, the graph produced by this technique is useful for
studying dynamic contact angles and contact angle hysteresis at different wetting
speeds (Yuan and Lee 2013).
The shape of a liquid drop ideally depends on the effects of interfacial and
gravity forces. Surface tension tends to minimize the surface area by making the
drop spherical, while gravity deforms the drop in two ways: (1) by elongating a
pendant drop and (2) flattening a sessile drop. The balance between surface tension
and external forces (gravity) is reflected in the Laplace equation, which offers the
possibility of determining surface tension by analyzing the drop shape. In this

analysis, the liquid drop is assumed to be part of a sphere. Since the work of
Bashforth and Adams used the Laplace equation to analyze the shape of droplet
proles, the task of determining surface tension became simple interpolation (Yuan
and Lee 2013). Ever since digital computers became popular, drop shape analysis
has been greatly improved, and many new methods have been developed.
Recent study on a new method based on drop prole image analysis shows that
this method is more technically practice than contact angle goniometer and has
flexibility to be implemented in clinical circumstances (Yulianto and Rinastiti
2014). The method involves placing a drop of solvent (water, buffer, nonaqueous
liquid) on substrate surface. The contact angle (very high for water if the surfaces
are hydrophobic) is determined by a series of photographs of the drop prole image.
If the surfaces are hydrophilic, the droplet quickly dissipates, disappearing into the
surfaces. The evaluation measurement uses the linier gradient equation and tan-
gential line formula. It is proved that the drop prole image analysis using the
tangential line formula is more reliable and sensitive than the linier one.
4.3 Surface Topography Evaluation
Light microscopy is a relatively simple technique that is used as the rst approach
to gain qualitative information about surface topography or to view thin sections of
a sample. Images can be further analyzed using specialized software to obtain semi
quantitative measures of certain colors (Temenoff and Mikos 2008).
Scanning electron microscopy (SEM) is commonly used to visualize the surface
topography of biomaterial or biomaterial with attached tissue or cells. SEM images
are produced by recording the production of secondary electrons after an area is
bombarded with the primary electron beam. Since the intensity of these electrons is
dependent on the surface topography of the sample, SEM is considered a surface
imaging technique (Temenoff and Mikos 2008).
Atomic force microscopy (AFM) can be utilized to image biomaterial surfaces as
well as those including adsorbed proteins. This technique produces a three
dimensional image. The analytical capabilities of AFM are limited to the uppermost
atomic layer of a sample because its operation is based on interactions with the
electron clouds of atoms at the surface (Temenoff and Mikos 2008).
4.4 Biolm Formation Testing
Biolm are formed on any solid surfaces exposed to a biological environment. It is

known that the initial bioadhesion depends on the surface characteristics, type of
protein, and fluid interface (Hannig and Hannig 2009). These factors affect the
nonspecic protein adsorption by different forces such as electrostatics and van der
116 S. Sunarintyas
Waals forces, hydrophobic interaction, and conformational rearrangements (Xu

et al. 2005; Noh and Voghler 2006). Several researchers investigated the protein
adsorption on surfaces as a function of different parameters: interactions between
protein and surface (Xu and Siedlecki 2007), pH, contact time, and wettability (Lee
and Park 1994). A variety of techniques have been used to investigate the properties
of protein adsorption such as ellipsometry (Watanabe et al. 1986), labelling with
fluorescence markers and time-of-flight secondary ion mass spectrometry
(ToF-SIMS) (Bersmann et al. 2008), scanning force microscopy (SFM) (Muller
et al. 2010).
Regarding to the bacterial adhesion on biomaterials, there are several techniques
used to evaluate such bioadhesion. It should be emphasised, that the in vitro
evaluation simplies measurements might be misleading, as the whole system is
complex and dynamic. In vivo, the substrate is under a dynamic state, the surface
may change composition with time and biological fluid flow may interact with the
surface. Moreover, an incoming bacterium may just attach to the surface (re-
versibly) or adhere rmly (irreversibly) or release a number of substances or present
a number of adhesive receptors whose specicity, activity and numbers may be a
function of time (Katsikogianni and Missirlis 2004).
The disadvantage of static evaluation is that it is a qualitative or
semi-quantitative test and it registers overall number of bacteria with varying
degree of attachment. The following statements describe the evaluation of static
state. First, it is prepared surface overlaid with a suspension of cells for a deter-
mined period of time. The non-adherent cells are removed by rinsing and the
remaining cells on the surface are counted or examine morphologically by light
microscopy or image analysed epifluorescence microscopy, SEM, scanning con-
focal laser microscopy, or atomic force microscopy. For viable bacterial counting
methods, it can be use: CFU (colony forming unit) plate counting, radiolabelling,
CTC (tetrazolium salt 5-cyano-2,3-ditoly1tetrazolium chloride) staining,
spechtrophotometry, coulter counter, or biological markers of ATP (adenosine
triphosphate) (Katsikogianni and Missirlis 2004).
The dynamic evaluation includes: parallel plate flow chamber, parallel-plate flow
chambers, rotating disc, atomic force microscopy, Interaction Forces. The
parallel-plate flow conguration is very common. It is simple to construct and the
general flow within the chamber can be mathematically analysed easily. The most
commonly used variation a pump provides a steady-state flow. The fluid enters
from one side and leaves from the opposite side in a rectangular chamber. The
upper plate is usually a glass coverslip while the bottom is the prepared surface
(transparent) on which the cells have been left to settle for a predetermined time.
The fluid movement creates a shear stress at the wall, which is calculated from
equation (Bruinsma et al. 2001).
Another technique is radial flow chamber (RFC). RFC consists of two flat disks
separated by a thin gap (200 m). The fluid dynamics in the RFC has been well
characterized. Dynamic flow patterns can be imposed, including pulsatile or
reversible steady-state flows. For example angular acceleration of a parallel disk
impart high shear stress transients to attached bacteria (Dickinson and Cooper
1995). Other fluid shear systems have been used is the rotating disc in liquid
(DeJong et al. 2002). In all these systems the major concern is that the measured
adhesion strength of bacteria to substrates is global for bacteria population.
The Atomic Force Microscope has proved useful in imaging the morphology of
individual microbial cells and bacterial biolm on solid surfaces, both in dried and
hydrated states (Robichon et al. 1999). It is being used increasingly for mapping
interaction forces at microbial surfaces (Alfonso and Goldmann 2003; Dufrene
2003). The major advantage of the AFM over other microscopical techniques is that
it can simultaneously provide information on local surface properties and interac-
tion forces.
5 Bioadhesion of Medical Devices
5.1 Polymers
Polymer materials play an important role in diagnostic and therapeutic procedures

of modern medicine. Their use as medical devices has rapidly increased. This has
led to medical progress for the benet of many patients. However, the price to be
paid is the occurance of complications producing new clinical syndromes. Infection
is one of the most frequent and important complications associated with the use of
polymer foreign bodies. Foreign body associated infections are nowadays clinical
routine phenomena, although they may have severe consequences for the individual
patient involved.
Phsysicochemical point of view describes bacterial adhesion to polymers can be
regarded as the adhesion of colloidal particles to a solid surface in a liquid environ-
ment. Besides the hydrodinamic conditions which regulate the transport of the particle
to the surface, the bioadhesion is governed by attractive physical interaction including
electrostatic, van der Waals interaction, dipole-dipole and hydrophobic interaction
(Rutter and Vincent 1980). If only electrostatic and van der Waals interactions are
considered, the DLVO (Derjaguin-Landau-Vervey-Overbeek) theory of lyophobic
colloid stabilization can be applied to bacterial adhesion (Jansen et al. 1988). For
in vivo situations, the DLVO model is not suitable due to other interactions which may
occur. Another phsycochemical model for describing bioadhesion mechanism is based
upon thermodynamical consideration (Absolom et al. 1982). Again, this approach can
only be applied for in vitro situation.
Specic interactions have been shown to mediate bioadhesion between bacteria
and natural substrate: adhesion of Streptococcus mutans to enamel (Sugarman and
Young 1984), Eschericia coli to uroephitelial cell (Eden et al. 1977). Although not
clearly demonstrated for bacterial adhesion to synthetic polymer, it is highly pos-
sible that specic interactions play an important role as well.
It is well known that polymers are rapidly coated with proteins or other sub-
stances when they are exposed to body fluids (blood, tissue liquid) (Bantjes 1978).
118 S. Sunarintyas
Bacteria can also become coated by substances from body fluids and undergo
changes of their surface properties (Mirner et al. 1980). A number of studies have
been done on the influence of adsorbed molecules on the adhesion using serum,
plasma, and singular proteins (Fleer and Verhoef 1986). It was found that almost in
all studies the presence of serum or plasma leads to a strong decrease in bacterial
adhesion. Coating polymer with various proteins like albumin, globulin or others
leads to a decrease in adhesion. It was assumed that the decreased adhesion is
caused by a change in surface properties from more hydrophobic to more hydro-
philic. If the polymers are preincubated 1 h with plasma, albumin, or brinogen,
and adhesion is performed later on in PBS (phosphate-buffered saline), in case of
Staphylococcus epidermidis KH 6 there is an inhibition observed; while in the case
of Staphylococcus epidermidis KH 11 only precoating with albumin leads to a
considerable reduction of adhesion, whereas on brinogen or plasma coated
polyurethane an increase in adhesion is noticed. This result suggests specic
interactions between Staphylococcus epidermidis KH 11 and receptor like structures
on the adsorbed brinogen molecule (Jansen et al. 1988). The increase in adhesion
of Staphylococcus epidermidis KH 11 on polyurethane preincubated 1 h in plasma
might also be due to interactions with brinogen. It was known that the major
protein adsorbed after 1 h from plasma like synthetic protein solution (Jansen and
Ellinghorst 1984). This nding is very useful since there is a close relationship
between thrombus formation and infection of polymeric devices, especially in
vascular prostheses and intravenous catheters.
Bacterial adhesion to polymer medical devices is the rst important step in the
pathogenesis of a foreign body infection. Although the mechanism of bacterial
bioadhesion to polymers are not fully clear, the development of antiadhesive and
also antiinfectious polymers seem to be the most reasonable approach for the
prevention of foreign body infection (Sutula et al. 2012).
Research of desirable bioadhesion on PLLA (poly-L-lactide) scaffold shows that
PLLA based scaffold demonstrates less cell interaction capability compares to
immobilized sericin protein coated on PLLA. PLLA is a hydrophobic polymer due
to the present of an extra methyl group in lactic acid. Sericin contains a large
amount of amino acids with polar functional groups. The strongly polar groups of
sericin influences the scaffold surface more wettable as indicated by the decreases
of contact angles (Yustisia et al. 2012). By improving the biomaterials surface
hydrophilicity, sericin facilitates the attachment and proliferation of cells, therefore
leads to new tissue formation (Sunarintyas et al. 2011; Sunarintyas and
Siswomihardjo 2011).
5.2 Metals
Surface roughness becomes one of the major research in orthopedic with the goal of
improving the performance of bone implants (Balasundaram et al. 2006).
Specically, compared with smooth surfaces, micron surface roughness (from 1 to
100 m surface features) on titanium substrates created by sandblasting, etching,

machining and the use of micron-sized metal bead coatings has enhanced osteoblast
functions such as adhesion, proliferation, production of alkaline phosphatase, and
deposition of calcium-containing mineral. Other strategies for improving the bio-
compatibility and osteogenic capacity of metal implants include surface modica-
tion with inorganic mineral coatings, particulates, or cements containing a diversity
of calcium salts. The idea of these strategies is to make the metal surface more
acceptable to bone cells so that enhances the body into rapid integration of the
implanted structure rather than brous encapsulation. Recent studies have provided
information that nanometer crystalline hydroxyapatite (HA) and amorphous cal-
cium phosphate compacts could be chemically functionalized with the arginine
glycineaspartic acid (RGD) peptide sequence using the aforementioned maleimide
chemistry. Results showed that the immobilization of the cell adhesive RGD
sequence increased osteoblast adhesion compared to those non-functionalized and
those functionalized with the non-cell adhesive control peptide. In this work various
modied titanium surfaces were subjected to cell viability studies to measure their
cell adhesion properties (Deligianni et al. 2001; Bacakova 2004).
Regarding to metal or alloy implant desirable bioadhesion in the body, it is
reported that the efcacy of bone regeneration is determined by surface charac-
teristics such as the chemical composition and physical properties of the implant
that controls initial protein adsorption (Balasundaram and Webster 2006). These
properties influence the adsorption of proteins which mediate the adhesion of
desirable (osteoblast) and undesirable (broblast) cells. It is believed that the lack of
attention paid to understanding cellular recognition to proteins initially adsorbed on
biomaterial surfaces to date could be one of the key reasons why current implant do
not last longer than 15 years. The understanding of common families of protein
adhesion is important. The majority of adhesion molecules can be grouped into:
cadherin, immunoglobulin superfamily (IgSF), integrins cell adhesion molecules of
focal adhesion contacts, and selectins (Baker and Greenham 1988).
The characteristic feature of the classic cadherins is their ability to mediate Ca2+
dependent homophilic adhesion with specicity being generated by sequence dif-
ferences at the adhesive face of the N-terminal domain. Unlike the cadherins, which
essentially mediate homophilic interactions via the antiparallel binding of the
N-terminal cadherin repeats with the equivalent domain on neighbouring cells, the
IgSF members show a broad range of ligand interactions. Integrins are so called
integrins cell adhesion molecules of focal adhesion contacts because they integrate
the extracellular matrix with the intracellular cytoskeleton and hence deliver
outside-in signals from the external environment to the cell to modify cellular
structure and functions: cell adhesion, motility, proliferation, apoptosis, induction
of gene transcription and differentiation. The three selectins, E-selectin (CD62E),
L-selectin (CD62L) and Pselectin (CD62P), are related both structurally and
functionally. They have been extensively studied due to their role in the inflam-
matory response and their potential use as therapeutic targets (Baker and Greenham
1988).
120 S. Sunarintyas
Previous studies indicate that surface roughness influences bacteria adhesion

(Kendall 2004; Quirynen et al. 1993). The cause for this phenomenon may include
a rough surface has a geater surface area and the depressions in the roughed surface
provide more favorauble for bacteria colonization. However, anothe study shows
that commercially pure titanium (cp Ti) surface roughness produces by 1201200
grit sandpaper polishing shows no effect on number of adhered Staphylococcus
epidermidis (An et al. 1995). Such two contrary results need further researches and
analysis regarding to surface area measurement and evaluation of surface cong-
uration. Further evaluation is necessary as there are various clinical different
prostheses or implant devices which have different surface roughnesses which may
play a role in bacterial adhesion and implant infection.
5.3 Ceramics
Biolms are believed to be formed on all surfaces exposed to the natural envi-
ronment. Although, initially the biolm formation on biomaterial surfaces in the
mouth could appear harmless, its consequences may be much more harmful and
severe. Increased amount of plaque on the rough surfaces of ceramics restoration in
the mouth will exert not only caries-causing virulence, but also a harmful influence
on periodontal tissue. For a full coverage crown or a bridge, caries incidence risk
would be slight, but instead much attention has to be given to the gingival tissues.
Previous research (Kawai et al. 2000) reported that more plaque was adhered over
glazed surfaces of ceramics as compared with their polished surfaces. This means
that a glazed surface would not be clinically acceptable from a biologic point of
view. Glazing can produce an undulating and rough surface that has irregularities,
inducing more adhesion of bacteria and other substances. Another research also
concluded that glazed surfaces are rougher as compared to the polished surfaces
(Rashid 2012). Although polished surfaces have been reported to have voids and
micro cracks on the subsurface of porcelain, these supercial defects did not
contribute to the amount of plaque adhesion (Patterson et al. 1992).
An in vitro study proved that the number of Staphylococcus epidermidis increased
in the rst 812 h after bioceramic implantation. The addition of 20 % zirconia to
hydroxyapatite proved to have been an effective concentration in inhibiting the
growth of Staphylococcus epidermidis. Scanning electron microscopy examination
showed that zirconia lled in the hydroyapatite pores, whereas the less pores the less
number of Staphylococcus epidermidis attached (Siswomihardjo et al. 2012).
5.4 Composites
Study on plaque accumulation on various dental biomaterials showed that poly-

ethylene ber reinforced composite (FRC) as the roughest material promoted
plaque accumulation signicantly more than the other smoother materials. Ceramic,
having the smoothest surface showed a trend towards less plaque accumulation,
although the difference was signicant only in comparison with polyethylene FRC.
Glass FRC and restorative bis-GMA (bisphenol-A-glicydyl methacrylate) com-
posite resin showed very similar plaque accumulation properties. These materials
resemble each other also in their surface physico-chemical properties. They are both
composite materials composed of inorganic ller particles in an organic polymer
matrix. In the case of glass FRC, glass bres are the inorganic llers. Polymer
matrices of both composites are commonly based on dimethacrylate monomer
systems. Their surface roughness values after polishing are also very similar and
signicantly lower than the roughness of polyethylene FRC (Tanner et al. 2003;
Mikhail et al. 2013).
In the oral environment, surface roughness seems to be a governing factor over
the influence of surface-free energy determining the amount of plaque accumulation
on dental materials (Quirynen and Bollern 1995). Study on early plaque formation
on dental composite and ceramic in vivo showed there was least growth of mutans
streptococci in plaque recovered from ceramic restoration. Seven of the 12 subjects
with mutans streptococci in their plaque had no growth of mutans streptococci on
the ceramic samples, whereas all 12 subjects showed colonisation of mutans
streptococci on polyethylene (Tanner et al. 2005). It was noted that dental biolm
unsatised the patients as decreasing aesthetic appearance and odor. Dental plaque
is a biolm consisting of more than 500 bacterial strains (Coulthwaite and Veran
2011). Further research is needed concerning more detail about dental plaque
bioadhesion in various biomaterials for medical devices.
6 Perspective
The implantation of medical devices is not without risks. Bacterial or fungal

infections can occur and the bodys strong immune response may lead to the
rejection of the implanted medical devices. Implantable medical devices are an ideal
interface for micro-organisms, which can easily colonize their surface. As such,
bacterial infection may occur and lead to an inflammatory reaction. This may cause
the implant to be rejected. These infections are mainly caused by bacteria such as
Staphylococcus aureus, originating in the body, and Pseudomonas aeruginosa.
These infections may also be fungal or caused by yeasts. The challenge presented
by implanting medical devices in the body is preventing the occurrence of these
infections, which lead to an immune response that compromises the success of the
implant. Antibiotics are currently used during surgery or to coat certain implants.
However, the emergence of multi-resistant bacteria now restricts their effectiveness.
Acknowledgment Mrs. Gusnaniar (BME, UGM), Mr. Dedy Kusuma (Dentistry, UGM) and Mr.
Bonifasius Primario (Dentistry, UGM) are acknowledged for their kind help in preparing the
pictures and literatures for this manuscript.
122 S. Sunarintyas
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Degradable Biomaterials for Temporary
Medical Implants
Ahmad Kafrawi Nasution and Hendra Hermawan
Abstract Degradable biomaterials bring possibilities to fabricate medical implants

that function for a determined period related to clinical events such as healing. They
can be made on the basis of polymers, ceramics and metals. These metals, which
are expected to corrode gradually in vivo with an appropriate host response and
then dissolve completely upon fullling the mission to assist with tissue healing, are
known as biodegradable metals. They constitute a novel class of bioactive bio-
materials which supports the healing process of temporary clinical problems. Three
classes of metals have been explored: magnesium-, zinc- and iron-based alloys.
Three targeted applications are envisaged: orthopaedic, cardiovascular and pediatric
implants. Three levels of investigations have been conducted: in vitro, in vivo and
clinical trials. Discussion on standardization has been initiated since 2013 with
representatives from ISO, DIN and ASTM and drafts of comprehensive standards
are now under preparation. The eld of biodegradable metals is exciting and
witnessing more development in the future including new advanced alloys and new
real breakthrough that leads to its clinical translation. This chapter starts with a
discussion on biodegradable polymers to gain important lessons learned for
advancing the research in biodegradable metals, the new emerging research interest
in the forefront of biomaterials loaded with full of great expectations.
Keywords Biodegradable Biomaterials Corrosion Metals Polymers
A.K. Nasution
Muhammadiyah University of Riau, Pekanbaru, Indonesia
e-mail: ahmad.kafrawi@umri.ac.id
H. Hermawan (&)

128 A.K. Nasution and H. Hermawan
1 Introduction
Biomaterials have been widely used to make implants or devices to replace a part or
a function of the body in a reliable, safe, physiologically acceptable and economic
manner (Park and Lakes 2007). Examples of such implants are articial heart
valves, coronary artery stents, total hip replacement, bone plate and screw, and
dental implants (Geetha et al. 2009). Biomaterials can be dened as natural or
synthetic materials engineered to interact with biological systems that are used for
medical treatment (Ulery et al. 2011). The development of the rst medical device
is based on the principles of medical and scientic acceptable for human use in the
late 1940s and early 1950s (Ratner et al. 2013). The diversity of biomaterials in
used today is the result of great advancement in materials technology since nearly
40 years ago (Hoffman 1996). Basically, as detailed in Table 1, they can be clas-
sied as metals, ceramics, polymers and their composites with 7080 % of implants
were made of metals (Niinomi et al. 2012).
The development of biomaterials is made possible thanks to strong interdisci-
plinary collaboration among clinicians, engineers, chemists, physicists and biolo-
gists as the key players (Ratner et al. 2013). Advanced biomaterials development
requires the input of knowledge from diverse areas with the ultimate goal to achieve
the true biological interaction between the materials and the human body
(Vallet-Reg 2010; Ulery et al. 2011). This chapter starts with an overview on the
currently used biomaterials then focuses further review on biodegradable polymers.
The main objective is to gain some lessons from the currently used biomaterials,
especially biodegradable polymers, for advancing the research in biodegradable
metals, the new emerging research interest in the forefront of biomaterials loaded
with full of great expectations.
Table 1 Biomaterials commonly used for biomedical applications

Materials Applications Advantages Disadvantages
Metals: stainless steel, Load bearing implants, joint Though, Non bioactive
Co-Cr alloys, Ti alloys, replacement, cardiovascular strong,
Mg alloys, etc. stents, dental implants, etc. ductile
Ceramics: alumina, Orthopaedic and dental implants Bioactive, Brittle, not
bioglass, calcium inert resilient
phosphate, zirconia, etc.
Polymers: polyethylene, Blood vessel grafts, hip sockets, Bioactive, Lack of strength
polyesters, nylon, sutures, etc. resilient for load bearing
polylactide, etc. implants
Composites: amalgam, Dental lling, resin bone cement, Tailor Relatively
ber-reinforced bone etc. made difcult to make
cement, etc.
Degradable Biomaterials for Temporary Medical Implants 129
2 Overview on Currently Used Biomaterials
Hundreds of type of metals for implants have been clinically used, but in general
they can be grouped into: (1) stainless steel alloys; (2) Co-Cr alloys; (3) Ti and its
alloys; and (4) precious alloys. These metallic biomaterials are always attractive due
to their nature in offering structural function and inertness, the two key features that
most implants need. However, as the medical science progresses and the demand
for better implants increases, nowadays it is desirable that an implant also possesses
bioactivities or biofunctionalities like blood compatibility and bone conductivity.
Therefore, the surface of metals are often modied, for examples: in order to
provide bone conductivity metal surface has been coated with hydroxyapatite
(Habibovic et al. 2002), or with poly(ethylene terephthalate) to improve blood
compatibility (Lahann et al. 1999). Today, development on metallic biomaterials
includes those composed of nontoxic and allergy-free elements such as Ni-free
stainless steel (Yang and Ren 2010) and biodegradable metals which are targeted
for temporary implants (Hermawan and Mantovani 2009).
One important lesson we can learn from inert metallic biomaterials is their high
strength and ductility. Mechanical properties of 316L stainless steel are often
viewed as the standard reference in developing new metallic biomaterials. This also
applies to biodegradable metals to ensure that the mechanical function of a specic
implant, such as coronary stent, remains the same despite its material is changed
from 316L stainless steel to biodegradable iron (Fe) or magnesium (Mg) alloys.
Although designed to be corrosion resistant, aggressive physiological environment,
that is not only corrosive but also introduces mechanical loading (static and
dynamic), contributes to metallic implant failures such as wear. High concentrations
of chloride and temperature of the human body have also found to induce localized
corrosion such as pitting, crevice and fretting (Tavares et al. 2010). Figure 1 shows
example of metal implant failure due to corrosion and wear.
Polymeric biomaterials offer main advantage over metals and ceramics in their
ease of manufacturability to form various shapes. Basically, these biomaterials can
be divided into: (1) inert polymers such as poly(methyl methacrylate), poly(amide)
or nylon, poly(ethylene), etc.; and (2) absorbable polymers such as poly(glycolic
acid) and poly(lactic acid), etc. Beside employed in their bulk, they are often made
into thin layer or coating onto metal surfaces with tailored mechanical and physical
properties. The recent development exploits absorbable polymers for use as drug
delivery carriers loaded with a specic drug in the form of coating, for example
drug eluting stents (Jenkins 2007).
Ceramics biomaterials provide inertness, high compressive strength and aes-
thetic appearance. They can be classied into: (1) inert bioceramics such as zir-
conia, alumina, aluminum nitrides and carbon; (2) bioactive ceramics such as
hydroxyapatite, bioglass, etc.; (3) biodegradable/resorbable ceramics such as cal-
cium aluminates, calcium phosphates, etc. The inherent surface qualities of
ceramics have been exploited to make implants such as dental crowns. The high
specic strength and blood compatibility of carbon makes carbon often used for
Fig. 1 Example of a component of a retrieved total hip implant revised due to adverse local tissue
reaction: a modular implants typically provide in large crevice geometries with differential aeration
that will be subjected to micromotion during loading and results result in abrasion and trigger a
series of reactions in the crevice that will lead to events such as cracks, pitting and cracks,
b corrosion at the modular neck junction, c corrosion debris (black deposits) is shown in the
stem-sleeve mating interface. Adapted from Rodrigues (2014) and Tischler and Austin (2014)
heart valves leaflets. Many bioceramics have been also applied as coating onto
metal surfaces including diamond like carbon, nitrides, bioglasses and hydroxya-
patites (Kokubo 2008).
Composite biomaterials can be made with metals, polymers or ceramics as their
matrix, and reinforced with one of these materials. Composites allow a control over
material properties whereas a combination of stiff, strong, resilient but lightweight
can be achieved all together. Bone is a composite of the low elastic modulus
organic matrix reinforced with the high elastic modulus mineral bers permeated
with pores lled with liquids. Other examples include orthopaedic implants with
porous structures, dental ller, and bone cement composed of reinforced poly
(methyl methacrylate) and ultra-high molecular weight poly(ethylene) (Ambrosio
2009).
3 Biodegradable Polymers
The current trend shows a shift in the use of the permanent prosthetic devices for
temporary therapeutic applications to biodegradable devices that can help the body
to repair and regenerate damaged tissue (Nair and Laurencin 2007). Basically, the
concept of biodegradable devices is providing a temporary support during the
healing process of diseased tissue and degrading away thereafter, progressively.
Precisely, temporary clinical problems need temporary intervention (i.e. temporary
presence of implants) and this can be provided by degradable biomaterials (Li et al.
2014). Temporary support is only obtained by using implants made from degrad-
able biomaterial (either biodegradable polymers or biodegradable metals) that
allows implant to relegate biologically after fullling its function (Barrows 1986;
Hermawan 2012). Examples of clinical problems that need temporary support for
healing are narrowed arteries, fractured bones and congenital cardiovascular defects
(Hermawan and Mantovani 2009). Some important properties that must be con-
sidered in the design of biodegradable biomaterials are summarized in Fig. 2.
Polymeric biomaterials has a long history of applications starting from catheters,
syringes, blood contacting extra corporeal devices till matrices for drug delivery,
cell encapsulation and tissue regeneration (Shastri 2003). Non-degradable polymers
such as nylon, poly(methylmethacrylate), poly(ester) and poly(vinyl chloride)
began to be used in the medical eldin the mid-1940s and remain important for
numbers of medical equipment till now (Grifth 2000; Hacker and Mikos 2011).
They are used as a component for permanent prosthetic devices including hip
implants, articial lenses, large diameter vascular grafts and catheters. Meanwhile,
degradable polymers adopted for surgery since 40 years ago as a surgical suture
material and bone xation devices (Kulkarni et al. 1971). In the last two decades
there has been a development of new generations of synthetic biodegradable
polymers and natural polymers specically developed for biomedical applications.
Fig. 2 Important properties

to be considered in the design
of degradable biomaterials.
Adapted from Lloyd (2002)
3.1 Natural Biodegradable Polymers
Natural polymers are formed in nature ranging from the growth cycle of all
organisms (Chandra and Rustgi 1998). They can be considered as the rst
biodegradable biomaterials used clinically. In the view of regenerative medicine,
natural polymers offer advantages similar to biological macro-molecules (such as
tissue) and its biological environment (Mano et al. 2007). Other inherent advan-
tages include bioactivity, the ability to receptor-binding ligands to cells, suscepti-
bility to cell-triggered proteolytic degradation and natural remodeling. While the
weakness of natural polymers including immunogenic response and the possibility
of disease transmission (Puppi et al. 2010).
Most natural polymers undergo enzymatic degradation and least undergoes
hydrolytic degradation. The enzymatic degradation at in vivo level varies
depending on the site of implantation, the availability and concentration of enzyme
(Nair and Laurencin 2007). Hydrolytically biodegradable polymers are polymers
that have a hydrolytically labile chemical bond that influences the level of degra-
dation and erosion mechanism (Grifth 2000; Ulery et al. 2011). When the rate of
degradation at the interface of water-degradable devices on the entire surface is
faster than the diffusion depth of the water, then this indicates surface erosion.
Conversely, if the water diffusion is faster than the degradation over the entire
surface and mass loss occurred throughout the bulk of the material, this is called as
bulk erosion. These categorizations are extremely important in determining which
material is best for a desired application, for example in drug delivery. Two most
important natural polymers used in biomedical eld are protein or poly(amino acid),
and poly(saccharide).
Proteins are polymers with amino acid monomers joined by amide bond and are
very common material in the human body. Included into proteins are collagen, poly
(amino acid), elastin and elastin-like poly(peptide), albumin and brin. Collagen is
a protein with signicant amounts in human body and is the main component of the
ligament, cartilage, tendon, skin and bone (Ulery et al. 2011). Collagen has been
studied for medical applications due to its biocompatibility, mechanical strength
and enzymatic degradability (collagenases and metalloproteinases) (Krane 2008).
Collagen has a good process-ability with high solubility in acidic solution to be
used as collagen sponges, tubes, sheets, powders and injectable (Matsuno et al.
2006; Bushnell et al. 2008; Choi et al. 2009; Liu et al. 2010). The majority of these
studies focused on the potential use of collagen as a biomaterial for a tissue
engineering scaffold, specically in load bearing applications. Collagen was also
used as composite materials (hydroxyapatite and collagen) with composition clo-
sely resemble to that of bone (Venugopal et al. 2008).
Natural poly(amino acid) is a biodegradable ionic polymers occurs naturally in
three different type: poly(L-lysine), poly(-glutamic acid), and cyanophycin
(Obst and Steinbchel 2004). This polymer has characteristic such as biocompat-
ibility and complete biodegradability that make this material as an ideal candidate
for applications in human. Poly(l-lysine) is known to have anti-bacterial, anti-viral
and anti-tumour activity and is considered to be a potential candidate for developing
drug carrier vehicles (Nair and Laurencin 2007). Poly(-glutamic acid) is capable to
degrade with the presence of water and developed as drug delivery vehicles, tissue
engineering scaffolds and thermo-sensitive polymers (Kishida et al. 1998).
Cyanophycin, is a comb-like polypeptide isolated from cyanobacteria that contains
-amino--carboxy-linked L-aspartic acid residues representing the poly(-
L-aspartic acid) backbone and L-arginine residues bound to the -carboxylic groups
of aspartic acids making it a highly poly-disperse polymer (Simon 1971). Synthetic
poly(amino acid) is also studied and showed high crystallinity, low degradation rate
and unfavorable mechanical properties (Ulery et al. 2011). Two synthetic bioma-
terials derived from poly(amino acids) are poly(L-glutamic acid) with high sus-
ceptibility to degradation by lysosomal enzymes and poly(aspartic acid) that is very
soluble in water and easily converted to a hydrogel by high energy radiation (Li
2002; Pitarresi et al. 2007).
Elastin is the major protein component of blood vessels and lung tissue (Ulery
et al. 2011). In vivo studies showed elastin has little interaction with platelets and
have limitations on the ability to obtain an immune response (Mithieux et al. 2004).
With this limitation, a synthetic elastin, elastin-like poly(peptide), was developed.
This articial poly(peptide), although very flexible as elastin, has characteristic that
are biocompatible and non-immunogenic (Ulery et al. 2011). It was studied as
delivery vehicles for chemotherapeutics (Bidwell III et al. 2007), antibiotics
(Adams et al. 2009) and proteins (Bessa et al. 2010), beside for the soft tissues
engineering due to its suitable elastic behavior (Nettles et al. 2010).
Albumin is a blood protein that is soluble in water and exists nearly 50 % of the
total mass of the plasma in the body. Albumin has a function as a carrier of
hydrophobic fatty acids around the blood stream and maintain blood pH (Ulery et al.
2011). The solubility of albumin allowed to be processed into various forms such as
bers (Regev et al. 2010), microparticles (Okoroukwu et al. 2010) and nanoparticles
(Shen et al. 2011). Albumin also has been studied as a carrier vehicle for intravenous
drug/gene delivery (Chuang et al. 2002) and as coating materials for cardiovascular
devices (Uchida et al. 2005).
Fibrin is a biopolymer that is similar to collagen and it is the initial biopolymer
used as biomaterials. It is characterized by its excellent biocompatibility,
biodegradability and inject-ability (Ulery et al. 2011). Fibrin degraded to brinol-
ysis in the human body in the presence of a complex cascade of enzymes (Erin and
Robert 2005). The rst product resulting from brin is brin sealant used clinically
for hemostasis and tissue sealing applications in various surgical procedures (Nair
and Laurencin 2007).
Poly(saccharide) are macromolecules formed from many monosaccharide units
joined together by glycosidic linkages (Ulery et al. 2011). By having good char-
acteristic such as biodegradability, process-ability and bioactivity, poly(saccharide)
are very promising natural biomaterials. Poly(saccharide) are divided into
polysaccharides of human and non-human origins. Hyaluronic acid and chondroitin
sulfate are biopolymers belongs to the poly(saccharide) of human origin.
Hyaluronic acid is a linear poly(saccharide), water-soluble and forms highly vis-
cous solutions with unique viscoelastic properties (Nair and Laurencin 2007). It has
an important role in various tissues including articular cartilage, the nucleus pul-
posus, skin, the cervis, and the glycocalyx of endothelial cells (Nair and Laurencin
2007). Half of the total content of hyaluronic acid in the human body is found in the
skin, while other sources for its isolation are rooster combs and bovine vitreous
humor (Ulery et al. 2011). Hyaluronic acid can undergo degradation within the
body by free radicals (Rapta et al. 2009), also via digestion by lysosomal enzymes
to form mono and disaccharides, which can be further converted into ammonia,
carbon dioxide and water via the Krebs cycle (Al-Assaf et al. 2003). Hyaluronic
acid plays an important role in tissue repair and drug delivery applications and is
very promising for numbers of regenerative therapies especially in soft tissue
engineering (Ulery et al. 2011). Chondrotin sulfate is the major component of
aggrecan, the most abundant glycosaminoglycan found in the proteoglycans of
articular cartilage (Nair and Laurencin 2007). It can stimulate the metabolic
response of cartilage tissue and has anti-inflammatory properties (Chan et al. 2005).
These showed the importance of these natural polymers used in biomedical
applications (Kosir et al. 2000).
Other than poly(saccharide) molecules that exists in the human body, there are a
number of similar molecules derived from other sources (poly(saccharide) of
non-human origin) as promising degradable polymeric biomaterials (Ulery et al.
2011). Included in this class are the cationic polymer, chitosan found in crustacean
skeletons and alginate found in brown algae, both used as drug delivery vehicles.
3.2 Synthetic Biodegradable Polymers
The disadvantages of natural polymers such as immunogenic response and the

possibility of disease transmission (Puppi et al. 2010) has led to the development of
synthetic biodegradable polymers. Among the rst developed synthetic biodegrad-
able polymers are the glycolide-based polymers, poly(glycolic acid) and poly(lactic
acid), which have been used in products such as degradable sutures since 1960s and
both have received approval by the FDA (Nair and Laurencin 2007). Table 2 list
some of biodegradable polymers that found their application in biomedical eld.
Poly(lactic acid) or PLA and poly(glycolic acid) or PGA are poly(-ester) grade
polymers which are thermoplastic and have characteristic that allows them to be
degraded via hydrolytic action (Nair and Laurencin 2007). PLA is much more
hydrophobic than PGA, making the rate of degradation of PLA slower (i.e. remain
stable for more than 1 year) (Sinha et al. 2004) compared to PGA, which can be
degraded within few weeks (Nair and Laurencin 2006). PGA are used clinically as
an internal xation device due to its higher rigidity than other degradable polymers
(Tormala 1992). It has elastic modulus about 12.5 GPa (Maurus and Kaeding 2004)
and very low solubility in organic solvents (Nair and Laurencin 2007). It will lose
its strength within 12 months and loss its mass within 612 months (Nair and
Laurencin 2007) and is broken down in vivo into glycine which can be removed
through the urine (Maurus and Kaeding 2004).
PLA has chiral molecules wherein the polymerization leads to the formation of a
semi-crystalline polymer and 4 different forms: poly(L-lactic acid) or PLLA, poly
(D-lactic acid) or PDLA, poly(D, L-lactic acid) PDLLA which is a mixture of
PLLA and PDLA, and meso-poly(lactic acid). So far, only PLLA and PDLLA have
been studied extensively in biomedical research (Ulery et al. 2011) and regarded as
an ideal biomaterial for load bearing applications, such as orthopedic xation
devices with high elastic modulus (about 4.8 GPa) (Middleton and Tipton 2000),
while PDLLA has lower elastic modulus of 1.9 GPa (Maurus and Kaeding 2004).
PLLA-based polymers replaced the non-degradable ber (Dacron) for scaffolds
materials (Wang et al. 2009). PLLA degradation rate is very low, and was reported
to take between 2 and 5.6 years for the amount of resorption in vivo (Middleton and
Tipton 2000). The copolymer of lactic acid and glycolic acid, poly(lactic-co-gly-
colic acid) or PLGA, degrades via hydrolytic action and its rate depends on various
parameters including ratio LA:GA, molecular weight, shape and structure of the
matrix. PLGA degrades in 12 months for a ratio of 50:50, 45 months for 75:25,
and 56 months for 85:15 (Nair and Laurencin 2007).
Poly(dioxanone) is a semicrystalline polymer monolament developed com-
mercially under the trade name of PDS and used for several orthopedic applications
such as bone xation screws (Nair and Laurencin 2007). Similar with PGA, PDS is
broken into glycine which can be removed through the urine. PDS has very low
elastic modulus (about 1.5 GPa) compared to PGA, and a decrease in strength
within 12 months and loss its mass by hydrolytic degradation within 612 months
(Maurus and Kaeding 2004).
Table 2 Some biodegradable polymers in medicine
136
Polymer Chemical structure Applications

Poly(glycolic acid) Tissue engineering, drug delivery
Poly(lactic acid) Tissue engineering, drug delivery
Poly(lactic-co-glycolic acid) Tissue regeneration, drug delivery
Poly(dioxanone) Orthopedic applications
Poly(caprolactone) Tissue engineering
Poly(trimethylene carbonate) Drug delivery, soft tissue regeneration
Poly(ortho ester) Drug delivery
Poly(anhydride) Drug delivery, tissue engineering
Poly(propylene fumarate) Orthopedic applications
(continued)
A.K. Nasution and H. Hermawan
Table 2 (continued)
Polymer Chemical structure Applications
Poly(alkyl cyanoacrylates) Drug delivery
Poly(phosphazene) Tissue engineering, vaccine adjuvant
Poly(phosphoester) Drug delivery, tissue engineering

Degradable Biomaterials for Temporary Medical Implants
137
Poly(caprolactone) or PCL is a semicrystalline poly(ester) soluble in various

organic solvents with slow degradation rate of about 23 years (Nair and Laurencin
2007). Extensive research is ongoing to develop various micro- and nano-sized
drug delivery vehicles based on PCL (Sinha et al. 2004). PCL has also been
extensively investigated as scaffolds for tissue engineering. PCL has low tensile
strength of about 23 MPa, but has high elongation of >700 % (breakage)
(Gunatillake et al. 2006).
Poly(trimethylene carbonate) or PTMC is an elastomeric aliphatic polyester with
excellent flexibility. PTMC has been developed for drug delivery vehicles and soft
tissue regeneration. The combination of glycolide, trimethylene carbonate and
dioxane can reduce rigidity and degrades within 34 months (Nair and Laurencin
2007). Binding ability of amide hydrogen bonds and biodegradation given by an
ester bond results the ester co-polymers with good mechanical and thermal prop-
erties. Poly(esteramide) or PEA and poly(orthoesters) or POE are thus identied as
degradable polymers suitable for orthopedic applications beside for drug delivery
vehicles (Gunatillake and Adhikari 2003). Preliminary in vivo studies showed that
POE increased bone growth when compared with PDLGA (Andriano et al. 1999).
With the addition of lactide segments as part of the polymer structure, degradation
began to be achieved from 15 to hundreds of days. The degradation of the lactide
segments produces carboxylic acids, which catalyze the degradation of the
orthoester (Gunatillake and Adhikari 2003).
Poly(anhydride) is one of the most extensive biodegradable polymers studied
with excellent biocompatibility and controlled release characteristics (Gunatillake
and Adhikari 2003). In 1996, this material has been approved by the FDA as
polymers for controlled drug delivery (Nair and Laurencin 2007). Mechanical
properties and degradation time can vary, depending on the monomers used. Poly
(anhydride) is generally classied as surface eroding polymers because of its linear
mass loss during erosion (Nair and Laurencin 2007). However, research shows that
the degradation is not entirely conned to the surface of the polymer matrix and
additional studies tried to explain other parameters that may affect the degradation
polyanhydride (Akbari et al. 1998). The good mechanical property of poly(anhy-
dride) was combine with surface-eroding characteristic of poly(imide) resulted into
poly(anhydride-co-imide) specically used for orthopaedic applications
(Gunatillake and Adhikari 2003). This co-polymers has signicantly improvement
in the mechanical properties, especially the compressive strength of about 50
60 MPa (Gunatillake and Adhikari 2003) compared with poly(anhydride). This
increase is based on succinic acid trimellitylimido glycine and trimellitylimido
alanine (Uhrich et al. 1995). Poly(anhydride-co-imide) degraded through hydrolysis
of anhydride bonds, followed by the hydrolysis of imide bonds (Uhrich et al. 1997).
Another approach to improve the mechanical strength of poly(anhydride) is by the
inclusion of acrylic functional groups in the monomeric units to form injectable
photo-cross linkable poly(anhydride) can be used for lling irregularly shaped bone
defects or for soft tissue repairs and can be molded into a desired shape under
physiological conditions (Nair and Laurencin 2007).
Poly(propylene fumarate) or PPF undergoes bulk erosion through hydrolysis of

the ester bond and its degradation time depends on several parameters, such as
molecular weight, type of cross-linker and cross-linking density (Nair and
Laurencin 2007). PPF injection system was developed as a material for orthopedic
implants (Temenoff and Mikos 2000). Cross-linked PPF was developed by
co-polymerization with acrylic monomers such as N-vinyl pyrolidone, using dif-
ferent types of polymerization initiators (Gunatillake and Adhikari 2003).
Poly(phosphazene) is a remarkable macromolecules because of its versatile
adaptation to a wide range of applications (Lakshmi et al. 2003) where its degra-
dation rate can be designed from a few hours to a year by varying the chemical side
groups (Nair and Laurencin 2007). The application of these polymers as a short-term
medical implants are drug delivery matrices and scaffolds for tissue engineering.
Although polyphosphazenes has tremendous potential as a biodegradable matrix, this
material is relatively under-utilized (Lakshmi et al. 2003).
3.3 Lesson Learned
Figure 3 shows examples of implants made of biodegradable polymers ranging

from bone related implants, such as screws and plates, till endovascular implants
such as the rst Igaki-Tamai stent till the most recent Abbots bioabsorbable stent.
Apart from the ease of fabrication and control of degradation, biodegradable
polymers might not best suited for temporary hard tissue application such as bone,
where adequate strength and elastic modulus are required. Polymeric structures are
Fig. 3 Biodegradable polymer implants: a various spine surgical implants made of PGA and PLA
(Medscape.com), b Igaki-Tamai stent made of PLLA (Kyoto Medical Planning, Japan),
c bioresorbale vascular stent made of PLLA (Abbot Vascular, USA). Note scale bars are
approximatively only
relatively weak and may not achieve sufcient level of the required strength
(Yarlagadda et al. 2005; Cheung et al. 2007) and they could suddenly loss their
mass and mechanical integrity due to degradation. Degradation of polymers affects
the surrounding tissue by lowering the pH and releasing acidic degradation and
resorption by-products which triggers inflammatory reactions (Gray et al. 1988;
Therin et al. 1992; Rehm et al. 1994; Bergsma et al. 1995; James and Kohn 1996).
This is a major concern in orthopaedic applications where implants with consid-
erable bulk size are required. Release of small particles during degradation also
triggers an inflammatory response (Taylor et al. 1994) and affects bone-remodeling
processes (Conley Wake et al. 1998). When the capacity of the surrounding tissue
to eliminate the by-products is low due to the poor vascularization or low metabolic
activity, the chemical composition of the by-products may lead to local temporary
disturbances (Bostman 1991).
The bioactive properties of biodegradable polymers, such as the antibacterial and
anticancer properties of poly(peptide), can be further exploited to be combined with
biodegradable metals to develop a strong yet bioactive temporary implants. The
controllable hydrolysis of synthetic biodegradable polymers such as poly(lactic-co-
glycolic acid) can be formulated as drug carrier and coated onto biodegradable
metals to also provide a strong scaffold with pharmacologic capabilities.
4 Biodegradable Metals
More than 100 years ago, history of bone fracture xation told us that metals were
used as implants but were then abandoned because of corrosion (Uhthoff et al.
2006). At that time, metals were selected on the trial and error basis (Witte and
Eliezer 2012). With the advancement in materials processing technology, the
problem of corrosion can be controlled by using corrosion resistant alloys as
described in the previous chapter. However, clinical reality showed that almost 10
12 % of inert metal implants were removed due to infection, exposure, pain and
discomfort (Meslemani and Kellman 2012). Some cases on bone fracture xator
(bone screws) showed complications such as reactions of rejection from body
(allergic) (Hallab et al. 2001; Kanerva and Frstrm 2001; Vos and Verhofstad
2013) that made most surgeons recommends implants removal once the bone has
unied (Ochs et al. 2012; Williams et al. 2012). Indeed, implants for treating bone
fractures are required only temporary during the period of tissue healing (Li et al.
2014).
The current promising solution to overcome the disadvantages of the inert (per-
manent) implants is the use of biodegradable ones. Presently, the choices can be taken
either from biodegradable polymers or biodegradable metals with both offer each
advantages and limitations. Biodegradable polymers have biomechanical limitation
compared to biodegradable metals (Suuronen et al. 1992; Henderson et al. 2014).
Biodegradable metals have both the strength and the ability to degrade that make them
extensively studied and proposed as new temporary implant materials for vascular
Fig. 4 Biodegradable metal implants: a Mg alloy cross pin (Drexel University), b Fe alloy stent
(Laval University), c Mg alloy stent (Biotronik, Germany), d Mg alloy compression screw
(Magnezix, Syntellix, Germany). Note scale bars are approximative only
intervention and osteosynthesis (Hermawan 2012; Zheng et al. 2014). In the current
development, variety of medical devices (or prototypes) have been made (or under
research and development) from biodegradable metals including bone pins, screws
and endovascular stents as shown in Fig. 4.
Based on materials science point of view, biodegradable metals can be classied
as pure metals (one metallic element with impurity levels lower than the com-
mercial tolerance limits), alloys (various microstructures and one or more alloying
elements) and metal matrix composites. Up to now, Mg, Fe and zinc (Zn) are the
three class of metals have been used in their pure states and as the matrix for
making alloys and composites.
4.1 Basic Concept
The emergence of biodegradable metals oppose the paradigm of implant materials

that they must be corrosion-resistant and inert within the body (Hermawan 2012;
Zheng et al. 2014). Biodegradable metals have been dened as metals that are
expected to corrode gradually in vivo, with an appropriate host response elicited by
released corrosion products, then dissolve completely upon fullling the mission to
assist with tissue healing with no implant residues. Furthermore, the major
Fig. 5 Schematic diagram showing ideal behavior biodegradable metal implants for bone fracture
xation where degradation rate keeps low during 36 months and increases thereafter, and
mechanical integrity which keeps relatively constant during 36 months and rapidly deteriorate
thereafter. Adapted from Zheng et al. (2014)
component of biodegradable metals should be essential metallic elements that can

be metabolized by the human body, and demonstrates appropriate degradation rates
and mechanism (Zheng et al. 2014).
Ideal biodegradable metal implants will give the required mechanical support
during the process of tissue reconstruction, and then degrade progressively with an
appropriate level of tolerable degradation products in the human body (Zheng et al.
2014; Liu and Zheng 2011a, b). In the case of bone fracture, the time required to
achieve hard bone union varies greatly depending on the fracture conguration and
location, status of the adjacent soft tissues, and patient characteristics (Zheng et al.
2014). Figure 5 models the degradation rate and the deterioration of mechanical
integrity of biodegradable metal implants to suit the bone fracture remodeling
period (Zheng et al. 2014).
Similarly, for endovascular applications, the biodegradable metal implants (i.e.
stent) behavior must suit the period of the vessels healing process. It starts by
inflammation period where platelet deposition and inltration of inflammatory cells
lasts for several days, followed by granulation period where endothelial cells
migrate to cover the injured surface and smooth muscle cells modulate and pro-
liferate for 12 weeks, nally remodeling period takes place where extracellular
matrix deposits and continues for months (Zheng et al. 2014). The total healing
period is not yet fully determined but some argued that the optimal mechanical
integrity of a stent must be maintained within 612 months (Schmig et al. 1994;
El-Omar et al. 2001).
Thus, the main issue is the control of degradation rate. Once implanted into the
human body, biodegradable metal implants are continually exposed to extracellular
tissue fluid. Their exposed surface undergoes an electrochemical dissolution of
material due to interactions with the human body environment that contains water,
complex organic compounds, dissolved oxygen, anions, cations and their complex,
amino acids, proteins, plasma, lymph, etc. Corrosion initiates at any site on the
surface which has potential difference (electrochemical cells) created from metal-
lurgical condition of the metals such as phase variation, grain boundaries, impu-
rities, etc., or from geometrical condition such as crevice formation at the interface
between a plate and a locking screw. Corrosion is the typical process of degradation
for biodegradable metals. Its an electrochemical process where oxidation and
reduction reactions occurred producing oxides, hydroxides, hydrogen gas, or other
compounds. In the physiological environment, corrosion generally involve the
following reactions:
M ! Mn ne anodic reaction) 1
2H2 O 2e ! H2 2OH cathodic reaction 2
2H2 O O2 4e ! 4OH cathodic reaction 3
Mn nOH ! MOHn product formation 4
Beside affecting mechanical integrity, degradation rate also influence the local
tissue response and the physiological environment (Witte and Eliezer 2012).
Degradation and tissue response interact reciprocally, the implantation causes injury
and the body responses to it by decreasing the pH value around the implantation site
(i.e. 5.35.6) that may accelerate corrosion process of the implant and reduce the
local oxygen concentration (Witte and Eliezer 2012). Our knowledge on this
complex interaction is still very limited. One of the recommendations of the latest
symposium on biodegradable metals in Italy in 2014 is to encourage more research
to understand in vivo degradation behavior and to determine its relation to the
in vitro degradation.
Numerous methods have been used to evaluate the corrosion behavior of
biodegradable metals in the laboratory, involving either qualitative measurements
of their implants into animals (in vivo) or quantitative electrochemical measure-
ments in simulated body fluid (in vitro). These methods so far are adopted from
those available for corrosion evaluation of inert metallic biomaterials. The in vitro
experiments are designed to closely simulate the in vivo situation even though some
important variables such as amino acids, proteins and ions at the proper temperature
and pH into the simulated body fluid are often excluded to maintain reproducibility
and minimize variables. Various in vitro degradation assessments are commonly
used from simple mass loss experiments to more complex electrochemical methods,
which each has its own unique benets and limitations (Kirkland et al. 2012).
Meanwhile, in vivo assessments used various animal models from small to bigger
mammals, and different analytical tools from radiographic (X-ray, CT scan, etc.),
blood analysis till histology (Dziuba et al. 2013).
4.2 Degradation Assessment Techniques
Three common assessment techniques to measure in vitro degradation rate and

determine degradation mechanism of biodegradable metals are weight loss, poten-
tiodynamic polarization and electrochemical impedance spectroscopy. Weight loss
method measures degradation rate based on mass difference of specimens before and
after a certain period where the specimens are usually immersed in simulated body
fluid solution. The ASTM standard G31 (Standard Practice for Laboratory
Immersion Corrosion Testing of Metals) is mostly referred with some modications.
This simple method typically produces accurate results when degradation layer is
optimally removed and when a substantial degree of corrosion is achieved but
multiple replicates are necessary to provide condence in the results (Kirkland et al.
2012). Weight loss experiments reveal how much degradation has occurred, but they
do not reveal the degradation mechanisms or explain why one alloy degrades faster
than another. Figure 6 shows typical results obtained from the potentiodynamic
polarization and electrochemical impedance spectroscopy techniques.
Different from the weight loss, potentiodynamic polarization method unveils the
instantaneous degradation rate of a metal under a specic condition. In this elec-
trochemical method, the metal surface is polarized by applying a range of potential
and in return, the generated current is measured by a potentiostat. Generally, a three
electrodes system: working, reference and counter electrodes is used and sub-
merged in the test solution. The ASTM standard G59 (Standard Test Method for
Conducting Potentiodynamic Polarization Resistance Measurements) is often
referred. The working electrode comprises the specimen with a determined exposed
surface area. Additionally, potentiodynamic polarization is also able to unveil
degradation behavior of the metals both thermodynamically and kinetically such as
passivation and activation or concentration controlled process.
Fig. 6 Example of electrochemical corrosion test results: a potentiodynamic polarization curves

for pure-Fe and Fe coated with hydroxyapatite (HA-Fe) and with composite of poly(caprolactone)
and hydroxyapatite (HA/PCL-Fe), b Nyquist plots and a proposed equivalent circuit for pure Mg,
pure Zn and cast Zn-3Mg alloy obtained by electrochemical impedance spectroscopy experiment.
Adapted from Mohd Daud et al. (2014)
Electrochemical impedance spectroscopy is a powerful technique for unveiling

information about surface characteristics of degrading metals. In this method, an
AC voltage is applied onto the metal surface, normally from higher to lower fre-
quency, followed by the generation of AC current. The two parameters are logged,
analyzed and transformed by a frequency analyzer to form impedance. The
experiment conguration of EIS is similar to that of potentiodynamic polarization.
The ASTM standard G106 (Standard Practice for Verication of Algorithm and
Equipment for Electrochemical Impedance Measurements) can be further referred.
The impedance data can be presented as Nyquist and Bode plots. Some basic
information can be extracted directly from the Nyquist plot are electrolyte resistance
(Re) that represents the internal solution resistance, and polarization resistance (Rp)
which is the sum of the resistances caused by the electrochemical process on the
working electrode surface and resistance due to the voltage drop between the
working electrode and counter electrode. Combined with a cross sectional and
surface analysis using microscopy and elemental analysis the characteristics of the
degradation layer formed during degradation process will be optimally revealed.
4.3 Type of Biodegradable Metals
Generally, it is known that the corrosion of Mg and its alloys is considered too fast
(Witte and Eliezer 2012); meanwhile, Fe and its alloys corrode relatively too slow
(Witte et al. 2005). Therefore, attempts have been made to manipulate their
microstructure and surface properties to control their degradation kinetics via diverse
advance material processing and surface modication techniques. In addition,
alternative metals have also been explored including Zn and its alloys (Murni et al.
2015; Vojtch et al. 2011). Table 3 summarizes the mechanical and degradation
properties of some metals and alloys used and proposed for biodegradable metals.
Mg and Its Alloys
History of Mg for use as an implant dated back to 1878, when it was used as
ligature to stop blood vessels bleeding (Hornberger et al. 2012; Witte 2010).
Abandoned due to limited mechanical properties, poor corrosion resistance and
high cost of production, Mg regained its popularity as innovative biomaterial for
temporary implants (Hornberger et al. 2012). It is a lightweight metal with density
of 1.74 g/cm3 and elastic modulus of *45 GPa (Black and Kohser 2008) which are
very close to those of human bones. It is also an essential element for human
metabolism and can be found in bone tissue (Saris et al. 2000; Okuma 2001;
Vormann 2003; Wolf and Cittadini 2003; Hartwig 2001). Biocompatibility of Mg
and its alloys has been conrmed by numbers of studies both in vitro and in vivo
(Heublein et al. 2003; Li et al. 2004, 2008; Witte et al. 2007a). However, their fast
degradation rate limits their applications.
Basically, two factors contributing for low degradation resistance of Mg are the
initial galvanic corrosion caused by second phase or impurities and the
Table 3 Mechanical and degradation properties of some biodegradable metals

Metal Mechanical properties Degradation rate*
E YS UTS (mm/year)
(GPa) (MPa) (MPa) (%)
Pure Mg (annealed) 45 30 100 7 8
MgAl (AZ31, extruded) 175 250 14 2.0
Mg-RE (WE43, 180 280 10 4.34
extruded)
Mg-1Ca (extruded) 135 240 10 1.4
Mg-1Zn (rolled) 160 240 7 1.52
Pure Fe (annealed) 200 150 200 40 0.2
Pure Fe (electroformed 270 290 18 0.75
annealed)
Fe-35Mn (PM annealed) 230 430 30 0.44
Fe-10Mn-1Pd (forged) 850 1450 10 0.42
Fe-30Mn-6Si (cast) 180 430 17 0.3
Pure Zn 100 20 0.3 0.5
Zn-1Mg (cast) 150 2 0.20
Zn-1Mg (extruded) 170 250 11 0.12
Zn-3Mg (ECAP)** 205 220 6 0.28
Note E elastic modulus, YS yield strength, UTS ultimate tensile strength, elongation.
*Degradation data were compiled from the most similar experimental set-up (i.e. PDP method,
SBF solution), but variation may occur and they may not be directly comparable. **Unpublished
data. Data compiled from: Moravej et al. (2010a), Hermawan et al. (2008), Schinhammer et al.
(2010), Xu et al. (2011), Liu et al. (2011), Gong et al. (2015), Dambatta et al. (2013), Gu et al.
(2009) and Vojtech et al. (2011)
quasi-passive hydroxide lm formed on the surface (Makar and Kruger 1993). The
corrosion of Mg follows the overall reactions:
Mg ! Mg2 2e anodic reaction) 5
2H2 O 2e ! H2 2OH cathodic reaction 2
Mg 2H2 O ! MgOH2 H2 overall reaction 6
The production of hydrogen (reaction 6) raises a concern as gas bubble forms

when Mg is implanted in vivo (Aghion et al. 2012). New Mg-based metallic glass
(Mg-Zn-Ca alloy) was developed and has not exhibited hydrogen evolution in
clinical trials (Zberg et al. 2009).
In general, there are two ways to improve the corrosion resistance of Mg and its
alloys: rstly, by tailoring their composition (purication and alloying) and
microstructure, including grain size (Hoog et al. 2008; Wang et al. 2008) and
texture (Xin et al. 2009) from base material (not only alloys) (Kaesel et al. 2005),
through optimal production method (Hort et al. 2010); secondly by employing
surface treatment or coating (Gray and Luan 2002) such as using ceramic, polymer
or composite layer (Hornberger et al. 2012). With the achieved improvement, variety
of medical devices were proposed to be made from Mg alloys including ligature wire,
pins, screws, plates and endovascular stents (Witte 2010; Henderson et al. 2014;
Witte et al. 2005, 2006, 2007b, c; Kim et al. 2008; Zhang et al. 2008; Song 2007;
Staiger et al. 2006; Song and Song 2007).
Pure Mg is Mg with other elements (impurities) within tolerance limit. Elements
such as Fe, Cu, Ni, Co and Be are considered as impurities and their content should
be limited to 3550 ppm for Fe, 100300 ppm for Cu, 2050 ppm for Ni, and up to
4 ppm for Be (Witte et al. 2008; Makar and Kruger 1993). When the impurities
exceed their tolerance limits, the corrosion rate will increase (Lee et al. 2009; Li and
Zheng 2013). More precisely, tolerance limit for Fe was reported as 170 ppm in
unalloyed as-cast Mg and 5 ppm in wrought Mg (Kraus et al. 2012; Hofstetter et al.
2015). Above this limit, Fe-rich particles are formed and thus electrochemically
active cathodic sites exist and accelerate corrosive rate drastically. Addition of
silicon, which is usually added to improve castability, promotes the formation and
growth of Fe-rich particles and thus provokes more corrosion (Hofstetter et al.
2015). Beside by purication, the corrosion resistance of pure Mg is higher by
improving the grain size through forging or rolling and heat treatment (Li and
Zheng 2013). The heating temperature and the length of time of the heat treatment
must be considered properly. Otherwise, it would get the opposite results (Li and
Zheng 2013). Although pure Mg demonstrated the ability to stimulate new bone
formation, but its mechanical properties in general is still considered insufcient for
orthopedic applications (Gao et al. 2010; Huang et al. 2007) and considered
unsuitable for vascular stents (Li and Zheng 2013).
Common alloying elements used in Mg for implants are Al, Mn, Zn, Ca, Li, Zr,
Yand rare earth elements (RE) (Xu et al. 2007; Witte et al. 2005, 2007c; Kannan
and Raman 2008; Rettig and Virtanen 2008; Qudong et al. 2001; Witte et al. 2008;
Gu et al. 2009). When viewed from the alloying elements, there are two major
groups of Mg alloys excluding pure: Al-containing alloys and Al-free alloys (Ren
et al. 2005; Song and Song 2007; Wang et al. 2008; Witte et al. 2008). Mg alloys
with Al as the main alloying element commonly form complex Mg17Al12 com-
pound which strengthens the alloys via solid solution and precipitation strength-
ening mechanism (Witte et al. 2008). However, the Mg17Al12 compound has low
melting point and thus cannot maintain the strength at high temperatures (Witte
et al. 2008). The addition of Al decreases the liquidus and solidus lines and thus
raises the alloys castability, but adding Al more than 2 wt% may result in
embrittlement (Housh and Mikucki 1990). The addition of Mn further increases the
ductility and corrosion resistance as Mn binds to Fe, while addition of Zn also
provide a solid solution strengthening (Mordike and Luk 2006) and improve
castability. Calcium (Ca) can contribute to strengthen the alloys as it forms Mg2Ca
and Al2Ca that act as precipitation and grain-boundaries strengthening but cannot
be added more than 1 wt% as it will cause hot tearing during casting (Witte et al.
2008). Lithium (Li) is a unique alloying element which can change the lattice
structure of the alloy from HCP into BCC (Nayeb-Hashemi and Clark 1988), but its
cytocompatibility is questionable.
The current interesting alloying elements for Mg is the RE as they are found to
contribute in the strengthening, raising the creep resistance, and increasing corro-
sion resistance (Rokhlin 2003). The RE are divided into two groups: (1) group of
elements with limited solubility such as Nd, La, Ce, Pr, Sm and Eu (Mordike and
Luk 2006), and (2) group of elements with large solubility such as Y, Gd, Tb, Dy,
Ho, Er, Tm, Yb and Lu (Nayeb-Hashemi and Clark 1988). Group 1 will form initial
intermetallic phases during solidication, while group 2 forms intermetallic phases
complex with Mg or Al as strengthening precipitates and inhibiting the movement
of dislocations at high temperatures (Witte et al. 2008). Examples of Al-containing
Mg alloys are the types of AZ91, AZ31, AE21, Ca-modied AZ alloys and AE42
(Mordike and Luk 2006, Housh and Mikucki 1990). LAE442 alloy is a further
development of AE42 with low density but with increasing ductility and corrosion
resistance (Bach et al. 2003).
Examples of Al-free Mg alloys are the types of WE, MZ, WZ and MgCa alloys
(Witte et al. 2008). The addition of elements such as Y, Zr, Zn and RE improves
creep resistance, high temperature stability and forging-ability of the alloys
(Mordike and Luk 2006; Housh and Mikucki 1990). Currently, the Al-free alloys
are the recommended types of Mg alloys for biomedical use in human (Zhang et al.
2010, 2012). In addition, the recommended alloying elements for these alloys
includes Ca, Mn and Zn (Song 2007; Xu et al. 2007; Li et al. 2008)
MgCa alloys became the rst most studied biodegradable alloys for bone
applications as Mg and Ca are two main elements that exist in human bone and
benecial for bone healing (Ilich and Kerstetter 2000; Serre et al. 1998). Their
biocompatibility was tested both in vitro and in vivo where Mg-(1 wt%) Ca pins
gradually degraded after 90 days and formation of new bone was evident (Li et al.
2008). Knowing that Zn is also an essential element in the human body, Mg-Zn
alloys also received attentions (Tapiero and Tew 2003). The in vitro cytocompat-
ibiliy of Mg-(6 wt%) Zn alloy was tested with broblast cells and showed positive
results, while the in vivo test in rabbits femoral bone showed a relatively slow
degradation rate (2.32 mm/year) without any evidence of toxicity (Zhang et al.
2010; Li and Zheng 2013). Mn does not affect mechanical properties of Mg alloys,
but it increases corrosion resistance and poses no toxicity (Li and Zheng 2013).
Normally, Mn is also added along with Zn and form ternary MgMnZn alloys. An
in vivo study showed that after 18 weeks, Mg-1.2Mn-1Zn alloy implants did not
cause an increase of serum Mg levels and renal impairment in rats (Xu et al. 2007).
Fe and Its Alloys
Fe widely involves in a large number of Fe containing enzymes and proteins in
human body. It involves in the decomposition of lipid, protein and DNA damages
due to its reactivity to oxygen molecules which might produce reactive species
through Fenton reaction (Mueller et al. 2006). It also plays signicant roles in
transport, reduction of ribonucleotides and dinitrogen, storage and activation of
molecular oxygen, etc. (Fontcave and Pierre 1993). The suitability of Fe as a
biodegradable implant material has been tested both in vitro and in vivo in variety
of cells and animal models (Waksman et al. 2008; Peuster et al. 2001a, 2003, 2006).
Even though no toxicity was observed (Peuster et al. 2001b), but the concentration
of Fe ions in the body should not reach higher than 50 g/ml as my cause toxicity
and cell death (Zhu et al. 2009; Siah et al. 2005). Elastic modulus of pure Fe (211
GPa) is higher than that of pure Mg (41 GPa) and its alloys (44 GPa) or SS316L
(190 GPa) (Song 2007). Obviously, Fe and its alloys possess superior mechanical
properties and can meet the mechanical requirement that Mg alloys cannot provide
(Hermawan et al. 2010a; Niinomi et al. 2012; Schinhammer et al. 2010). However,
their slow degradation is unmatched with the tissue healing period and has become
the major drawback which limit their applications (Peuster et al. 2006; Kraus et al.
2014).
Different from Mg, Fe degradation is dependent on oxygen availability.
Generally, it degrades via corrosion following reactions:
Fe ! Fe2 2e anodic reaction 7
2Fe 2H2 O O2 ! 2FeOH2 overall reaction 4
The formation of Fe oxides have been identied as the major inhibitor for a
faster degradation (Hermawan et al. 2010b; Kraus et al. 2014). Dense degradation
products such as Fe-hydroxides, Fe-carbonates and Fe-phosphate layers greatly
hinder oxygen transport to the fresh Fe surface (Drynda et al. 2014; Chen et al.
2014; Kraus et al. 2014). Attempts to accelerate the degradation kinetics of Fe have
been explored through alloying, thermomechanical treatment and by making
composite of Fe with bioceramics (Ulum et al. 2014, 2015). In the design of Fe
alloys, several key points must be considered including manufacturing process (i.e.
melting temperature of Fe n is higher than that of Mg which associate with cost and
equipment), selection of alloying elements (Peuster et al. 2001b, 2006; Hermawan et al.
2010a) and heat treatment to control the grain size (Hermawan et al. 2010a;
Moravej et al. 2010b; Niinomi et al. 2012).
Moreover, Fe is ferromagnetic in nature, therefore ideal alloying elements
should change this property to make Fe alloys compatible with high magnetic eld
such as that generated by Magnetic Resonance Imaging (MRI) which become
widely used for post-implantation monitoring and diagnostic (Hermawan et al.
2010a). Fe was made via a bottom-up electroforming process that produced ner
grain sizes and preferential textures and resulted into a slight increase of corrosion
rate (Moravej et al. 2011). By using surface treatment approach, Fe was also coated
with micro-patterned Au disc arrays and produced a more uniform corrosion with
an almost four times higher degradation rate than the uncoated ones (Cheng et al.
2015). Another attempt was by making composite of Fe with Fe2O3 to create more
phase/grain boundaries which theoretically act as active sites for accelerating
degradation (Cheng et al. 2014).
Zn and its Alloys

Zn is an important essential trace element for cell development and growth, immune
and nervous system. It can be found in the bone extracellular matrix where Zn is
co-deposited with calcium hydroxyapatite (McCall et al. 2000) and shows a stim-
ulatory effect on the growth of new bone tissues (Zhang et al. 2010; Hnzi et al.
2010). The dietary intake of Zn for adult varies from 5 to 20 mg/day and its excess
will be excreted by the kidney (Nriagu 2007; Fosmire 1990). The cytocompatibility
of Zn alloy has been comprehensively studied where Zn-3Mg alloy extract
exhibited adjustable cytotoxic effects on normal human osteoblast cells and found
suitable in the view of its applications for bone implants (Murni et al. 2015). In Mg
alloys, Zn is often used as a major alloying element such as Mg-Zn, Mg-Zn-Mn-Ca,
Mg-Zn-Y, Mg-Gd, Mg-Zn-Si (Vojtch et al. 2011) and positively affect the cor-
rosion resistance and strength of Mg (Vojtch et al. 2011).
The interest toward Zn alloys began since the work on Mg-Zn-Ca glasses (with
*50 wt% Zn) that observed a signicant reduction of hydrogen evolution during
in vitro and in vivo studies (Zberg et al. 2009). However, the use of Zn in the
context of biodegradable implants is relatively new (Bowen et al. 2013;
Vojtch et al. 2011). Alloying Zn with Mg (<4 wt%) was reported to enhance its
corrosion resistance and mechanical properties (Prosek et al. 2008). Zn alloys with
up to 3 wt% Mg was recently investigated for bone xation applications (Vojtch
et al. 2011). Zn alloys could be preferable over Mg alloys since they can be
fabricated by classical routes such as die casting and hot rolling. Moreover, they
have lower melting point, lower reactivity, and superior machinability compared to
Mg alloys. Zn-Mg alloys were found to have a degradation rate that is slower than
Mg alloys but faster than Fe alloys (Vojtch et al. 2011). Similar to Fe, Zn
degradation needs oxygen and it generally degrades via the following reactions:
Zn ! Zn2 2e anodic reaction 8
2Zn 2H2 O O2 ! 2ZnOH2 overall reaction 9
Pure Zn has alow strength (*20 MPa) compared to Mg, but once alloyed, such
as that Zn-(13 wt%)Mg, it can be superior to some Mg alloys (Vojtch et al. 2011).
Beside alloying, mechanical properties of Zn alloy can be further improved by
(severe) plastic deformation such as extrusion, equal-channel angular pressing, high
pressure torsion, drawing and forging (Zheng et al. 2014; Zhang et al. 2013). Latest
report on hot extrusion of Zn1 Mg alloy revealed a signicant grain size reduction
resulting into increase strength twice than that of pure Zn with a much more uniform
degradation behavior (Gong et al. 2015). The cytocompatibility of Zn alloys have
been comprehensively studied against various cells such as broblast, osteoblast and
osteosarcoma, with a conclusion that the Zn alloys have potential for bone implant
applications (Murni et al. 2015; Kubsek et al. 2016). However, more works have to
be done on Zn alloys to conrm their suitability as biodegradable metals.
5 Perspective
The advance of our knowledge in implant-tissue interactions indicates that bio-

materials should exhibit bio-functional capability while maintain a superior
mechanical property. The study of innovative degradable biomaterials is one of the
most interesting research topics at the forefront of biomaterials in the present days.
Biodegradable metals constitute a novel class of bioactive biomaterials which
support healing process of a temporary clinical problem. They are expected to
corrode gradually in vivo, with an appropriate host response elicited by released
corrosion products, then dissolve completely upon fullling the mission to assist
with tissue healing with no implant residues. From the two recent annual sympo-
siums on biodegradable metals for biomedical applications, 2014 in Maratea, Italy
and 2013 in Umang Island, Indonesia, we witnessed many developments. Three
classes of metals have been explored: Mg-, Zn- and Fe-based alloys. Three targeted
applications are envisaged: orthopaedic, cardiovascular and pediatric implants.
Three levels of investigations have been conducted: in vitro, in vivo and human
clinical trials. Discussion on standardization has been initiated since 2013 with
representatives from ISO, DIN and ASTM and a draft of comprehensive standard
was now under preparation. While at least two companies have launched their
biodegradable metal-based implants into the market: Swiss and Korea.
Although we can feel the high excitement, especially in the industrial side, we
still observed the lack of knowledge in this eld. At least, two questions remain
unanswered satisfactorily: (1) interaction between metals and their degradation
products with the surrounding implantation sites including the fate of the degra-
dation products and its effects on the physiology and body functions, and (2) cor-
relation between in vitro and in vivo studies including degradation mechanism and
its kinetics that occurred differently. Over all, the eld of biodegradable metals is
exciting and we will witness more publications in the future reporting advanced
alloys and hopefully real breakthrough that leads to the translation toward clinical
practice.
In Indonesia, research on biodegradable metals was initiated by researchers at
the Faculty of Veterinary Medicine, Bogor Agricultural University in collaboration
with partners from Universiti Teknologi Malaysia and Laval University (Ulum et al.
2014, 2015; Nasution et al. 2015). In 2013, we have successfully brought the 5th
Annual Symposium on Biodegradable Metals, which usually held in Europe, to
Indonesian exotic beauty of Umang Island. In addition, with the establishment of
the Indonesian Biomaterials Society in 2012, research potentials on biomaterials in
Indonesia become more exposed and initiate more multidisciplinary collaborations
among researchers within Indonesia and overseas.
Acknowledgment The authors deeply thank Mr. Ng Boon Sing for the discussion on corrosion
assessment part, and Miss Zulaika Miswan for the help on the language. We acknowledge the
support of the Fonds de dmarrage from CHU de Qubec Research Center, Laval University.
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Biomaterials in Orthopaedics
Ferdiansyah Mahyudin, Lukas Widhiyanto and Hendra Hermawan
Abstract In general knowledge, orthopaedic surgery treats the disease and injuries
of musculoskeletal system including bone fractures, anomalies, degenerative dis-
ease, tumor, and infection. Signicant difference in orthopaedic cases occurs
between developed and developing countries. In the latter, the majority of cases are
caused by injury and infection. Most surgical treatment needs the use of implants
for both traumatic and reconstructive procedures. Orthopedic implants can be
selected from metals, polymers and ceramics or their combination. In Indonesia,
certain type of orthopaedic implants have been produced locally but still cannot
fulll the high demand. The current technology used by local manufacturers has
some limitations in production capacity and product variety mainly for complex
implants like arthroplasty. Collaboration in R&D activities on orthopaedic implants
is on-going between local manufacturers with universities and government insti-
tutions under the assistance of orthopaedic surgeons. This collaboration receives a
full support from the Indonesian Government as it aligns with the national pro-
gramme on supporting local products and the new general health insurance pro-
gramme which covers every citizen of Indonesia.
Keywords Biomaterials Bone implant Injury Manufacture Orthopaedic

Surgery
F. Mahyudin (&) L. Widhiyanto

Airlangga University, Surabaya, Indonesia
e-mail: ferdyortho@yahoo.com
L. Widhiyanto
e-mail: lukas-w@fk.unair.ac.id
H. Hermawan (&)

162 F. Mahyudin et al.
1 Introduction
Orthopaedic is a branch of medical science that concerns with promotion, pre-

vention, investigation, and treatment of disease and injury of musculoskeletal
system by medication, physical therapy and surgery. Scope of orthopaedic eld
includes congenital anomaly, degenerative disease, tumor, injury, arthritis and
inflammation, infection, muscle weakness and sensory disturbance (Salter 1999).
There are signicant differences in orthopaedic cases between developed countries
and developing countries. In developed countries, the majority of orthopaedic cases
are caused by degenerative diseases such as osteoarthritis and canal stenosis of
spine. On the other hand, in developing countries, most cases are caused by trauma
and infection. Orthopaedic surgeon is a profession that frequently applies implants
in their practice. Orthopedic implants consist of traumatic implants, which can be
used as internal xation in trauma cases, and also reconstructive implants, that can
be used to replace damaged bone and joint structure thus recovering the function as
well. The material used for orthopedic implants can be selected from various
options such as metals, polymers and ceramics or the combination of two or more.
2 The Most Common Orthopaedic Problems in Indonesia
Currently, the life expectancy in Indonesia has increased. Indonesia is one of the
countries in the world that has rapid industrial and economic growth, as well as
increasing growth in education level. Those changes bring a shift to the pattern of
diseases in Indonesian. Nowadays, trauma and infectious diseases are still the
dominant cases in the eld of orthopedics. Trauma cases are closely related to trafc
accidents and occupational hazard, for example in construction work. While, the
infection cases are closely related with the level of environmental health, level of
welfare and also the level of public education.
In line with the growth of economic and the society welfare, the degenerative
disease that closely links with aging, the metabolic diseases which are influenced by
changes in lifestyle and diet, and cancer are growing and start to become major
diseases in the developing countries including Indonesia. Cause of death has also
changed. Death caused by heart attacks and cancer have equaled and even exceeded
deaths due to infection.
Looking at the tendencies described above, in the not too distant future the
pattern of diseases in Indonesia would resemble the case in developed countries,
where cases of infection and trauma will be decreased and replaced by degenera-
tive, metabolic and cancer diseases. The incidence of orthopaedic cases in
Indonesia is high and mostly due to trafc accidents. Most of Indonesian people use
private vehicle, especially motorcycles (Fig. 1). Mass transport is still not provided
very well therefore cheap and high flexibility vehicle is the best choice. The number
of motorcycles has grown very fast in 10 years and becomes the highest cause of
trafc accidents in Indonesia.
Biomaterials in Orthopaedics 163
Fig. 1 Typical trafc condition in Indonesian main cities during rush hours, where motorcycles
slipping around cars risking their own safety (Photo credit: Letterview.com)
Fig. 2 Examples of frequent fracture cases due to trafc accidents: a lower leg fracture; b forearm
fracture (Courtesy of Dr. Soetomo General Hospital, Surabaya)
Accidents are counted for the third death cause in Indonesia that lead to bone
fractures and disability. Fractures happen more commonly to men compared to
women under the age of 45 years old. They are often associated with sports, work,
or injuries caused by motor vehicles. While in elderly, women are more often than
men to experience fractures which associate with increasing incidence of osteo-
porosis due to hormonal changes at menopause. According to data recorded at the
Department of Orthopaedic and Traumatology, Airlangga UniversityDr.
Soetomo General Hospital, Surabaya, from October 2009 to October 2012 there
were as many as 7,134 patients admitted to the emergency room because of frac-
tures (Fig. 2).
Fig. 3 Typical MRI pictures of the TB of the spine (Courtesy of Dr. Soetomo General Hospital,
Surabaya)
The increase in the degree of welfare, education and intensive government

healthcare program has considerably lowered the incidence of cases of infection in
Indonesia although infection is still the second most common case in orthopaedics. It
is mostly caused by mycobacterium infection such as tuberculosis (TB). The second
most frequent TB infection following the lung TB is an infection of the bone. TB of
the spine is still a major problem in Indonesia. TB of the spine (Fig. 3) will cause
destruction of the bone, causing kyphotic deformities and compression of the spinal
cord and eventually paralysis of the extremities. In addition to spinal tuberculosis,
there are also infection to the joints, especially the hip joint and the knee.
In line with the increasing life expectancy in Indonesia, there is also an increased
incidence of degenerative cases. Degenerative musculoskeletal diseases that have a
relatively high incidence and cause of morbidity in patients is a degenerative joint
disease (osteoarthritis) and osteoporosis (Fig. 4). Osteoarthritis is characterized by
symptoms of joint pain, especially after activity, stiff joints and decrease of range of
motion. Osteoarthritis can occur in all joints of the body, but the most debilitating is
the one that affects large joints of the body such as the knee joint, hip joint and
spine.
Osteoporosis is a disease that occurs due to disturbances in bone mineralization,
causing bones to become susceptible to fracture. The disease is common in women
after menopause. Pathologic fractures due to osteoporosis is most common in the
spine, pelvis and wrist joints. The incidence of osteoporosis in Indonesia in age less
than 70 years for women as much as 1836 %, while men 2027 %, for age above
70 years for women 53.6 %, men 38 % (Tirtarahardja et al. 2006). Osteoarthritis
(OA) is the most common joint degenerative disease in the society, especially in
elderly. Indonesia belongs to the 10 countries with a large elderly population.
Fig. 4 Degenerative cases commonly found in Indonesia: a osteoarthritis of the hip;

b osteoarthritis of the knee; c pathological femoral neck fracture caused by osteoporosis
(Courtesy of Dr. Soetomo General Hospital, Surabaya)
In 1991, the number of people aged over 60 years was already 16 million, and is
rapidly increasing. A population-based survey in a rural setting in Indonesia
reported that the prevalence of radiographic OA of the knee in subjects aged
15 years and above was as high as 15.5 % among men and 12.7 % among women
(Soeroso et al. 2005; Darmawan et al. 1992).
3 Surgical Intervention and Implants
3.1 Biomaterials in Orthopaedic Surgery
Biomaterials are commonly used in orthopaedic eld. Firstly, it is used for aug-
mentation of bone such as in the cases of fracture treatment. Secondly, they are also
in very good use in replacement and reconstruction of musculoskeletal organs like
joints, ligaments, intervertebral disc, resected bone due to malignancy, and defec-
tive joints due to degenerative changes (Grimm 2003). The denition of biomate-
rials itself is any material intended to perform the function of an organ or a tissue
partly or completely in living organisms. Those which are usually used in ortho-
paedic are commonly called implants (Koksal 2014).
Biocompatibility, appropriate design, manufacturability, mechanical reliability,
biological stabilities, special properties such as tensile strength, yield strength,
elastic modulus, corrosion and fatigue resistance, surface nish, creep, and hard-
ness, resistance to implant wear and aseptic loosening and corrosion of implants are
all contributing to characteristic of implants. There are several basic requirements
that need to be fullled in order for the devices to function properly (Patel and
Gohil 2012). The main biomaterials used in orthopaedic surgery are divided into
two groups: metals and non-metals.
Metals
The use of metals for orthopaedic devices started long time ago. In the 17th century,
metals have started been used, and later on, in the 18th century a metal screw
implant was used for the rst time. Metals have their main applications in
load-bearing systems such as hip and knee prostheses and for the xation of internal
and external bone fractures. The metallic implants that are widely used in ortho-
paedic surgery are: low carbon grade austenitic stainless steels, titanium (Ti) and its
alloys, and cobalt-chromium (Co-Cr) alloys.
Stainless Steels: Like any steel, it is an iron-carbon alloy. Alloying elements
were added and contributed to the ability of stainless steel to resist corrosion. The
rst biomedical 18-8 steel alloy contained vanadium (V) but subsequent studies
indicate that it provides the alloy with insufcient corrosion resistance, and there-
fore the medical use of vanadium steel has been discontinued (Ivanova et al. 2014).
Further study yielded new resistance property in which modern corrosion resistant
(stainless) steel is made by adding typically 18 wt% of Cr, which resulting in a thin
Cr oxide (Cr2O3) lm on the surface and 8 wt% of nickel (Ni) which contributes to
austenite phase formation in the alloy. This Cr2O3 lm is characterized by its low
chemical reactivity and displays a self-healing capability in contact with oxygen.
Based on phase composition, these steels are classied into three categories: aus-
tenitic, martensitic or ferritic stainless steels. They considered as the good choice
for number of biomedical applications. In practice, stainless steels are used pre-
dominantly in temporary implant devices, such as fracture plates, screws, and hip
nails, although stainless steel also is used in some Charnley-style femoral com-
ponents for hip replacement. The microstructure of austenitic stainless steels is
characterized by its gamma () phase with faced-centered cubic structure which
contributes excellent workability (both forming and machining) and non-magnetic
properties. Those belong to this group are the types 302, 316 and the famous 316L
which remains popular as an implant material and a low-cost alternative compared
to Ti and Co-Cr alloys (Buhagiar and Dong 2012). Despite its special attributes,
there is some downward of stainless steels such as the reported Ni toxicity to the
host organism, and vulnerability of the alloy to pitting and crevice corrosion as well
as stress-corrosion cracking. Therefore, the use of stainless steels is generally
limited to temporary use as biomedical devices despite its role in modern use as
orthopaedics and load-bearing implants (Buhagiar et al. 2012).
Ti and its Alloys: They are commonly used for dental and orthopaedic implants.
Different alpha and beta structure leads to three different structural types of Ti
alloys: alpha (), alpha-beta (-), and metastable and -phase alloys. Their
excellent corrosion resistance is a result of inert TiO2 lm formation on their
surface. For dental implants, commercially pure (CP) Ti, typically with single-phase
alpha microstructure, is commonly used, while Ti6Al4 V, with a biphasic
alpha-beta microstructure, is most commonly used in orthopaedic applications. The
presence of aluminum (Al) and V alloying elements not only contributes to the
mechanical stability but also improves the microstructure of alpha-beta in relation
to CP Ti. These properties are modulated by heat treatment and deformational
works. Despite Ti and its alloys combine a range of excellent properties, i.e.
mechanical properties, corrosion resistance, fatigue-corrosion resistance, low den-
sity and relatively low modulus, their processing is not easy whether it is
machining, forging or heat treating (Navarro et al. 2008). The -phase in Ti alloys
tends to exhibit a much lower Youngs modulus than that of the -phase, therefore
it satises most of the necessities or requirements for orthopaedic applications.
However, the presence of Al and V in long term use of Ti alloys (especially Ti64)
poses potential hazard of toxicity. The release Al and V ions from the alloys has
been associated with the potential for Alzheimer and neuropathy disease (Patel and
Gohil 2012).
Co-Cr Alloys: These alloys, which have been used for many decades, can be
basically categorized into two types: Co-Cr-Mo alloys [Cr (2730 %), Mo (57 %),
Ni (2.5 %)] generally used in dentistry and articial joints; and Co-Ni-Cr-Mo alloys
[Cr (1921 %), Ni (3337 %), and Mo (911 %)] mostly used for making the stems
of prostheses of heavily loaded joints, such as knee and hip (Patel and Gohil 2012).
Involvement of heat during processing of Co-Cr-Mo alloys modies the alloys
microstructure and leads to the alteration of electrochemical and mechanical
properties of the alloys. In term of corrosion resistance, Co-Cr alloys are consid-
erably superior to stainless steels as it demonstrates better performance in
chloride-rich environment. However, the corrosion products of Co-Cr-Mo, espe-
cially the possible release of Cr ions is potentially more toxic than that of stainless
steel 316L (Chen and Thouas 2015).
Polymers
Apart from metals, polymers, the organic or inorganic materials that form large
chains made up of many repeating units, are extensively used in joint replacement
components. Currently the most used polymers in joint replacements are: ultrahigh
molecular weight poly(ethylene) or UHMWPE, poly(methyl methacrylate) bone
cement or PMMA, thermoplastic poly(ether ether ketone) or PEEK, and bioab-
sorbable type of polymers.
UHMWPE: Being used since early 1960s, it is a semi-crystalline polymer with
roughly half of its chains is structurally organized in crystalline lamellae and the
balance is entangled in a random amorphous state. At the body temperature, this
polymer behaves between its glass transition temperature and melting point,
enabling unique viscous amorphous behavior combined with a solid-like crystalline
phase. The microstructural arrangement of UHMWPE provides desirable material
properties for use in total joint arthroplasty, including wear, strength and fatigue
resistance in comparison with other polymeric materials. Therefore, UHMWE is
used as a bearing surface in total joint arthroplasty (Ansari et al. 2015). However,
UHMWPE is not a perfect material because small amount of fluids can be bound
which makes discoloration of components as retrieved from infected sites. It is
subjected to fatigue failure and displays a tendency to creep for long-term appli-
cations, though this is reduced in its highly cross-linked form. Highly cross-linked
and thermally treated UHMWPE is generally acknowledged as the special structure
for hip arthroplasty. Since the introduction of its rst-generation, clinical perfor-
mance of highly cross-linked implants is generally considered successful, though
there has been a small number of reports on the rim fractures of some thinner liners
implanted at high abduction angles. Highly cross-linked UHMWPE is currently less
used in the knee owing to the inherent reduction in ductility and fracture resistance
as the result of irradiation used to initiate the cross-links, despite its superior
mechanical performance (Ong et al. 2014).
PMMA: In 1970s, Charnley introduced the use of acrylic plastic bone cement
made from PMMA (Leong and Lu 2004). PMMA cement is formed by mixing
liquid monomer and powdered polymer which produce an exothermic reaction at
temperature of 4856 C in vivo. The monomer component varies a little among
different available preparations while the powder typical contains polymer,
copolymers of different molecular weights, initiator, radio-opacier, accelerator,
and antibiotics and dye (Duffy and Shafritz 2011; Webb and Spencer 2007).
Antibiotics and barium are added in order to reduce the risk of infection and
increase radiographic visualization, respectively. Being available in both
high-viscosity and low-viscosity preparation, PMMA does not adhere to bone or
metal, but rather acts as a grout, interdigitating between the bony trabeculae and
increasing the contact area. Its elastic modulus lies between 14 GPa which is close
to that of cancellous (102,000 MPa) and cortical (1020 GPa) bones. PMMA has
viscoelastic properties that demonstrate an increase of stiffness with higher rates of
loading, as well as creep and stress relaxation. It reaches its strongest point under
compression (Wright and Maher 2008).
PEEK: It is a semicrystalline thermoplastic consisting of an aromatic molecular
chain interconnected by ketone and ether functional groups. In orthopedic appli-
cations, PEEK has been utilized for bearing surfaces, fracture xation plates, total
joint arthroplasty parts, and spinal implants. In addition, PEEK is widely used for
interbody fusion cages or components in spine xation systems. PEEK is radi-
olucent which facilitates assessment of the surgical site with plain radiography, CT
or MRI (Li et al. 2015). Due to its high quality and imperviousness to degradation,
PEEK materials are utilized as a part of a wide assortment of mechanical appli-
cations. PEEK can be utilized as a part of an unlled state, with added substances,
for example, carbon or red strands, or with bioactive added substances, for example,
hydroxyapatite. Unlled PEEK has a flexible Youngs modulus of 4 GPa, but a
composite (lled PEEK) could has a higher elastic modulus than that of Ti alloy (110
GPa). By lling 30 % weight with carbon ber, PEEK composite can reach a
versatile modulus of 20 GPa, while at 68 % reaches 135 GPa (Abdullah et al. 2015;
Schwitalla and Muller 2013).
Bioabsorbable Polymers: Some polymers are resorbable in their nature and are
suitable for initial xation and stabilization. In orthopaedic surgery, bioabsorbable
polymers are commonly used when the permanent presence of a device is not
needed or desired, such as sutures, suture anchors, fracture xation pins, and bone
screws. Over time, these implants will undergo resorption through hydrolysis
process at a predetermined rate, lose their mechanical integrity and becomes less stiff
and loses its ability to support a load. During this process, the load is transferred
increasingly through the healing tissue. Therefore, the rate at which the bioabsorbable
polymer device loses integrity is an important consideration (Burg et al. 2000;
Farraro et al. 2014). Bioabsorbable polymers can also provide a mean of releasing
drugs locally to the surgery site. The rate of drug elution can be designed to correspond
to the factors affecting healing or bone regeneration process. Some of the most
frequently used bioabsorbable polymers are poly(glycolic acid), poly(lactic acid), and
copolymers derived from them. The process of natural hydrolysis in the body will
degrade these polymers to yield glycolic acid or lactic acid monomers, respectively
(Ulery et al. 2011). Poly(glycolic acid) has higher elastic modulus of 7 GPa compared
to that of 46-poly-L-lactic of 2.7 GPa, but poly(glycolic acid) has shorter degradation
time of 612 months compared to that of the latter which degrades after 24 months.
Elastic modulus and degradation time can be modulated by varying copolymer for-
mulations, for instance, a formulation of half lactic acid and half glycolic acid results
into low elastic modulus of 2 GPa and very short degradation time of 12 months
(Middleton and Tipton 2000).
Ceramics
Ceramics are polycrystalline materials made of metallic and non-metallic elements
bound by ionic or non-ionic bonds with occasional covalent bond, and are char-
acterized by both brittleness and hardness. Many types of ceramic materials are
used in practice and they are generally divided into two large groups: inert ceramics
such as alumina (dense aluminum oxide), zirconia (zirconium oxide), calcium
sulfate, and pyrolytic carbon; and bioactive ceramics that are designed to induce a
reaction from the surrounding tissue such as hydroxyapatite, -tricalcium phos-
phate, and silica-based or calcium-based bioglasses.
Inert Ceramics: Alumina has a very low coefcient of friction when articulated
against UHMWPE due to its high wettability that reduces friction and provide
self-lubrication during articulation. The combination of low friction, improved
lubrication, and reduced wear has led to the popularity of alumina as a bearing
surface for the femoral head in total hip replacement (Garino 2013; Piconi 2011).
Zirconia is stronger and denser than alumina, and it can be polished to a ner
surface nish, resulting in lower wear rates than alumina in a laboratory setting.
Zirconia is also used as femoral bearing surfaces in total hip implants and in
powdered form as a radiopacier in some formulations of PMMA bone cement.
Unlike alumina, zirconia should not be used in ceramic-on-ceramic articulations.
A high rate of early fracture of zirconia heads has led to a large recall, hence the
use of zirconia as bearing surface subsequently decreased. However, newer
zirconia-toughened alumina matrix composites have been developed to provide
greater strength and fracture toughness than alumina alone (Chang 2014; Heyse et al.
2012).
Bioactive Ceramics: These materials possess special characteristic that allows a
formation of bonding with living tissue. They take advantage of the tissues cellular
physiology and structural component materials to induce bone remodeling, growth,
and integration into the implant (Rahaman 2014). An ideal bioactive ceramic would
actually spur bone growth adjacent to the implant, promote integration of the bone
with the implant structure, and gradually biodegrade as healthy bone tissue replaces
the articial structure. Calcium-based ceramics (such as calcium phosphate, calcium
sulfate, and hydroxyapatite) and bioglasses are two general categories of bioactive
ceramics that have been developed. Bioglass is mineral rich structure that can be
tailored to optimize the tissue response. Hydroxyapatite (Ca10[PO4]6 [OH]2) is a
logical choice for an osteophilic substrate since it is naturally occurs in bone

mineral. Hydroxyapatite coatings have been used for decades both in dental and
orthopaedic applications. As commonly occurs with bioactive agents, there was
initial enthusiasm for coating the entire implant with hydroxyapatite to provide
strong xation to surrounding bone. However, over time it became apparent that
hydroxyapatite is best used tactically to enhance regional bone xation. In total hip
replacement implants, for example, hydroxyapatite coating is best used around the
implant shoulder, which is the most important region for robust bone apposition and
implant xation (Bose et al. 2015). -tricalcium phosphate (Ca3[PO4]2) and bio-
glasses are usually utilized as a part of basic applications (e.g. lling cancellous
bone defects), for bone graft replacement as substitutes or extenders, and especially
as an aide to fracture repair or fusion in the setting of trauma, orthopaedic oncology,
or spine surgery (Goff et al. 2013; Hartigan and Cohen 2005). The llers are
available in forms including granules, pastes, and malleable sheets.
3.2 Types and Applications of Orthopaedic Implants
Orthopaedic surgeons are the most common users of implants for treating,
improving, or replacing anatomical elements of musculoskeletal system. Various
implant sizes and shapes are used which are determined by the location and the
disease to be treated. Metal implants consist of many types of plate and screw
systems, intramedullary nail system, pedicle screw system that are used for fracture
and reconstruction of bone and spine (Fig. 5). Polymer implants mostly used for
biodegradable screw, while hydroxyapatite ceramic is used as a bone graft to
accelerate bone healing. Certain implants use a combination of biomaterials such as
Fig. 5 Various types of implants used for traumatic purposes: a plates in various types and sizes;
b angled-blade plate, commonly used for proximal or distal femoral fractures; c dynamic hip
screw, widely used for cases in proximal femoral fracture; d interlocking nail, suitable for long
bone fracture of lower extremity; and e pedicle screw and rod, used for posterior spine stabilization
the case of a total joint replacement that combines metal and polymer or ceramic. In
general, implants used by orthopaedic surgeon are divided into: traumatic implants
mainly for fracture xation; and reconstructive implants which are used to replace
body parts damaged by a disease such as osteoporosis. In Indonesia, the most used
type is currently the traumatic implants, but gradually the use of reconstructive
implants also begins to increase with the aging Indonesian population.
Traumatic Implants
Due to high incidence of trauma cases in Indonesia, traumatic implants are still the
most frequent type of implants used in Indonesia. These include screws, plates,
nails, and pins either to be used as internal or external xation of fractures (Fig. 6).
External xator is preferable to be used for open fracture with severe soft tissue
injuries in order to stabilize the fracture comminution and to handle the risk of
postoperative infection. In the case of extramedullary xation, plates are combined
with screws above and below the fracture or using rods or nails inserted into
medullary canal through the fracture site (Ito et al. 2015).
Like any other living tissue, bone responds to environmental and physiological
changes. When bone grows, there is an increase of extracellular matrix material to
the endosteum and periosteum layer. This will result in bone growth of both in
length and diameter. Wolff hypothesized in 1892 that under continuous loading
bone will grow better. Bone that does not get enough loading will lose its mass,
while bone experiencing greater load will increases its mass in response to reduce
stress (Frost 1994). Throughout life time, the process of removal and replacement
of bone occurs continuously, known as remodelling. In fracture healing, this
Fig. 6 Application of traumatic implants: a angled-blade plate for proximal femoral fracture,
b dynamic hip screw for femoral neck fracture, c intramedullary nail used in femoral shaft fracture,
d pedicle screw and rod applied for lumbar stabilisation (Courtesy of Dr. Soetomo General
Hospital, Surabaya)
process enables the recycling process to occur continuously on the bone and into
healthy tissue to prevent the accumulation of micro fractures that can lead to failure
of the bone structure (Grimm 2003).
Fracture can heal with or without the formation of external callus depending on
the mechanical environment supporting the healing process. The one that is xed
more anatomically and more rigidly will heal without the formation of external
callus whereas that of being less rigidly xed will form external callus. In overall,
the process of fracture healing requires a suitable and favorable biological and
mechanical environment (Cunningham 2001). A higher mechanical resistance of
metallic implants (i.e. Youngs modulus) compared to cortical bone leads to a
decrease in mechanical stress received by the fracture site, known as stress
shielding effect. In long-term xation, this condition will result in increased bone
resorption surrounding the implants. This device-related osteopenia or osteoporosis
is caused by the increasing activity of osteoclast in respond to stress-shielding
effect. This effect must be avoided in order to maintain good bone strength and it is
advisable to remove the implant after certain period of bone union especially in
weight-bearing bone (Ito et al. 2015).
When an implant is strained under continuous stress, it will reach a point of
ultimate resistance which will result in failure when the point is surpassed (Fig. 7).
One of the most commonly encountered failure is fatigue where cyclic load, which
does not necessary to be massive, cause a repeated stress below ultimate strength
leading to crack propagation and ultimately fracture (Kanchanomai et al. 2008;
Mann and Allen 2013). In details, fatigue failure occurs at three stages: crack
initiation, propagation and nally the catastrophic manifestation when the crack
reaches a critical length of which the remaining material cannot withstand the
applied stress (Rabbe and Anquez 2013). Under fatigue condition, the number of
stress cycles that the material can withstand is inversely proportional to the mag-
nitude of the applied stress; that is, the number of stress cycles the material can
withstand increases as the stress intensity is reduced (Mann and Allen 2013). When
environment is in favor to enhance crack formation, for example in exposure of
Fig. 7 Failure of implants: a fracture of a plate; b fracture on hemiarthroplasty of a hip joint

implants to scratches and nicking, the fatigue failure will be more rapidly reach and
the device life span will be greatly reduced. Any factor that arrests or slows down
crack propagation will increase fatigue life. In a certain composite system, a crack
propagates through a ber-reinforced matrix will stop when it reaches the boundary
of a strong ber within the matrix. The crack will remain stagnant until enough
damage accumulates to move the crack through the ber (Wright and Maher 2008).
The environment inside human body is physically and chemically different from
the ambient condition. Consequently, a metal that performs well (inert or passive)
in the air may suffer a severe corrosion in the body. Corrosion creates two prob-
lems: (1) it often leaves behind damaged regions on the surface of orthopaedic
implants that act as stress risers, markedly decreasing implant strength; and (2) it
releases to the surrounding environment corrosion products that can adversely affect
biocompatibility, cause pain, swelling, and destruction of nearby tissue.
Orthopaedic implants can be susceptible to several corrosion modes, depending on
their geometry and manufacturing history, the in vivo conditions under which they
perform, and the presence of surface defects (Chen and Thouas 2015; Wright and
Maher 2008). The most common forms of corrosion are uniform corrosion, inter-
granular, galvanic, pitting, fatigue corrosion and stress corrosion cracking.
Corrosion process is determined by two factors: (1) thermodynamic driving forces,
which cause corrosion (oxidation and reduction) reactions; and (2) kinetics, which
determines the rate of those reactions. The thermodynamic driving force corre-
sponds with the energy required or released during a reaction, while the kinetics
barriers are related to factors that impede or prevent corrosion reactions from taking
place (Jacobs et al. 1998; Manivasagam et al. 2010). Oxide lm formed on the
surface of metallic materials plays an important role as an inhibitor for the release of
metallic ions. During corrosion process, the composition of oxide lm changes
according to reactions at the interface of metal surface and living tissue, and hence
this lm plays a very important role, not only for corrosion resistance but also for
tissue compatibility (Manivasagam et al. 2010).
Reconstructive Implants
Articial joints are indicated for patients with severe destruction of any joints from
those on small ngers to hips or knees caused by trauma, osteoarthritis or tumors.
The affected joints are therefore replaced by prosthetic devices in order to restore its
normal function and eliminate pain. Figure 8 shows example of various implants
used in reconstructive surgeries. Hip prostheses consists of two separate compo-
nents, namely the femoral and acetabular parts. The femoral part itself is further
constructed by two main parts which are the head and the stem. Unlike the femoral
part, the acetabular one can be separated into the cup and its liner. Materials used
for making the components can come from metal alloys such as Co-Cr-Mo or Ti
alloys, or ceramics and polymers. Since the invention of early prostheses by
Charnley in 1970s, the most widely used combination for bearing surfaces is the
metal-on-poly(ethylene). This combination is consistently being developed for all
the prostheses to improve its design and techniques of implantation. The
metal-on-poly(ethylene) bearing has become the most favorable and the gold
standard in hip prostheses as it proved its safety, predictability and

cost-effectiveness. However, the risk of complication caused by the presence of
poly(ethylene) debris remains a major concern and downside. The debris might lead
to accumulation of cytokines and proteolytic enzymes which causes peri-prosthetic
osteolysis. In the end, this process may lead into the most feared complication of
implant failure due to aseptic loosening. Several measures had been taken to
minimize the complication caused by the debris by improving the wear resistance
through gamma irradiation. However, despite the effort of minimizing the com-
plication, there has been shift of interest towards the use of metal-on-metal bearings
(Knight et al. 2011).
Due to the risk of metal toxicity, cancer development, hypersensitivity reaction
and prosthetic loosening, metal-on-metal bearing was abandoned in 1970s.
However, it was later found out that the cause of failure of the early model of this
prosthetic was not due to the nature of the bearing material itself but rather caused
by improper design and implantation technique. The metal-on-metal bearing is
favorable than the metal-on-poly(ethylene) since it has better wear resistance (*60
times more resistant), lower brittleness of the femoral head component, better joint
stability (due to larger possible head diameter), lower incidence of dislocation, and
lower osteolytic and peri-prosthetic inflammation reaction. However, there is pos-
sible risk from debris released from metal-on-metal bearing. The released metal
ions increase the Co and Cr ions blood level three to ve times higher, even though
the long-term effect is still being investigated (Zywiel et al. 2011; Drummond et al.
2015).
Due to issue of wear resistance and friction problem in the two previously
mentioned bearings, ceramic-on-ceramic bearing was then introduced by using
alumina and zirconia as the materials. This type of bearing is more superior to metal
or poly(ethylene) counterparts in term of hardness, scratch resistance, and inert
characteristic of the debris. Ceramic bearing is very suitable for active and mobile
patients as it has very good durability and low friction. The low friction comes from
its hydrophilic property which improve lubrication on its surface. However, apart
from its superiority, the cost of ceramic bearing is higher. The adverse complication
might occur as a result of loose body presence. This loose body usually originates
from chipped parts of the contact surface when improper technique of insertion is
applied or when head dislocation occurs (Zywiel et al. 2011; Macdonald and
Bankes 2014).
Apart from the characteristic of the bearing surface materials, the interface
between bone and prostheses is not less important. There are two kind of
bone-implant xation: cementless and cemented xations. Cementless implants
provide better possibility for revision surgery when needed and they also have
better soft tissue preservation when being implanted. When cement is not used, the
implants must have special characteristics on their surface to ensure xation (i.e.
porous or grit-blasted surface). The most recent special surface in cementless
prostheses is the use of hydroxyapatite coating that promotes bone growth onto the
implant surface, therefore increases xation strength. On the other hand, cement is
used as space ller rather than as glue. Cemented implants use methacrylate cement
Fig. 8 Various prostheses

used in reconstructive
surgery: a total hip
arthroplasty; b total knee
arthroplasty; c mega
prostheses for distal femur
(Courtesy of Dr. Soetomo
General Hospital, Surabaya)
to improve xation. In around 1950s, Charnley introduced the used of dental

cement although in later time, the failure of cement shifted the favor of cemented
implants (Khanuja et al. 2011). Comparing the durability of both xation tech-
niques, cemented one has lower durability after 10 years compared to the
cementless one, thus causes a higher rate of revision surgery due to aseptic loos-
ening. However, without counting the revision surgery, cemented stem performs
slightly better than cementless one (Mkel et al. 2008).
Wear and osteolysis following total joint arthroplasty occur as a result of a
complex interaction of many variables. These variables include: patient-specic
characteristics (e.g. weight, activity level and age) which affect the magnitude and
direction of loads across the joint as well as joint kinematics; and implant design
and material factors that control how the implant components respond to the
mechanical burden placed upon them (Gillespie and Porteous 2007; Foran et al.
2004). Equally important, surgical factors (e.g. component position and orientation)
can also affect joint loads and kinematics. When surgical technique is optimized,
the ideal implant position is realized and the best possible wear performance of the
total joint arthroplasty can be achieved. However, when malposition, damaged, or
misassembled occurred, a specic prosthesis may experience greatly increased
wear. Osteolysis can occur as a response to peri-prosthetic particulate debris that
results from and is dependent on material type as well as particle size, shape, and
amount. In overall, the multiple factors influencing clinical wear performance of hip
and knee arthroplasty can be separated into patient specic, implant-specic, and
surgical factors that contribute to wear directly or indirectly (Tsao et al. 2008).
4 Recent Development of Orthopaedic Implants

in Indonesia
4.1 The Rise of Local Implant Industry
Until the era of 1990s, all orthopedic implants required for surgeries in Indonesia
are imported from overseas. There was no local implant industry. Imported implants
are relatively expensive for Indonesian people as most of the population is not
covered by adequate health insurance. Moreover, as the products were mostly
imported from Europe and USA, their size is often too big to t Indonesian people
anatomy. These factors has caused orthopaedic service was not optimally delivered
and many patients then looked for alternative therapies such as the service of bone
setter that offers lower price. This condition has been causing a high number of
disability on orthopaedic patients. Nowadays, in line with the improvement of
Indonesian economic, education and lifestyle, alternative medicine has been
becoming less popular that hospital (modern) medicine. On the other side, traumatic
fracture incidences also increases following the increasing number of motor vehicle
accidents, especially motorcycle. Therefore, the need for implants in Indonesia
especially the traumatic type is very real.
Fig. 9 Locally made orthopaedic implants: various plates, screws and arthroplasty implants
(Courtesy Dr. Soetomo General Hospital, Surabaya)
This situation has become a trigger for many orthopaedic surgeons at Dr.
Soetomo General Hospital, afliated with the Faculty of Medicine, Airlangga
University in Surabaya, to become the pioneer in producing local implants. In 1993,
the rst implant manufacturer company was established with the main products
focused on plates and screws and arthoplasty implants (Fig. 9). The material used
for producing the implants was mostly type 316L stainless steel sheets, rods and
ingots imported from the overseas. The manufacturing process involved machining
and casting processes. For fabricating bone plates, the stainless steel sheet was cut
and drilled according to the predetermined size (patient specic) and number of
holes, and then nished by polishing. Since the implants are made locally and near
to the hospital, they offer competitive price and deliverability. Beside more rea-
sonable price, the implants offer many advantages including adjustable size that ts
to Indonesian people posture, and can be custom-made for specic patients need
Fig. 10 Investment casting process of bone plates: a implant model; b waxed model; c cast
product with casting system; d pre-nished implants (Courtesy of Dr. Soetomo General Hospital,
Surabaya)
and disorder. This local implant industry has received a lot of appreciation from
many users in the country and the implants have been distributed not only in East
Java but started to reach every corner of Indonesia.
4.2 The Challenge and Collaboration
Nowadays there are several implant factories that produce local implants, but still
they could not fulll the high demand of implants in Indonesia. Moreover, the
technology used by local manufacturers still has many limitations including low
production capacity and limited product variety (mainly for complex shaped
implants such as arthroplasty). The type of raw materials being used is still limited
to stainless steels as the price for other metals (e.g. Ti and Co-Cr alloys) are still
considerably too expensive.
The orthopaedists at Dr. Soetomo General Hospital have been collaborating with
metallurgical scientists and engineers to address the above challenges. They have
been conducting R&D activities on orthopaedic implants manufacturing technology
with the main purpose to produce high quality implants in large quality at low or
reasonable price. Since 2001, the Department of Orthopaedics and Traumatology,
Faculty of Medicine, Airlangga University has been collaborating with the Centre
of Material Technology, Indonesian Agency for the Assessment and Application of
Technology (better known as BPPT) in making bone graft from synthetic
hydroxyapatite. Since 2005, this collaboration has been focusing on developing
investment casting technology for orthopaedic implants (Fig. 10). This collabora-
tion receives a full support from the Indonesia Government as it aligns with the
national programme on supporting local products and the new general health
insurance programme which covers every citizen of Indonesia.
Acknowledgment The authors acknowledge the supports from Dr. Soetomo General Hospital,
Surabaya and the Indonesian Ministry of Health (FM, LW), and the Axis of Regenerative
Medicine, CHU de Quebec Research Center at Saint-Franois dAssise Hospital, Qubec City
(HH).
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Biomaterials in Dentistry
Margareta Rinastiti
Abstract Dental materials are used for the replacement of destroyed or lost
structures and for the restoration of disturbed functions of the orofacial organ (hard
tooth substance, teeth, and soft tissues of the mouth). Among the main challenges in
restorative dentistry in Indonesia are the caries, recurrent caries due to the leakage
or restoration failure that may lead to infection of the pulp and periodontal tissue.
Therefore, it is desirable to develop dental materials having ability to seal the
marginal interface between material and tooth structure, bioactivity to promote
remineralization and good bonding with tooth structure and antimicrobial capa-
bilities. This chapter describes dental materials in restorative dentistry, the most
common dental problems in Indonesia, and the development of local bioactive
dental materials by utilizing the diversity of natural resources in Indonesia.
Keywords Biomaterials caries dental restorative material operative den-

tistry natural material
1 The Importance of Oral Health and Dental Problem
The mouth is the gateway to the body, performing dozens of functions that place
high demands on its unique hard and soft tissues. Oral health is essential to general
health and quality of life. Good oral health enhances our ability in speaking,
chewing, biting, tasting, swallowing and psychosocial wellbeing. The most
prominent features of the oral cavity are the teeth that are composed of three
specialized calcied tissues, enamel, dentin and cementum that are supported by
bone and gingival tissue. The teeth has four major functions: mastication, aesthetic,
phonetic and protection of supporting tissue. Normal tooth form and proper
alignment ensure efciency in mastication. The teeth cut, tear and grind food in the
M. Rinastiti (&)
Department of Conservative Dentistry, Faculty of Dentistry,
e-mail: rinastiti@ugm.ac.id

184 M. Rinastiti
mouth, enable digestive enzymes greater access to the food material and so assists
their role in the digestive process. A harmonious form, contour, color, position of
the teeth are important to a persons physical appearance. Speech articulation is
dependent on the form and alignment of both anterior and posterior teeth.
Moreover, form and alignment of the teeth assist in sustaining the teeth in the dental
arches by assisting the developmental and protection of the gingival tissues and
alveolar bone that supports them (Heymann et al. 2012). A defect of the tooth will
disturb teeth function and may lead to more serious problems.
There are four conditions that result in defective tooth structure: dental caries,
tooth wear, trauma and developmental defects (Fig. 1) (Kidd et al. 2003). Among
those conditions, dental caries is a major public health problem globally, affecting
6090 % of school aged children and the vast majority of adults (Petersen et al.
2009). The development of dental caries is a dynamic process causing progressive
destruction of hard tooth substance (enamel, dentine and cementum) (Yip and
Smales 2013). This occurs as an interaction between the biolm and the tooth
surface and subsurface. When the demineralization and remineralization equilib-
rium is out of balance, it leads to mineral loss. Remineralization can arrest or
reserve progression of disease that lead to change the quality of minerals (Pitts
2004). A caries lesion can be progressive and if not treated may expand in size and
progress to the pulp leading to pulp inflammation thus pain and discomfort, and the
end result will be loss of vitality and loss of the tooth.
Instead of caries, the loss of dental hard tissue occurs as a result of tooth wear.
Tooth wear is a common clinical occurrence and may cause challenges in diagnosis
and treatment. The lost of dental tissue may become excessive as a result of erosion,
attrition, abrasion or abfraction (Fig. 2). Similar to the effects of dental caries, these
conditions may exhibit dental problems such as: exposure of dentin, notched cer-
vical surfaces, sensitivity, pulpitis, loss of vitality and inability to make contact
between worn incisal and occlusal surfaces in any excursion of the mandible
(Heymann et al. 2012). In contrast to caries and tooth wear that arise in slow onset,
Fig. 1 Defective tooth structure: a enamel caries lesion in the buccal ssure of mandibular rst
molar; b dentin caries lesion in the proximal area of maxillary rst premolar; c extensive dentin
caries lesion with pulp polyp of the mandibular second molar (Courtesy of HA Pribadi)
Biomaterials in Dentistry 185
Fig. 2 Lost of dental tissue: a traumatized maxillary rst incisal that has become non-vital;
b abfraction lesion involving rst and second premolar (Courtesy of L Suprapto)
traumatic injuries are acquired suddenly and can produce local injuries like lacer-
ations, alveolar fracture, root fracture, fracture of the crown and luxation of the
tooth (Kidd et al. 2003). Under those circumstances, highly deleterious effects on
the function of teeth will occur. The main issues that arises from tooth wear are poor
appearance, poor function, sensitivity, and ongoing concerns about continued wear
(Ricketts and Bartlett 2011). Consequently, the defect of the tooth requires
non-operative or operative intervention as preventive and curative treatment.
2 The Most Common Dental Problems in Indonesia
In 2013, the Indonesian Ministry of Health conducted the epidemiology research on

health states of Indonesia population, including oral health states. The study cov-
ered 33 provinces and 497 regions and generated the prevalence and incidence of
oral health, including the assessment of dental caries experienced amongst the
population by using DMF-T index. DMF-T was introduced by Klein, Palmer and
Knutson in 1938, modied by WHO (World Health Organization). The DMF Index
is applied to the permanent dentition and is expressed as the total number of teeth or
surfaces that are decayed (D), missing (M), or lled (F) in an individual. When the
index is applied to teeth specically, it is called the DMF-T index, and scores per
individual can range from 0 to 28 or 32, depending on whether the third molars are
included in the scoring. When the index is applied only to tooth surfaces (ve per
posterior tooth and four per anterior tooth), it is called the DMFS index, and scores
per individual can range from 0 to 128 or 148, depending on whether the third
molars are included in the scoring (Cappeli and Mobley 2007).
The DMF-T index in Indonesia is 4.6 composed of D-T = 1.6, M-T = 2.9,
F-T = 0.08. Index 4.6 can be interpreted that in a population of 100 people, there are
460 decayed, missing or restored teeth. This index is higher than goals for the year
186 M. Rinastiti
2000, which indicated a rate of not more than 3 DMF-T. Based on the data pub-
lished by the Indonesian Ministry of Health, in 2013, the DMF-T index of each
province in Indonesia can be seen in Tables 1 and 2 below (Department of Research
and Development 2013):
It can be concluded that the linear increases in caries with age in both children
and adults indicate that caries affect individuals throughout their life. The
Table 1 DMT index of Indonesia provinces

Province D-T M-T F-T DF-T DMF-T
Aceh 1.4 2.6 0.08 0.02 4.0
North Sumatra 1.3 2.3 0.05 0.02 3.6
West Sumatra 1.7 3.1 0.06 0.03 4.7
Riau 1.6 2.3 0.12 0.03 4.0
Jambi 2.3 3.1 0.04 0.01 5.5
South Sumatra 1.9 3.3 0.09 0.03 5.3
Bengkulu 1.3 2.0 0.09 0.03 3.3
Lampung 2.1 2.3 0.07 0.02 4.5
Bangka Belitung 3.0 5.5 0.05 0.01 8.5
Riau Island 1.6 3.2 0.11 0.03 4.9
Jakarta 1.1 2.5 0.32 0.08 3.8
West Java 1.6 2.5 0.08 0.02 4.1
Central Java 1.4 2.9 0.05 0.01 4.3
Yogyakarta 1.3 4.5 0.13 0.02 5.9
Jawa Timur 1.6 3.8 0.08 0.03 5.5
Banten 1.6 2.0 0.09 0.02 3.7
Bali 1.1 3.0 0.12 0.02 4.1
West Nusa Tenggara 0.8 2.1 0.03 0.01 3.0
East Nusa Tenggara 1.5 1.7 0.04 0.01 3.2
West Kalimantan 3.2 2.9 0.10 0.03 6.2
Cental Kalimantan 2.2 2.8 0.13 0.04 5.0
South Kalimantan 2.2 5.0 0.11 0.02 7.2
East Kalimantan 1.9 2.8 0.09 0.02 4.7
North Sulawesi 1.9 3.4 0.06 0.03 5.4
Central Sulawesi 2.0 3.5 0.05 0.01 5.5
South Sulawesi 2.0 4.0 0.05 0.01 6.0
Southeast Sulawesi 1.4 2.8 0.08 0.04 4.3
Gorontalo 1.3 3.0 0.01 0.00 4.3
West Sulawesi 1.5 4.0 0.03 0.01 5.5
Maluku 1.5 2.9 0.07 0.03 4.5
North Maluku 0.9 2.1 0.02 0.01 3.0
West Papua 1.1 1.5 0.02 0.00 2.6
Papua 1.6 1.5 0.11 0.03 3.1
Indonesia 1.6 2.9 0.08 0.02 4.6
Table 2 Indonesian Age (year) D-T M-T F-T DF-T DMF-T

age-categorized DMF index
12 1.02 0.34 0.04 0.02 1.4
15 1.07 0.34 0.05 0.01 1.5
18 1.14 0.45 0.07 0.03 1.6
3544 2.00 3.35 0.11 0.03 5.4
4554 2.13 5.65 0.14 0.04 7.9
5564 2.15 10.13 0.09 0.03 12.3
65+ 1.84 17.05 0.06 0.02 18.9
proportion of edentulous adults aged 65 years or more is still high, while the decay
teeth of population with ages 3364 years old revealed the highest index.
Since January 1, 2014, Indonesia has been started to roll out the National Health
Insurance System. Indonesian public awareness of oral health is low, and they tend
to seek treatment when there is a specic problem with their tooth. Therefore, the
cost of dental treatment is high due to the complexity and advanced nature of the
oral health problems. The effective demand of oral health care in Indonesia is low
(7 % of the population). Due to the delay treatment, the majority of dental health
cases ended with tooth loss (Dewanto and Lestari 2014). The National Health
Insurance System is expected to raise the dental visits and decrease the number of
oral health problems in Indonesia. Moreover, it also conforming to the global goals
for oral health 2020.
According to the Global goals for oral health 2020, caries needs to be managed
depending on the stage of progress, to prevent new lesions from forming and to
detect lesions sufciently early in the process. By the year 2020 the following will
have been achieved over dental caries baseline: (1) to increase the proportion of
caries free 6-year-olds by X %; (2) to reduce the DMFT particularly the D com-
ponent at age 12 years by X %, with special attention to high-risk groups within
populations, utilising both distributions and means; and (3) to reduce the number of
teeth extracted due to dental caries at ages 18, 3544 and 6574 years by X %
(Hobdell et al. 2003). Based on those goals, the use of appropriate biomaterial
should be considered.
3 Biomaterials in Restorative Dentistry
Dental materials are used for the replacement of destroyed or lost structures, (hard
tooth substance, teeth, soft tissues of the mouth) and for the restoration of disturbed
functions (masticatory, phonetic, esthetic, physiognomic) of the orofacial organ
(Tesk et al. 2000). Recently, the market for dentistry materials has been increasing
because restorative treatment remains the primary work of dentists. Restorative
biomaterials are designed to recover the shape and the function of the teeth, while
preventive materials are used to prevent oral health problems.
188 M. Rinastiti
3.1 Preventive Materials
The purpose of modern dentistry is the early prevention of tooth decay rather than
invasive restoration therapy. The materials that are categorized as preventive
materials are tooth paste, mouth washes, topical application and sealants. There are
two important principles that should be followed in the treatment of early decay:
(1) to reduce the etymological factor, i.e. dental plaque or bacterial biolm; and
(2) to increase the amount of remineralizing substances (Gonzalez-Cabezas 2010).
Toothpaste
Toothpaste is a colloidal suspension of a mixture of ingredients that must be
carefully balanced in order to provide an efcacious, safe, and consumer friendly
product. The removal of oral biolms from a tooths hard surfaces is crucial to
caries control and is most effectively accomplished by mechanical brushing with
toothpaste, especially in interproximal regions and posterior teeth along with the
use of adjunctive chemical agents (Sakguchi and Powers 2012). Generally tooth-
pastes are composed of colloidal binding agent; humectants; preservatives;
flavoring agents; abrasives to remove plaque, stains and calculus; detergents to
reduce surface tension and enhance removal of debris and therapeutic agents such
as stannous fluoride. It is widely understood that fluoride is the most important
component of toothpaste. There is strong evidence that daily use of fluoride
toothpaste has a signicant caries-reducing effect in young permanent teeth, inhibit
the development of caries 1927 % and providing remineralization of enamel
(Marinho et al, 2009; Twetman et al. 2003). To promote remineralization of pre-
viously demineralized enamel relies on calcium and phosphate ions from saliva, 10
calcium ions and 6 phosphate ions are required for every 2 fluoride ions to form one
unit cell of fluorapatite ([Ca10(PO4)6F2]) (Reynolds et al. 2008). Therefore, several
new remineralizing agents have been introduced to supplement and enhance the
ability of fluoride to restore tooth minerals.
Calcium phosphate formulations have been developed for addition to toothpaste,
varnishes, and gum. A milk product, calcium phosphate remineralization technol-
ogy based on casein phosphopeptideamorphous calcium phosphate (CPP-ACP)
was effective in remineralizing enamel subsurface lesions (Sakguchi and Powers
2012). Casein phosphopeptide forms nanoclusters with amorphous calcium phos-
phate providing a pool of calcium and phosphate which can stabilize calcium
phosphate on tooth surface, thereby maintaining high concentration gradients of
calcium and phosphate ions, and promoting remineralization. Additionally, CPP
can also decrease the count of S. Mutans as it has got the ability to integrate in the
pellicle. Even though CPP-APP is promising as a preventive material, its use in
products like fluoride varnishes remains problematic. The total time taken by CPP
ACP for remineralization is still not clearly established and needs further investi-
gation (Farooq et al. 2013).
Several commercial toothpastes are branded as treatment for sensitive teeth.
A study compared calcium sodium phosphosilicate-containing toothpaste with a
potassium nitrate, sodium fluoride, and silica dioxide containing toothpaste, and a
potassium citrate, sodium monofluorophosphate and silica dioxide containing

toothpaste, showed that those three desensitising toothpastes may be useful prod-
ucts for dentine hypersensitivity therapy. However, after immersion in the citric
acid solution and articial saliva the efcacy of tubular blocking was decreased
(Wang et al. 2010).
Mouth Rinses
Mouth rinses are used for a variety of reasons: to help prevent and control tooth
decay, to freshen breath, to reduce plaque, to prevent or treat gingivitis, to reduce
the speed that calculus forms on the teeth, or to produce a combination of these
effects. In conjunction with brushing and flossing, the general population often uses
these products as part of a daily oral care regimen (Silverman and Wilder 2006).
Typically, mouth rinses contains of active agent as an anti-caries or antimicrobial
such as bis-biguanides, phenols, quaternary ammonium compounds, oxygenating
compounds, plant extracts, fluorides, antibiotics and antimicrobial combinations
(Walker 1988). The solution generally consists of water, alcohol and preservative;
and surfactant, for instance Na laurylsulphate with the ph range from 3.4 to 6.6.
Mouth rinses reduce plaque by between 1360 % (Barnett 2006), and thereby
may reduce the cariogenic bacteria. Since 1960s, mouth rinses have been used as a
prophylactic method to prevent the dental caries in children and adolescents and has
shown average efcacy of caries reduction between 2050 %. Sodium fluoride,
stannous fluoride and amine fluoride are commonly used as agents in fluoride
mouth rinses to help control dental caries incidence efciently (Reich et al. 2002).
The alcohol-free chlorhexidine used as mouth rinse have been shown to result in a
signicant reduction in S. mutans and lactobacilli (Albertsson et al. 2012). Due to
its bacteriocidal properties, iodine has been utilized as an antiseptic mouth rinse.
Essential oil and herbal mouth rinses have also been introduced to the market. The
combination of fluoride and essential oils in a mouth rinse may provide anti-caries
efcacy, in addition to essential oils established anti-gingivitis efcacy (Zero et al.
2004). Although less potent than chlorhexidine, the herbal mouth rinse is a more
effective antimicrobial agent than the essential oil mouth rinse in inhibiting the
growth of oral bacteria in vitro. Furthermore, it may serve as a natural antimicrobial
mouthrinse alternative for patients who wish to avoid alcohol, articial preserva-
tives, and articial flavors and colors (Haffajee et al. 2008).
Topical Application
Topical application is a preventive treatment by apply varnish or gel containing
antimicrobial agent on the surface of tooth to prevent caries. In 2006, the Council
on Scientic Affairs (CSA) of the American Dental Association (ADA) published
recommendations for the use of professionally-applied topical fluorides for caries
prevention (American Dental Association Council on Scientic Affairs 2006).
Fluoride is the primary agent available for caries prevention. The local availability
of fluoride to the tooth surface has been shown to prevent caries by primarily three
mechanisms: (1) inhibiting demineralization of tooth enamel; (2) enhancing rem-
ineralization of tooth enamel prior to lesion progression; and (3) inhibiting the
enzyme activity of cariogenic bacteria (Featherstone 2000; Marquis 1995). Fluoride
190 M. Rinastiti
varnish and gel can be an effective agent in preventing new caries and in arresting
dental caries in the primary teeth of the children (Weyant et al. 2013).
Topical application containing Chlorhexidine (CHX), the component of bis-
biguanides is a promising new treatment for the prevention of dental caries. Overall,
the caries inhibiting effect of CHX of around 46 % (van Rijkom et al. 1996). CHX
varnish has a moderate caries-inhibiting effect when applied every 34 months.
However, after 2 years of application, it seems to diminish (Zhang et al. 2006).
Another agent that is used for topical application is xylitol, a ve carbon sugar
alcohol that looks and tastes like sucrose, thus it is a good sugar substitute.
Additionally its benecial effect is that it is not metabolized by the cariogenic
bacteri. It has caries- or MS-reducing effects of in young children and adults
(Mkinen et al. 2013).
Fissure Sealant
Caries potential is directly related to shape and depth of the pit and ssures.
A ssure sealant is a material that is placed in the pits and ssures of teeth in order
to prevent or arrest the development of dental caries. The sealant forms a smooth,
protective barrier by covering all the little grooves and dips (pits and ssures) in the
surface of the tooth, forming a micromechanically bonded, protective layer cutting
the access of caries-producing bacteria from their source of nutrients (Simonsen and
Neal 2011). The clinical success of sealings depends on the ability of the material to
solidly adhere to the enamel surface and securely isolate pits and ssures from the
oral environment. The application of sealants is often as soon as the emergence of
adult teeth, usually between 6 and 7 years of age. The rest are usually sealed as soon
as they appear, which can be any time between 11 and 14. Instead of being used for
primary caries prevention, current evidence indicates that sealants also are an
effective secondary preventive approach when placed on early non-cavitated cari-
ous lesions. In clinical situations in which a sealant has ben lost or partially
retained, it should be reapplied to ensure effectiveness (Beauchamp et al. 2008). It is
generally accepted that the effectiveness of sealants for caries prevention depends
on long-term retention which is related to the biodegradation of materials due to the
caries biolm, acid challenges, salivary enzymes, food and beverage (Beauchamp
et al. 2008) and biological outcomes such as the absence of caries in pits and
ssures after sealant application (Yengopal and Mickenautsch 2009). Therefore an
appropriate material should be chosen. The materials that are used to seal the pit and
ssure of the tooth, pit and ssure sealant are glass ionomer cement (GIC), resin
modication of glass ionomer and resin composite.
The use of GIC-based restorative materials as ssure sealant is advantageous
because they bond to dentin and enamel, release fluoride across an extended period
and are biocompatible. They also are technically less sensitive than conventional
resin-based materials. GICs adhere to dentin and enamel via ionic and polar
bonding. This action creates an intimate contact that facilitates fluoride ion
exchange of the hydroxyl ions in the adjacent enamel apatite (Francisconi et al.
2009). However, the clinical effect of fluoride release from glass ionomer cement is
not well-established (Beauchamp et al. 2008).
According to the results of a systematic review of the literature, sealing with

resin-based sealants is a recommended procedure to prevent caries of the occlusal
surfaces of permanent molars (Alonso et al. 2005). Resin modication of GI cement
(RMGI) was designed to produce favorable physical properties similar to composite
resins and retaining the features of GIC with a better physical properties, more
aesthetic and less water sensitive then conventional GIC (Sakguchi and Powers
2012). The addition of resin likewise should strengthen the relatively poor fracture
and wear resistance of RMGI thus increasing the retention rate beyond that of GIC
sealants (Winkler et al. 1996).
Another type of sealant material used today are resin-based composite adhesives
with a main component of Bis-GMA, in combination with 37 % phosphoric acid for
etching. The composites are lightly lled in order to keep the viscosity low, thus
allowing for a deep penetration of the material into pits and ssures (Donly 2002).
The action of resin-based materials as ssure sealant relies on the establishment of
an effective mechanical obstacle to the leakage of nutrients to cariogenic
microorganisms in the deeper parts of ssures (Simonsen 1991). Recently, use of
flowable resin composite as ssure sealant has increased due to its benecial
properties including low viscosity, low modulus of elasticity and ease of handling.
Preventive pit and ssure sealing does not seem to require materials with high
mechanical properties. A flowable resin composite with lower viscosity has a better
ability to flow by itself in small cavities and ssures than composites with a higher
viscosity, and hence can facilitate better application of the sealant material
(Beun et al. 2012). Flowable resin composite material, in conjunction with a
total-etch, single-bottle adhesive, showed slightly better retention rates than con-
ventional resin-based ssure sealant over a 24-month period (Erdemir et al. 2014).
Kantovitz evaluated the degradation of three sealant materials: resin, RMGIC
and GIC under acid in vitro (Kantovitz et al. 2009). The results showed that acidic
solution lead to fluoride release with both of the ionomeric materials. This phe-
nomenon is caused by an accentuated erosion of the polysalt matrix of the glass
ionomer and because of the dissolution of this material, which increases with low
pH. Typically, the high release of fluoride is followed by the degradation of
materials, as a result reduces the retention of ionomeric sealant. It was concluded
that the resin ssure sealant is less susceptible to degradation than RMGIC and GI.
Interestingly, when GIC sealant is lost partially or totally, the opening of the
ssures remains sealed. It is highly effective because of the isolation of bacteria
from nutrients in the substrate below early carious lesions that have been sealed
and/or the release of fluoride into the dentin (Oong et al. 2008). In contrast,
resin-based sealants have been shown to lose almost all of their protective effect
once their retention is lost (Yengopal and Mickenautsch 2009). A 2-year report on
the clinical performance of a RMGI sealant compared to a light-initiated
resin-based sealant showed 0 % complete retention and 38 % complete loss of
the RMGI sealant, and 32 % complete retention and 10 % complete loss of the
resin-based sealant (Smales and Wong 1999). Another researcher reported that
retention rates of GIC sealant ranges from 83 % at 6 months to 70 % at 3 years, with
overall retention at 44.6 % and partial retention was 83.1 % (Komatsu et al. 1994).
192 M. Rinastiti
3.2 Operative Dentistry Materials
The operative treatment is chosen when caries or non caries lesions have progressed
into a clinical breakdown of the enamel surface with dentin exposure.
Glass Ionomer Cement
Glass ionomer cement (GIC) is an appropriate material for use in minimally invasive
dentistry (MID). The objective of the dentist in operative dentistry based upon the
MID concept is to preserve a healthy set of natural teeth for each patient while aiming
to optimally conserve the human body and its function. Glass ionomer cement
materials, presented in a variety of formulations designed for particular clinical
indications, present unique opportunities to accomplish a variety of clinical objec-
tives and consist of three types. Type I is intended as luting cement, type II as
restorative materials, and type III as liners and basis. As lining cement, GICs that can
be used are biological seal and cariostatic. Type II GICs are indicated for area without
stress bearing, class III and V restorations in adult, class I and II restoration in primary
dentition, temporary restorations, restoration of erosive/abrasive lesions without
cavity preparation, sealing and lling of occlusal pit and ssures, repair of defective
margins in restorations, minimal cavity preparations in a proximal lesions through
buccal and occlusal approach (tunnel preparations), core built up, and provisional
restorations where future veneer crowns are contemplated. The using of GIC for
luting purpose because of their fluoride leach which useful in patients with high caries
incidence and its translucency (Kidd et al. 2003; Sakguchi and Powers 2012).
Glass ionomers are water-based cements that are formed by an acid-base reac-
tion between a calcium-based fluoroaluminosilicate glass powder and a polyalk-
enoic acid liquid. The acid attacks the glass particles, causing a release of calcium,
aluminum and fluoride ions. The fluoride ions become incorporated into the matrix
and can readily diffuse into the surrounding tooth structure and saliva (Tyas et al.
2000). Additionally, it can take up fluoride from the environment, which is pro-
vided by exposure to fluoride treatments and toothpaste (Rothwell et al. 1998).
The acid-base reaction involved in the setting mechanism for these materials was
hydrolytically unstable in its early stages. This meant that they were very sensitive
to water loss and water uptake for at least 1 h after mixing and possible for the
cement to dehydrate if left exposed to air. It was subsequently shown that the period
of sensitivity for the restorative esthetic materials is even longer, and it is conve-
nient to maintain them in isolation for up to 24 h (Wilder et al. 2000). In spite of
some shortcomings, the advantages of GICs as restoration material showed very
low polymerization shrinkage and are thermally compatible with tooth structure.
These materials can bond to dentin surfaces without removing the smear layer and
their biological compatibility is well proven (Francisconi et al. 2009). In addition,
using the most current formulation of GIC can be placed and nished in a single
visit and have achieved an aesthetic translucency that is highly desirable.
As a luting cement, GICs fulll clinical requirements in that: (1) they adhere
chemically to the tooth structure, providing a sealing of the dentinal surface,
(2) they are hydrophilic and, therefore, provide an appropriate compatibility with
the challenging environment of the mouth, and (3) they are easily cleaned from the
surrounding area after cementation (Francisconi et al. 2009; Kilpatrick 1996). The
rationale for using GICs as liners is that they can be easily manipulated into cavity
preparations and provide a release of fluoride thereby reducing the risk of recurrent
caries.
Resin Composite
Resin-based composites are increasingly used in dentistry in order to restore
damaged parts of dental tissues or to reconstruct missing teeth. Composites have
good aesthetic properties and by employing adhesive technologies, they allow for
minimally invasive interventions which may not always require tooth preparation
(Bouschlicher et al. 1997; Gordan et al. 2003). Composites are materials consisting
of at least two different classes of materials i.e. metals, ceramics, and polymers with
signicantly different physical and chemical properties. The different materials
remain separated upon mixing. Composite resins consist of an organic resin matrix,
inorganic llers, a coupling agent and additional component, like an initiator, sta-
bilizer and pigments to produce the different shades (Ferracane 1995).
The resin component of resin composite is monomer that builds repetitive units
that are bound together to form a polymeric matrix. Polymerization occurs through
the carbon-carbon double bonds of two methacrylate groups (Peutzfeldt 1997). The
2,2-bis[4-(2-hydroxy-3-methacryloyloxypropoxy) phenyl] propane: BisGMA is
most commonly used as the organic phase of dental restorative materials because of
its high level of strength and hardness (Amirouche-Korichi et al. 2009). However, it
has drawback properties: very high viscosity, owing to hydrogen bondings between
the hydroxyl groups, which limited the incorporation of inorganic llers and hence
a low nal DC (Atai et al. 2004). Therefore, a reactive diluent, such as triethylene
glycol dimethacrylate (TEGDMA), ethoxylated bisphenolglycidil methacrylate
(Bis-EMA), triethylene glycol methacrylate (TEGMA), and diurethane
dimethacrylate (DUDMA) is added to improve the viscosity, reactivity in the nal
conversion of the matrix phase (Bowen and Marjenhoff 1992; Eckerman et al.
2004; Ferracane 1994).
Filler particles influence the physical and mechanical properties of the com-
posite. They reduce the coefcient of thermal expansion, cure shrinkage, provide
radio-opacity, improve handling and increase aesthetic results (Labella et al. 1999).
The main llers are silicon dioxide, boron silicate and lithium aluminum silicates
(Xu 1999). In some composites, heavy metal particles that are radioopaque such as
barium, strontium, zinc, aluminum or zirconium are added (Hosoda et al. 1990).
According to the particle size, a composite can be categorized as: traditional
composite (1020 m), microlled (0.010.05 m), hybrid (large particle: 10
20 m; colloidal silica: 0.010.05 m), microhybrid (0.16.0 m), nanohybrid
(microller: 0.12.5 m; nanoller: 2050 nm) and nanolled (5100 nm)
(Sakguchi and Powers 2012).
A good adhesion between matrix and ller prevents erosion of the ller surface
and facilitates stress transfer between those two components, thus increasing the
mechanical properties of composites (Lin et al. 2000). The ller particles are
194 M. Rinastiti
silanated for suitable adhesion to the organic matrix. The organofunctional silane
most commonly used in dental-composites is -methacryloxypropyltrimethoxysi-
lane (-MPS) (Ferracane 1995). Dental composites also contain chemical sub-
stances which initiate and promote the polymerization reaction such as benzoyl or
lauryl peroxide, various tertiary amines and camphorquinone (Ruyter 1988). The
newer initiator is called ivocerin. It is capable of absorbing light at a higher
wavelength range than acyl phosphine oxide, and can therefore be activated by all
commercially available (halogen, LED) polymerization lights (Todd and Wanner
2014). To prevent polymerization during the storage of composite and avoid,
butylated hydroxytoluene and hydroquione are usually used in dental composites
(Klapdohr and Mozner 2005).
As operative dentistry materials, resin composites are used for a restorative
materials, cavity liners, pit and ssure sealants, cores and build ups, inlays, onlays,
crowns, provisional restorations, cements for single or multiple tooth prostheses or
crown, and root canal posts (Ferracane 2011). The development of resin composite
is very progressive. Recently, the size of ller is reduced to get a more easily and
effectively polished material, instead of to improve wear resistance. Hitherto the
development of matrix is not as fast as the development of ller particle, it is known
that some new resin matrices or combination of monomer have been investigated to
reduce polymerization shrinkage and degradation. The latest development is resin
composite bulk ll that enable up to 4- or 5-mm thick increments to be cured in one
step (Ilie et al. 2013), allowing for quicker procedures without impairing properties
such as depth of cure, conversion, polymerization shrinkage, and shrinkage stress
(Ilie et al. 2013; Moorthy et al. 2012; Ilie and Durner 2013). Nowadays a new
sonic-activated bulk-ll system was introduced to the market for posterior bulk
restorations. According to the manufacturers data, the Sonicll system is a unique,
sonic-activated bulk-ll system comprised of a specially designed hand piece and a
new composite material in unidose tips. The composite is a combination of flowable
and universal composites and incorporates a highly-lled proprietary resin with
special modiers that react to sonic energy. As sonic energy is applied to the hand
piece with ve different levels of flowability, the modier causes the viscosity to
drop (up to 87 %), increasing the flowability of the composite. When the sonic
energy is stopped, the composite returns to a more viscous, non-slumping state for
carving and contouring (Jackson 2011).
Compomers and Resin Modied Glass Ionomer Cements
Compomer is said to provide the combined benets of composites (the comp in
their name) and glass ionomers (omer). It is a polyacid-modied composite resin
which does not have water in its composition and the majority of components are
the same as for composite resins. Compomers consist of conventional composite
resin monomers (BisGMA or UDMA), together with novel monomers containing a
small number of carboxylic acid functional groups. The ller is similar to the
leachable ller on GIC which consists of conventional unreactive silica particles,
together with a small amount of acid leachable glass, strontium aluminosilicate or
barium aluminosilicate based, capable of forming glassionomer type structures
within the material (Eliades et al. 1998). The polymerization is activated by light
and followed by an acidbase reaction. The water activates the acid functional
groups and enables them to react with the strontium or barium glass and the excess
base might act to neutralize lactic acid in clinical active caries. The disadvantage of
compomer is the sorption to water that will decrease its mechanical properties
(Meyer et al. 1998; Nicholson and Alsarheed 1998).
Clinically, compomers are indicated to class II cavities, small clas I and clas II
cabities, root care, high risk patients, deciduous teeth and cervical defects. A high
bearing situations such as class II and clas IV is contraindicated. To overcome the
problems of moisture sensitivity and low mechanical strengths of GICs, some
hybrid versions of GIC, called resin modied glass ionomer cements (RMGIC)
were introduced. These materials maintain the clinical advantages of GIC and
include a small quantity of resin components such as HEMA or BIS-GMA which is
polymerized by light activation. RMGIC is focused on the matrix by grafting
unsaturated carbon-carbon bonds onto the polyalkenoate backbone and/or by
incorporating (di)methacrylate monomer(s) into the composition (Randall and
Wilson 1999; Wilson 1989).
The presence of unsaturated carbon-carbon bonds enables the covalent
cross-linking of the matrix via free radical polymerization reactions which signif-
icantly improves the mechanical properties RMGIC. The advantage of RMGIC is
the level of fluoride release that is similar to GIC. In addition, the mechanical
properties of RMGIC are weaker than resin composite but stronger than conven-
tional glass ionomer cement (Uno et al. 1996).
Metals
Metals have been used as dental materials for over a century. Generally, most metals
are strong enough to withstand maximum possible oral forces (Upadhyay et al. 2006).
Amalgam has been used as a direct lling material for more than a century. It is
created by mixing elemental mercury (4354 %) and an alloy powder (4657 %)
composed of mercury with silver and other metals such as tin and copper to give a set
material. Amalgam does not adhere to tooth structure and therefore needs to be
retained within the cavity by mechanical retention (Kidd et al. 2003). Amalgam is
very strong and lasts a long time, therefore it is indicated to restore those that are
subject to a lot of wear and tear such as molars. Amalgam is relatively inexpensive,
generally completed in one visit and resistance to further decay. However, it has some
disadvantages, such as requiring removal of some healthy teeth, its unaesthetic color,
that larger amalgam llings the remaining tooth may weaken and fracture, enhance a
temporary sensitivity to hot and cold and contact with other metals may cause
electrical flow (Kidd et al. 2003; Sakguchi and Powers 2012). In addition, a diversity
of opinion exists regarding the safety of dental amalgams due to toxicity of mercury.
The mercury could be released when lling is placed and during the functional
life of amalgam restoration (Kidd et al. 2003). However, based on analysis, it has
been concluded that the evidence supporting the safety of amalgam restorations is
compelling (Dodes 2001). The American Dental Association (ADA) and Food and
196 M. Rinastiti
Drink Administration (FDA) afrmed that amalgam is a safe and durable restorative
material (Donovan and Heymann 2010). Therefore, it is believed that the use of
amalgam should continue to be taught in dental school. Amalgam restoration is also
practiced in Indonesia. Another issue with amalgam is safety of the natural envi-
ronment. When mercury waste is incinerated, the volatilized mercury precipitates to
the environment and will enter the soil, surface waters, and food chain, thus an
appropriate management of amalgam waste have to be taken into consideration.
The dental alloys include noble alloys such as gold and palladium based alloys,
Au and Ca alloy combinations (for direct lling and wrought alloys), platinum and
platinum alloys and base metal alloys such as cobaltchromium casting alloys (for
partial dentures), chromium-containing casting alloys (for crowns and bridges), and
titanium alloys (for implants, partial dentures, crowns, and bridges) (Considine
2005; Morris et al. 1992a). Dental cast alloy has good mechanical properties in tin
section to replace lost tissue function. There are two categories of dental alloy:
noble alloys (gold and palladium based) and base metal alloys (nickel, iron and
cobalt based) (Morris et al. 1992b). These alloys are used for crown, metal ceramic
crown, removable and xed dentures, inlay and onlay.
Ceramics
Porcelain and ceramic materials have been used for fabricating esthetic dental
restorations since the early 1800s. Glass-ceramics are a popular choice due to their
excellent aesthetics and ability to bond to tooth structure allowing for a more
conservative approach. Common uses of ceramics are as full coverage crown, inlays
and onlays, bridge, veneering agents, castable ceramic and porcelain-fused-to-metal
(PFM) restorations (Leinfelder 2000). All-ceramic restorations are contraindicated for
the region where there is inadequate room for the ceramic to achieve its peak physical
properties or where tooth structure is inadequate to prepare the tooth (Lowe 2012).
Based on the processing technique, ceramic restoration materials can be clas-
sied as: (1) Powder/liquid, glass-based systems, (2) machinable or pressable
blocks of glass-based systems and (3) Computer-assisted design/computer-assisted
manufacture (CAD/CAM) or slurry, die-processed, mostly crystalline (alumina or
zirconia) systems (Kelly 2004). Based on the main composition, ceramic can be
categorized into: predominantly glassy materials, particle lled glasses and poly-
cristalline (Kelly 2008).
Predominantly glass ceramics are the best in mimicking enamel and dentin.
Optical effects are controlled by manufacturers by adding small amount of ller
particles. Glasses are three dimensional networks of atoms having no regular pat-
tern to the spacing (distance and angle) between nearest or next nearest neighbors,
thus their structure is amorphous or without form. Glasses in dental ceramics
derive principally from a group of mined minerals called feldspar and are based on
silica (silicon oxide) and alumina (aluminum oxide), hence feldspathic porcelains
belong to a family called aluminosilicate glasses (Kelly 2004). To improve
mechanical properties such as strength, thermal expansion and contraction behav-
ior, ller particles are inserted to the base glass composition. Particle lled glasses
are a product of inltrating molten glass to partially sintered metal oxides such as
alumina, magnesium alumina, and partially stabilized zirconia. They are divided
into two main groups: leucite-reinforced glass ceramic (LRGCs) and the lithium
disilicate glass ceramics (LDGCs). LRGCs are recommended for anterior restora-
tion, however, due to its high translucency, for the tooth with metal core, the nal
shades of the crown are not satisfactory, because this ceramic is unable to hide a
dark discolored core after endodontic treatment (Kelly 2004; Lowe 2012).
Polycrystalline ceramics contain no glass and generally are much tougher and
stronger than glass-based ceramics. These ceramics are solid-sintered, monophase
ceramics are materials that are formed by directly sintering crystals together without
any intervening matrix to from a dense, air-free, glass-free, polycrystalline structure
(Kelly 2008; Shenoy and Shenoy 2010).
Ceramics are brittle materials and may therefore undergo fracture during func-
tion or affects wear opposing dentition and restoration. There are many attempts to
toughen the brittle ceramics. Fabrication of interpenetrating phase ceramic com-
posites (IPCs) having three-dimensional interconnected microstructure can enhance
fracture resistance of the ceramics (He et al. 2011; Yang et al. 2003). An in vitro
study reported that the polymer-inltrated ceramic had higher fracture toughness
than the pre-sintered ceramics preforms. However, the hardness values were lower
than those in conventional porcelain. Combination of positive characteristics of
ceramic and composite resulting in a great strength, high reliability, precise and
accurate restoration (He and Swain 2011).
4 Recent Development on Dental Biomaterials

in Indonesia
Dental practice today utilizes a large number of biomaterials, becoming big busi-
ness for the dental industry in manufacturing and marketing materials for use by
dentists. Recently, the communication and collaboration between industry,
researchers and dental practitioners has been enhanced. The correlation between
laboratory and clinical data should be evaluated to increase the quality of bioma-
terials. In addition, the dental material research should emphasize the methodology
of bringing problems from the clinic to laboratory and vice versa. Based on the
index of DMF-T in Indonesia, it is clear that demand for restorative materials as the
foundation for replacement tooth structure is high. Moreover, to attain the World
Health Organizations Global goals for oral health 2020, the application of pre-
ventive dental material also crucial. Based on the data from Prof. Dr. Soedomo Oral
and Dental Hospital, Faculty of Dentistry, Universitas Gadjah Mada (UGM),
Yogyakarta, more than 95 % of dental materials used are imported products.
Indonesia has an enormous diversity in its natural resources. Therefore, as the
leading university on dentistry in Indonesia, many researchers in UGM have
worked on developing locally-sourced dental materials.
198 M. Rinastiti
Preventive materials including tooth paste and mouth rinses play an important
role in the in the prevention of caries. Handajani and colleagues developed tooth
paste and mouth rinses containing tea leaves extract (Camelia sinensis). Polyphenols
(catecihns) in tea leaves are known to have antimicrobial effects against some
bacteria. Epigallocatechin gallate (EGCG) is known as the most polyphenolic of tea
varieties. Two types of dentifrice containing of 2 % tea leaf ethanolic extract and
0.15 EGCG decreased the level of sIgA in gingivitis patients (Handajani 2006) and
decreased the dental plaque index (Handajani 2009). In addition, the increasing of
tea extract in dentrice heightened the antimicrobial effect against A.
Actinomysetemcomitants (Handajani 2012). As a mouth rinse, EGCG showed a
signicant decrease in the gingivitis index (Nirmaladewi et al. 2007).
Zeolite, a large group of natural and synthetic hydrated aluminium silicates can be
found in 46 locations in Indonesia. The zeolite from the area of Gunung Kidul and
Kulonprogo was investigated by Irnawati and colleagues as a potential antibacterial
and antifungal agent due to its copper content (Cu) (Irnawati et al. 2013). The initial study
showed that at a range of 0.20.25 M concentration Cu concentration in the Cu-natural
zolite influenced the antifungal activity towards C. Albicans (Irnawati et al. 2010).
Further research is being undertaken to create a zeolite dental cleanser.
Hydroxyapatite (HAp) has a structure similar to human bone hard tissue and can
be developed for many purposes in medical application. Indonesia has a lot of
natural resources that can be prepared as synthesis HAp. One of them is calcite
minerals extracted from Indonesian mines that is developed by Tontowi and col-
leagues (Pujiyanto et al. 2006). Mulyawati and colleagues developed this material
as root canal sealer. The ideal root canal treatment should be able to close hard
tissue from the periapical tissues and prevent chronic irritation and foreign body
reactions to material components. Sealers play an important role in sealing the root
canal system from foreign microorganisms and lling inaccessible areas of prepared
canals. The ller addition to resin based sealers will enhance the physical properties
of the polymer. Based on its properties, HAp can be proposed as ller for dental
materials. The results showed that epoxy-based-resin sealer with the addition of
30 % calcite synthesized HAp satisfy the physical properties of sealer in regards to
its contact angle and lm thickness. Furthermore, the microhardness of the
epoxy-resin based sealer increased (Mulyawati et al. 2015).
Herliansyah and colleagues developed material stake with the concept of func-
tionally graded material (FGM) from Ti/40HAp material that is composed of ve
layers with concentrations of HAp from 040 % wt through the process of uni-axial
pressing followed by sintering at 1200 and 1400 C in argon gas. This material was
intended as endodontic post after-endodontic treatment. Endodontic posts that are
commercially available have homogenous composition and strength. The rotational
moment that is transmitted through homogenous endodontic post to dentin may
result in the fracture of roots. The FGM layer is expected to solve the problem by
adjusting the mechanical properties of each post to the nature of the teeth. It was
concluded that Ti/40HAp200 and Ti/40HAp200 composite materials can be pro-
duced by decreasing its hardness as the rising concentrations of HAp in each section
(Herliansyah et al. 2013).
As described above, the current choice of caries treatment is restore the tooth by
using restorative materials. However, the advent of tissue engineering is allowing
dentistry to move forward in the use of regeneration as an underlying principle for
the treatment of dental disease. The regenerative dentistry is possible for making
enamel, dentin, dental pulp and the entire tooth (Nr 2006). In this sense, the
development of materials that may heal the injured pulp offers a promising eld of
study. Ardhani and colleagues investigated an application of combined of gelatin
hydrogel lm and Platelet Rich Plasma (PRP) to induce functional recovery of the
sciatic nerve crushed by injury in the Wistar rat model. It was found that the
application of gelatin hydrogel lm with controlled release manner combined with
PRP results faster axonal regeneration (Ardhani et al. 2015). Further research is
needed to conrm the effectiveness of the strategy for pulp nerve regeneration.
Another interesting eld of research is the development of the material to
minimize the effect of radiography exposure. Radiographic examinations are an
important tool that help dentists to diagnose, plan treatments and monitor both
treatments and lesion development. According to the UNSCEAR report and IAEA
RS-G-1.5, dental examinations are the most frequent type of radiological procedure,
and account for 21 % of the total worldwide. The estimated annual number of
dental examinations is about 520 million, with a frequency ranging from less than
one to more than 800 per 1000 population per year (Shantiningsih 2015).
Individual doses are small but collective doses cannot be ignored due to the high
volume of procedures. One of the effects of panoramic radiography exposure is
micronucleus apparently in oral mucosa which is seen as a marker of early stage
carcinogenesis mechanism. A betacarotene patch has been developed by
Shantiningsih and colleagues as radioprotector to prevent the effect of radiation
exposure. The ex vivo study resulted that gingival mucoadhesive patch containing
betacarotene had the capability of penetrating through mucous membrane of rabbit
plate. This patch is supposed to function as radioprotection agent of panoramic
radiography exposure and further investigation has been done by the research group
(Shantiningsih 2015).
5 Perspective
Biomaterials are required in most of dental treatment and its development in dental
restorations represents the main challenge of future research activities. One of the
main problem in restorative dentistry is recurrent caries due to the leakage or
damage of restoration. Therefore, a material which is able to seal the marginal
interface between material and tooth structure, to prevent the bacterial invasion to
dentinal tubulus and the pulp is potential to be developed. Bioactive materials can be
dened as materials that elicit a specic biological response at the interface between
tissues and the material, which results in the formation of a bond (Watson et al.
2014). Bioactive material that can promote remineralization without loss of the
mechanical characteristics, has a good bonding with tooth structure and antimicrobial
200 M. Rinastiti
properties is potentially developed as base material. This base material may promote
pulpal healing, furthermore it is expected to protect pulp from bacterial invasion
when restoration leakage is arised. The diversity of natural resources in Indonesia is
potentially evolved as bioactive material.
Acknowledgment The author thanks Dr. Hermawan, Laval University, for the discussion during
the preparation of this chapter and revision of the nal manuscript.
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Tissue Bank and Tissue Engineering
Ferdiansyah Mahyudin and Heri Suroto
Abstract Permanent damage on the tissue or organ are still a major problem and
chalenge to be solved in the world of medicine. Humankind has tried to solve the
problem using technologies available in their respective era since long time ago. We
can read from various literature about the efforts already made to replace and
consequently heal the damaged tissue or organ. Tissue or organ damage caused by
war and many other causes became the main reason of the tissue bank's estabil-
ishment in many parts of the earth. Tissue bank strife to provide safe and high
quality products to be used as natural biomaterial for damaged tissue reconstruction
in patients. Several processes started from procurement, processing, and nally
sterilization has been done to guarantee safe and useful products for the patients in
need. In line with the recent technological advancement, especially with the
introduction of stem cell usage, tissue and organ reconstruction has entered a new
era that will bring greater hope for patients. If the previous methods that used
biomaterial only employ dead tissue in the reconstruction procedures, tissue engi-
neering will make the combination between stem cell and biomaterial as scaffold
possible, thus enabling the living tissue to be used in reconstruction. This method,
albeit still in the process of research, is expected to yield better results.
Keywords Tissue and organ damage Biomaterial Tissue bank Stem cells
Tissue engineering
F. Mahyudin (&) H. Suroto

e-mail: ortopedi@rad.net.id; ferdyortho@yahoo.com
H. Suroto
e-mail: hsuroto2000@yahoo.com

208 F. Mahyudin and H. Suroto
1 Introduction
Tissue and organ injuries causing functional damage is the challenge yet to be
solved in medical science. In the history of mankind, countless trials and procedures
have been tried to solve this problem. Creating an organ, or at least an articial one,
is a long-life dream of mankind, which started to be realized after so many decades
and technology advancement until now. The legend of transplantation itself was
depicted in the painting of Healing of Justinian by St. Cosmas and St. Damien.
The painting describe a lower leg transplantation on a soldier who has been injured
during war. Cosmas and Damien themselves were Arabic-Christian twin brothers
whose profession are doctors and lived in the area that we call Turkey at present
(Meyer 2009; Nather and Zheng 2010; Vacanti and Vacanti 2014).
In 600 BC, Shusruta Samhita from Northern India performed a skin graft for
war victim soldiers and criminals who received nose mutilation as punishment
(Nichter et al. 1983; Ang 2005). A Bolognese surgeon named Gaspare Tagliacozzi
(15451595) published his idea in a book named De Curtorum Chirurgica per
Institionem (Surgery of the Mutilated by Grafting) which describes about forearm
flap technique that harvests inner side of forearm to perform reconstruction of the
nose and then the termination of pedicle connection several weeks later. The rst
allogenic skin graft were performed by Jaqcues-Louis Reverdin in 1869 by using
epidermal grafts which also known now as split thickness grafts. George Pollock of
England introduce epidermal graft on combustion injury in 1871. The following
year in 1872 Louis Xavier Edouard Leopold Ollier reported his success in trans-
planting the skin using whole epidermis and part of dermis. And at last in 1886,
Karl Thiersch introduce split thickness skin grafting technique to further extend
area of skin graft coverage (Meyer 2009; Nather and Zheng 2010; Phillips 1998a;
Vacanti and Vacanti 2014).
The early efforts to replace damaged part of body use metal, ivory, wood and
several other as biomaterial for reconstruction. On Galileo-Roman period, teeth
replacement which is the early phase of dental implant has been performed.
Anthropologic discovery of human skull lled with metal on the showed early effort
of tissue reconstruction using substitution material (Crubzy et al. 1998). Ambroise
Par (15101590) described in his work Dix livres de la chirurgie measures to
reconstruct teeth, noses, and other parts of the body (Pare 1634). Early success of
premolar reimplantation due to trauma were reported by John Hunter (1771) on his
book titled The Treatise on the Natural History of the Human Teeth (Meyer 2009;
Nather and Zheng 2010). Reconstruction using donor tissue to cover the defect on
musculoskeletal system were reported by MacEwen in 1880. Lexer reported 23
cases of articular cartilage transplantation between 1908 and 1925 and reported
50 % success rate. Noyes and Shino began to use allografts in ligament recon-
struction in 1981 and have subsequently reported good results. Milachowski was
the rst to transplant a human meniscus in 1984 (Shelton et al. 1998).
There are a lot of materials available at present to be used for defect recon-
struction procedure on a tissue or organ to restore its function. The materials used to
Tissue Bank and Tissue Engineering 209
replace the tissue defect are labeled as biomaterials. American National Institute of
Health describes biomaterial as any substance or combination of substances, other
than drugs, synthetic or natural in origin, which can be used for any period of time,
which augments or replaces partially or totally any tissue, organ or function of the
body, in order to maintain or improve the quality of life of the individual.
Biomaterial that is being used came from polymers, metals, ceramic, and com-
posites whether it is obtained from human or animal (natural) or purposely invented
by human (synthetic). The usage of biomaterial is varied depend on the disease and
tissue that need to be restored. On cardiovascular cases, biomaterial is needed to
produce stent in treating coronary diseases, while dentist will need biomaterial for
their implant to treat the patient. One of the profession that use implant frequently is
orthopedic surgeon. Biomaterial in orthopedic are used as internal xation for
fracture of the bone such as screw, plate, and nail system, to replace damaged joint
with articial one (endoprosthesis), and as bone graft or bone material substitute to
promote and stimulation for bone healing (Navarro et al. 2008).
2 Natural Biomaterials
Natural biomaterials refer to organic and inorganic matrix that is obtained from
human or animal. The source of biomaterial from human came from tissue or donor
donation, or tissue that is being removed after certain procedure such as total joint
replacement and craniotomy. Decellularized extracellular matrix tissue can be
obtained from hard tissues such as bone and teeth, or soft tissues such as skin,
amniotic membrane, intestine, vascular, heart valve, duramater, cornea, etc. There
are several advantages using ECM biomaterials as biomaterial ingredients. First of
all, each of molecules in ECM can be broken down by using normal enzymatic
processes. Another advantage is that the three-dimensional structure and mor-
phology of the ECM copies the structure and morphology of the original tissue that
is being transplanted. Lastly, researchers can design a prosthesis that works not only
on a macroscopic level, but also on the cellular level due to the innate potential of
the biomaterial. There are, of course, several certain disadvantages using ECM. It
usually triggers immune system of the recipient thus causing severe reactions.
There are also many ancillary molecules that change the way the prosthetic will
interact with surrounding recipient tissue when placed in vivo. While there are some
molecules that would promote the regenerative capabilities of the recipient tissue,
others might stimulate an immune responses. In the end, there is an abundant of
potential in ECM biomaterials as well as its problems yet to be solved (Coburn and
Pandit 2007).
Natural biomaterials that are being used mostly are intact extracellular matrix,
collagen, chitosan, hyaluronoic acid and alginate. Collagen is protein that construct
a human body the most. More than 30 % protein of human body are collagen
(Nimni et al. 1987). Chitosans are the second most abundant biopolymer in nature
and represent a family of biodegradable cationic polysaccharides consisting of
glucosamine and randomly distributed N-acetylglucosamine linked in a (14)

manner, and have a chemical structure similar to hyaluronic acid (Dornish et al.
2001). Instead of protein, another substance that frequently used as scaffold is
mineral hydroxyapatite (HAp). These minerals can be obtained from nature such as
humans, animals, or corrals or made for specic purposes (synthetic). Orthopaedic
surgeon applies mineral HAp as bone graft. Mineral HAp can be obtained from
bovine bone and corral as scaffold materials. The preparation of HA will decide the
composition and structure. First is HA with the organic matrix, unsintered; secondly
is without organic matrix, unsintered; and last one is without the organic matrix and
sintered. Sintered and unsintered HA differs in their consistency. Unsintered bone
mineral consists of small crystals of bone apatite (carbonate HA), while sintered
bone mineral consists of larger apatite crystals without carbonate when heated
above 1000 C. The unsintered material has organic matrix that resembles structure
in the context of the three dimensional macro- and microstructure of the bone.
Natural HAs possess an interconnecting macroporosity that make the cells penetrate
into the scaffold possible both in vivo and in vitro (Wiesmann and Meyer 2009).
3 Tissue Bank
Transplantation is an effort to move a cell, tissue, or even an organ from a donor to

a recipient in order to restore its function. Tissue transplantation differs from organ
transplantation, whereby the process is more complicated, more expensive, and
usually is a life-saving procedure. Organ transplantation, such as kidney, heart,
liver, lung and many other require a healthy and functional donor to replace the
damaged function of the recipient. Consequently, the source of donor organ must be
alive or at least in vegetative state in which the function of the organ transplanted is
still functional. After harvesting the donor, the organ must be immediately trans-
planted to the recipient in order to prevent death of the organs cell. Tissue
transplantation, however, can be harvested from cadaver since it consist of
non-viable tissue such as cornea, bone, joint, ligament and meniscus. Therefore it is
not necessary to perform the transplantation immediately if it is storage properly
either in room temperature or deep freezer (Phillips 1998b).
The place to store the donor tissue is called Tissue Bank. Tissue bank, by
denition, is an entity that provides or engages in one or more services involving
tissue from living or cadaveric individuals for transplantation purposes. These
services include assessing donor suitability, tissue recovery, tissue processing,
sterilization, storage, labelling and distribution (Nather et al. 2007). Tissue bank
connects the donor and recipient that needs the tissue. Main function of tissue bank
is to provide various type of high quality and safe tissue for recipients.
Korean War is the rst trigger to the establishment of rst tissue bank in USA.
Huge number of war victims that needed various tissue, especially musculoskeletal,
as the result of the war inspired George Hyatt to build Bethesda Naval Tissue Bank
in the United States in 1950, with Ken Sell becoming Director in 1965. Almost in
the same time, Rudolph Klen set up the tissue bank in Hradec Kralove in the old
Czechoslovakia in 1952, and then followed by Frank Dexter who established The
Leeds Tissue bank in 1956, and then The Charit Hospital Tissue Bank in Berlin in
the old East Germany was set up in 1956. Nowadays tissue bank have improved
greatly worldwide and several regional organization is formed such as American
Association of Tissue Bank (AATB), European Association of Tissue Bank
(EATB), Asia-Pacic Association of Surgical Tissue Banking (APASTB) and Latin
American Association of Tissue Banks (ALABAT) (Pfeffer 2009; Phillips 2016). In
Indonesia there are three tissue banks located at the National Nuclear Research
Institute (BATAN) in Jakarta (1988), Dr. Soetomo General Hospital in Surabaya,
East Java (1990) and Dr. M. Jamil Hospital in Padang, West Sumatera.
3.1 Regulation
Availability of the tissue is the main requirement on establishing a tissue bank.

Tissue donation is an act of humanity, as it enables one to alleviate the sufferings of
fellow human beings. Organ donation is a complex situation in which involving
many aspects such as social, ethic, regulation, medical, infrastructure and skills of
the doctors in charge. Organ donation aims to obtain potential donor that ll the
criteria and regulation on its own respective country. The aspects mentioned above,
unfortunately, cause an imbalance between supply and demand of a tissue,
unavoidably causing longer waiting list for a patient to receive a tissue from the
donor (Nijkamp et al. 2008; Anderson and Trias 2009).
Tissue and organ can be obtained from living donor or cadaver. Tissue harvest
can be executed if prior agreement exist. Different countries may have different
regulations regarding this matter. The rst is presumed consent or opt-out system,
where a deceased individual which fulll the criteria may have his/her organ har-
vested unless there were prior objection from him/herself. The second is informed
consent or opt-in system, where people make their agreement with tissue bank
regarding the timing and condition of tissue harvest. Usually the donor receive an
ID card from tissue bank in exchange. Several countries in Europe adopt opt-out
system, while USA, UK, and most of Asia except for Singapore adopt opt-in system
(Phillips 1998b; Gevers et al. 2004; Rithalia et al. 2009; Douville et al. 2014;
Hutchison 2016; Rid and Dinhofer 2009).
Monetary inducement for donation is subject to the following restrictions.
Payment to the donor is prohibited. Monetary payment or advantages for the
donation shall not be made to living donors, cadaver donors next of kin or any
donor-related party. As regards compensation for donation-related expenses, donors
or their family shall not be nancially responsible for expenses related to retrieval
of tissues. Anonymity between donor and unrelated recipient shall be strictly pre-
served. Anonymity between donor and recipient shall allow tracking of tissues,
through anonymous identication numbers (Phillips 2003; Nather et al. 2007).
Fig. 9.1 Flow chart of production of human tissue at Surabaya Cell and Tissue Bank
The procedure for tissue harvesting varied in every country depend not only by
the consent, but from socio-culture, ethic, religion and nearest family. The role of
family is influential in the decision making. In UK on 2006, refusal of donor
agreement caused by the family reach 41 % while Spain record 15 % regarding the
same problem (Rithalia et al. 2009). A certain belief that a deceased must be buried
with its complete parts of body is the main barrier of tissue harvesting and organ
donor in Indonesia. Figure 9.1 illustrate the procedure of human tissue production at
the Cell and Tissue Bank of Dr. Soetomo General Hospital in Surabaya (hereafter
named as Surabaya Cell and Tissue Bank).
3.2 Donors Selection
Main aim of a Tissue Bank is to obtain a safe and high quality tissue to be provided
to the patient. Therefore each and every tissue must be examined thoroughly. Donor
suitability for a donation of tissue allograft depend on medical and behavioural,
medical records review, physical examination, cadaveric donor autopsy ndings
(if an autopsy is performed) and laboratory tests (Phillips 2003; Nather et al. 2007;
Navarro et al. 2008).
Donor history evaluation includes an interview of the potential living donor or

the cadaveric donors next of kin, performed by suitably trained personnel, using a
questionnaire. A qualied physician shall approve the donor evaluation process.
According to APASTB Standards for Tissue Bank General Contraindications the
use of tissues for therapeutic purposes:
History of chronic viral Hepatitis.
Presence of active viral Hepatitis or jaundice of unknown etiology.
History of, or clinical evidence, or suspicion, or laboratory evidence of HIV
infection.
Risk factors for HIV, HBV and HCV have to be assessed by the Medical
Director according to existing National Regulations taking into account national
epidemiology.
Presence or suspicion of central degenerative neurological diseases of possible
infectious origin, including dementia (e.g. Alzheimers disease,
Creutzfeldt-Jakob disease or familial history of Creutzfeldt-Jakob disease and
multiple sclerosis).
Use of all native human pituitary derived hormones (e.g. growth hormone),
possible history of duramater allograft, including unspecied intracranial
surgery.
Septicaemia and systemic viral disease or mycosis or active tuberculosis at the
time of procurement preclude procurement of tissues. In case of other active
bacterial infection, tissue may be used only if processed using a validated
method for bacterial inactivation and after approval by the Medical Director.
Presence or history of malignant disease. Exceptions may include primary basal
cell carcinoma of the skin, histologically proven and un-metastatic primary brain
tumour.
Signicant history of connective tissue disease (e.g. systemic lupus erythe-
matosus and rheumatoid arthritis) or any immunosuppressive treatment.
Signicant exposure to a toxic substance that may be transferred in toxic doses
or damage the tissue (e.g. cyanide, lead, mercury and gold).
Presence or evidence of infection or prior irradiation at the site of donation.
Unknown cause of death.
Age criteria varied depends on tissue being harvested. There is no age limit for
musculoskeletal tissue donor such as cancellous bone. Heart valves and pulmonary
valve must be harvested under 65 years old, while aortic valve under 50 years old
and mitral valve under 50 years old. Skin tissue is harvested under 75 years old and
artery under 50 years old and vein under 60 years old (Phillips 1998c; Nather et al.
2007; Navarro 2010).
There is another way to examine medical and social history that hasnt been
reported previously. A physician will perform a thorough examination to a donor
candidate to nd out any sign of risky behaviour or possibility of infection or viral
disease. If any of these signs listed below exist on a donor, it is necessary to ask to
the family or the closest relative about the time the sign shows (e.g. skin piercing,
tattoo). The donor shall be rejected if the sign is proved to be critical. The physical
examination has to be performed systematically in each and every patient with a

specic aim to nd the signs mentioned before. There are signs that should be
specically looked for, such as risk of sexual transmitted diseases: syphilis, ulcers,
herpes simples, chancroid, and perianal lesions. Physical evidence of non-medical
percutaneous drug abuse, acupuncture or tattoos including the presence of ear or
body piercing. Signicant enlarged lymph nodes might be present. Oral thrush, blue
spots or purple ones characteristics of Kaposis sarcoma. Generalized rash that could
point to sepsis or unexplained jaundice. Necrotic lesions after previous vaccination.
Donors physical examination shall be recorded in the donors history and collected
by the retrieval team (Phillips 1998c; Nather et al. 2007; Navarro 2010).
The obtained tissues will be tested for transmissible diseases depends on law and
practice in each respectful country. In case of living donors, further procedure for
blood testing might be performed. Tests will be performed and deemed legitimate
on blood samples from the donor using recognized, licensed tests and according to
manufacturers instructions. Tests will be performed by a qualied, licensed lab-
oratory and according to Good Laboratory Practice (GLP). There is 24 hours time
limit for blood screening on deceased donors after death. Blood screening for living
donors must be taken at least 7 days before tissue harvesting. For potential tissue
donors who experience more than 50 % hemodilution due to additional fluid such as
blood, blood components, or plasma volume expanders within 48 h before death, a
pre-transfusion blood screening must be done. The physician will be notied of
conrmed positive result that has clinical signicance according to the existing law.
Sample of donor blood examination will be securely sealed and stored frozen for
5 years after the tissue harvested is expired or in accordance to existing law on each
country. Minimum Blood Tests shall include (Phillips 1998c; Nather et al. 2007):
Human Immunodeciency Virus Antibodies (HIV-1/2-Ab)
Hepatitis B Virus Surface Antigen (HBs-Ag)
Hepatitis C Virus Antibodies (HCV-Ab)
Syphilis: nonspecic (e.g. VDRL) or preferably specic (e.g. TPHA)
Optional Blood Tests could be necessary for compliance with applicable
Intergovernmental, National, Regional and Local Law or Regulation and/or to
screen for endemic diseases (Phillips 1998c; Nather et al. 2007):
Hepatitis B core antibodies (HBc-Ab): HBc-Ab should be negative for tissue
validation. Though, if the HBc-Ab test is positive and the HBs-Ag is negative,
conrmation cascade should be entered. If the antibodies against the surface
antigen are found (HBs-Ab), the donor can then be considered to have been
recovered from an infection and the tissue can be used for transplantation.
Antigen test for HIV (p24 antigen) or HCV or validated Molecular Biology Test
for HIV and HCV (e.g. PCR), if performed by an experienced laboratory.
Antibody to HTLV 1: depending on the prevalence in some regions.
Cytomegalovirus (CMV), Ebstein-Barr Virus (EBV) and Toxoplasmosis
Antibodies: for immunosuppressed patients.
Alanine Aminotransferase (ALT) for Living Donors: In addition to the general

testing requirements, testing living donors of tissue for Alanine
Aminotransferase (ALT) is recommended.
HIV and HCV retest is recommended in living donors in 180 days after prior
examination. Any other method that will yield better result (antigen testing,
molecular biology or viral inactivation method) is used rather than retesting with the
same method and the result will be recorded in the same document.
Samples of each obtained tissue will be cultured if the tissues are going to be
processed without terminal sterilization. Before the tissue exposed to antibiotic
containing solution, representative sample shall be taken. The culture procedure
must enable the growth of both aerobic and anaerobic bacteria and fungi as well. If
the harvest is performed on a cadaver, blood culture might be useful in examining
the condition of the cadaver. They must be examined by the experts of this eld. If
the result shows low virulence or commonly considered non-pathogenic microor-
ganisms growing, the tissue should be distributed after being further processed
through decontamination. Tissue which shows high virulence microorganisms
growth is not acceptable for transplantation, unless the decontamination is done to
render the microorganism inactivate without harmful potential effects, including
possibility of residual endotoxins (Phillips 1998c; Nather et al. 2007).
3.3 Tissue Procurement
Tissues can be obtained from either living donors or deceased donors, which can be
divided into vegetative state or heart beating donors, deceased due to cardiopul-
monary arrest donors, and non-heart beating donors. The available tissue to be
obtained are bone, joint, musculoskeletal tissues (ligament, tendon, fascia lata,
meniscus), duramater, heart valve, and skin tissues.
The deceased shall had his/her death pronounced or death certicate signed by
doctors other than those involved in tissue management. All aspect of law regarding
determination of death shall be respected. The cadaver that is going to be used as
donor must be identied thoroughly before harvesting began. Harvesting shall be
done in adequate facility such as operating room or mortuary with facilities needed.
Sterilization of all equipment shall be done between harvests of different cadaver.
Tissues may be obtained using aseptic technique, where harvesting process is
prepared using a standard surgical technique and resembling standard operating
room practice. Another way is to perform clean or non-sterile technique, only if the
sterilization is adequate to remove all pathogens after the procedure (Phillips 1998c;
Phillips 2003; Nather et al. 2007):
Aseptic technique: aseptic technique shall be observed throughout the pro-
curement procedure. Procurement sites shall be prepared using a standard sur-
gical technique; all methods shall be consistent with standard operating room
practice.
Clean/non-sterile technique: allografts procured using clean/non-sterile tech-

niques are suitable for transplantation, if efcient validated sterilizing methods
are used to eliminate pathogens after retrieval.
A sample should be taken for microbiological examination if possible. After
tissue harvesting, the cadaver must be reconstructed to achieve its previous state
before the event of funeral. Time needed to obtain the tissue after the death of the
donor is an important issue as well. An optimum time of harvest is between 6 and
24 h (if the cadaver if stored at room temperature), or between 12 and 48 h (if the
cadaver is kept in a refrigerator at 4 C before the rst 4 h post-mortem). Residual
tissues after a therapeutic surgical procedure (e.g. femoral head, skin and amnion)
can be obtained for another therapeutic use in other patient or research purposes.
Informed consent is required before the residual tissue can be obtained from the
donor.
Potential donor of amnion membrane can be sorted from obstetrician list of
patient that is going to undergo elective caesarean section deliveries. Inform con-
sent for amniotic membrane harvest can be made before the patient get the surgery,
therefore the possibility of the patient to agree donating the membrane is higher
because of longer pre-surgery discussion regarding donation in elective patient
compared to those who undergone emergency caesarean section deliveries. The
same discussion can also be performed in patient with possible bone donation after
a surgical procedure, although the patient list is made according his/her medical and
behavioural history (Warwick 2010).
3.4 Quarantine
After procurement, the tissue is temporary kept in a 20 C freezer to wait for the
laboratory test result. If the result is negative, then the process proceeds. If, how-
ever, the result is positive, the tissue is deemed unusable and will be terminated.
3.5 Processing of the Tissue
The tissue bank is a storage to keep tissues in non-viable state, which will be
sterilized later to prevent disease spread from donor to the patient as well as
contamination during processing of the tissue. Non-viable tissue will decrease acute
allograft rejection reaction. Cartilage and cornea are exceptions to this rule. Both
tissue are normally avascular and will not experience vascularization, render it able
to be transplanted in viable condition without causing acute allograft rejection
reaction (Kearney 2010).
Tissue preservation are meant to avoid matrix tissue damage due to the enzy-
matic processes. Enzyme that plays big role in tissue degradation processes is
proteolytic. Lipid peroxidation also has great potential to destroy the tissue matrix.
Both processes activities mentioned above depends greatly on water availability.
Therefore decreasing the amount of water through freeze drying (lyophilisation) or
water immobilization using deep freezing technique is very important to preserve
the tissue. The methods for tissue preservation depends on the type of tissue being
processed (Kearney 2010). Another process to decrease tissue antigenicity is by
removing all dead cell and their products (Mirsadraee et al. 2007; Vinci et al. 2013).
Bone can be processed by deep freezing and terminal sterilization using
chemical and gamma-irradiation, cryopreservation without irradiation, freeze-dried
and demineralized with gamma-irradiation. The obtained bone, both from living or
deceased donor, can be processed using methods mentioned above. On deep
freezing process, the bone will be stored in deep freezer with temperature
of 80 C. This method will not decrease the mechanical strength of the bone,
therefore it is used for large bone graft allograft that will be used as structural bone
graft for large bone defect reconstruction. After all examination yield negative
result, the bone is wrapped and put into deep freezer. Both cell in the bone and soft
tissue will necrotize and disappear microscopically in 2 weeks time. This process
will signicantly reduce tissue antigenicity. It is best for the tissue to be issued from
tissue bank after 1 month to ensure whole process is completed. Freeze drying, on
the other hand, is water reduction process by sublimation where the water will
vaporized directly from solid ice state without going through liquid state. The aim
of this process is to get biological scaffold that is collagen network containing HAp,
decreasing antigenicity, decreasing amount of the microbes, and facilitate steril-
ization. This process decreased the amount of water in tissue until 58 % by
sublimation mean. Freeze drying will decrease bone strength signicantly.
Therefore small bone allograft will be used on small bone defect as ller to facilitate
bone healing. Freeze-dried tissue can only be stored in room temperature (Phillips
1998d; Nather and Tay 2010).
Bone demineralization is a chain of process in which soft tissue, blood and fat is
removed from the bone, continued by removal of bone mineral using HCl. The
process is halted if the amount of the calcium is decreased to 8 % and will be called
forth as demineralized bone matrix (DBM). This process exposes mineral trapped
within the bone. DBM is a composite of collagens (mostly type I with some types
IV and X), non-collagenous proteins, various growth factors, few residual calcium
phosphate mineral (16 %) and some small percent cellular debris. DBM is natu-
rally osteoinductive with better potential compared to the unprocessed bone thus
provide better bone healing. Final processing of demineralized bone matrix is freeze
drying so the demineralized bone matrix can be keep in room temperature (Nather
and Tay 2010; Gruskin et al. 2012).
Musculoskeletal soft tissue allograft such as ligament, tendon, fascia, meniscus
processed and stored in deep freezer with 80 C temperature at least 1 month
before being used. Tissue sterilization is needed to guarantee there is no disease

spreading from the donor to the recipient. Sterilization is needed to ensure there is
no proliferating microorganism and to decrease the amount of microorganism until
acceptable level called as sterility assurance level (SAL). Tissue sterilization can be
done either by chemical sterilization or gamma irradiation therapy. Chemical
sterilization is done by using ethylene oxide, glutaraldehyde, and peracetic acid.
Each chemical compound have several negative impacts to the tissue therefore its
selection and usage require decent knowledge of characteristic and function of each
compound to obtain optimal result. Sterilization using gamma ray is usually done
with dose of 25 kGy. Gamma irradiation works directly by causing damage on
DNA structure of the microorganism and indirectly by forming free radical that will
cause damage to the protein, enzyme and nucleus material of the cell. Gamma
irradiation might cause decrease on mechanical strength on bone allograft or soft
tissue allograft, causing some tissue bank refuse to do terminal sterilization process.
On these conditions, allograft harvest must be done in aseptic technique and
thoroughly monitored to prevent disease spread or contamination (Kearney 2010;
Yusof and Hilmy 2010).
3.6 Tissue Bank Products
Product spectrum produced by tissue bank varied depend on the purpose of the
tissue bank itself, available facility, and human resources. Tissue that can be pro-
duced by tissue bank are bone, joint, skin, amniotic membrane, ligament, tendon,
fascia, heart valve, duramater, and many other cell product.
The Surabaya Cell and Tissue Bank was established in 1990. Earlier, it was
called bone bank since the only tissue obtained from cadaver and donor are bone.
With additional human resource and equipment, the bone bank started producing
humans soft tissue such as tendon, ligament, duramater and amniotic membrane,
hence the name changed into Biomaterial CenterTissue Bank since 2010. In
2014, the Bank began a research of stem cell in collaboration with the Regenerative
Medicine and Stem Cells Center of Dr. Soetomo Hospital, Faculty of Medicine, and
Institute of Tropical Disease of Airlangga University Surabaya. The name
Biomaterial CenterTissue Bank changed again into Cell and Tissue Bank in the
same year. The Surabaya Cell and Tissue Bank has the signature products such as
deep frozen tissue consist of bone, joint, amniotic membrane, fascia, duramater,
tendon and ligament, as well as freeze-dried tissue consist of amniotic membrane,
bone, demineralized bone (DBM), and tendon (Figs. 9.2, 9.3 and 9.4). The
Indonesian Ministry of Health has appointed Dr. Soetomo Hospital as center of
service, education and research for stem cell in Indonesia. According to the regu-
lation in Indonesia, clinical trial can only be done using adult stem cells, while
embryonic and animal stem cell are still prohibited.
Fig. 9.2 a Left and middle, humerus and femur joint for osteoarticular bone allograft and right
shaft of tibia bone for intercalary bone allograft, b various size and shape of freeze dried bone
Fig. 9.3 Various form of demineralized bone matrix (Courtesy of Dr. Soetomo General Hospital,
Surabaya)
Fig. 9.4 a Placenta, b processing of amniotitc membrane, c nal product of amniotic membrane
3.7 Orthopaedic Applications
Spectrum of disease traded by an orthopedist consist of congenital anomaly,

infection and inflammation, trauma, arthritis, tumor, metabolic and degenerative
disease, and also sensory disturbance and muscle weakness. Most of the diseases
mentioned above will cause defect on musculoskeletal system, leading to functional
disturbance later on. Reconstruction using bone, ligament, tendon, fascia as graft is
performed to treat the defect in musculoskeletal tissue. The tissue graft can be
obtained from the patients themselves, which is called autograft, from other person,
which is called allograft, and even another species, which is called xenograft. The
most ideal graft came from the patient themselves because there will be no rejection
reaction, rendering perfect incorporation with the body. Autograft, however, has
several weakness that is limited source of harvest, unable to reconstruct large
defect, sacrice some part of normal body structure, need surgical procedure to
harvest the graft with risk of pain, infection, and blood loss (Ebraheim et al. 2001;
Dimitriou et al. 2011; Loeffler et al. 2012; Shelton and Fagan 2011; Myeroff and
Archdeacon 2011). Bone graft is the most tissue transfer transplantation procedure
after blood transfusion. Bone autograft has ideal biologic composition to treat bone
defect that is osteoconductive matrix, in which the graft act as scaffold or trellis that
supports the growth of new bone; second is osteoinductive proteins, which stim-
ulate and support mitogenesis of undifferentiated perivascular cells to form osteo-
progenitor cells; and the last one is osteogenic cells, which are capable of forming
bone if placed into the proper environment (Finkemeier 2002; Myeroff and
Archdeacon 2011). Cancellous bone autograft has osteoconductive, osteoinductive
and osteogenesis properties but no structural strength, meanwhile cortical bone
autograft has a structural strength but osteoconductive, osteoinductive and osteo-
genesis properties lower than cancellous autograft. Cancellous bone allograft, both
frozen and freeze dried, osteoconductive properties similar to cortical allograft,
osteoinduction properties lower than cortical allograft, but no osteogenesis prop-
erties also no structural strength. Frozen cortical bone allograft has similar structural
strength with cortical bone autograft, osteoconduction lower than cancellous bone
allograft and no osteoinduction also osteogenesis properties. Freeze dried cancellous
bone allograft has lower structural strength and osteoconduction (same with frozen
cortical bone allograft) and no osteoinduction also osteogenesis properties.
Demineralized bone matrix (DBM) allograft has osteoconductive properties
(similar cortical bone allograft), meanwhile osteoinductive properties is similar to cor-
tical bone allograft and has no mechanical strength and osteogenesis (Greenwald et al.
2001).
Allograft has several advantages compared to the autograft. It doesnt need any
extra surgical procedure on the patient means that no further morbidity caused, no
need to sacrice any part of the patients body, and it is available with different size
and shape. With all those advantages, however, it has only osteoconductive and
osteoinductive components, therefore it takes longer for the defect to heal and a
good processing is required to prevent disease transmission. Frozen allograft needs
to be stored in 80 C for a minimum 1 month period. The structural strength will

never decrease along with the decrease of enzyme degradation and host immune
response during the process. Due to its strength, frozen allograft is used for large
bone defect reconstruction such as joint replacement (osteoarticular) and bone shaft
defect (intercalary). Reports on large bone allograft usage shows satisfactory result
with excellent allograft survival, although few complication occurred such as
fracture of graft, infection, and graft resorption (Muscolo et al. 2006; Bus et al.
2014; Bus et al. 2015). Reports from Dr. Soetomo General Hospital in 19902010
stated that there were 85 large bone allograft procedure performed (Figs. 9.5
and 9.6) with 87 % excellent and good functional evaluation with complication of
Fig. 9.5 a Giant cell tumor of distal femur, b tumor after resection, c osteoarticular bone allograft
(17 cm), d X-ray after reconstruction of the distal femur including knee joint (Courtesy of
Dr. Soetomo General Hospital, Surabaya)
Fig. 9.6 a Malignant soft tissue tumor with ulna bone inltration, b tumor after bone resection,
c intercalary bone allograft (10 cm), d X-ray after ulna bone reconstruction (Courtesy of
Fig. 9.7 a Left, benign bone tumor, right, after surgery and bone graft; b freeze dried bone
allograft; c left fracture of intercondylar femur, right, after surgery and bone graft (Courtesy of
infection in two cases, fracture of bone allograft in two cases, and one case of bone
resorption.
Other types of allograft are freeze dried and demineralized bone matrix
(Fig. 9.7). Freeze dried bone allograft is processed by decreasing the amount of
water in the bone until 58 %. The objective of freeze drying is to obtain a
chemically stable product at room temperature and to preserve the properties of the
tissue, so that the tissue can be kept easily at room temperature and then distributed
to the user after being sterilized. Freeze dried bone allograft has osteoconductive
and minimal osteoinductive properties, but greatly decreased structural strength
instead (Ferdiansyah 2007). While demineralized bone matrix has better osteoin-
ductive properties, structural strength is also decreased, comparable to those of
freeze dried bone allograft. Both types of allograft is used to ll small bone defect
for procedures in dentistry, maxillofacial, spinal fusion, etc. (Gruskin et al. 2012).
4 Tissue Engineering
In present days, tissue and organ damage can be treated by reconstruction or

transplantation surgery. Surgical reconstruction procedure has widely implemented
on various tissue damage. On musculoskeletal system, orthopedic surgeons have
performed reconstruction surgeries by using biologic biomaterial (allograft) from
donor such as bone, joint, meniscus, ligament and tendon. Several other procedures
might use synthetic biomaterial (implant and endoprosthesis) that is composed from
metal alloy, polymer and ceramic. Reconstruction surgery on cardiovascular,
ophthalmology and other medical discipline is also rapidly improving by using
biologic or synthetic biomaterial as substitute for damaged tissue and eventually
restore its normal function. Nevertheless, there are still problems in using biologic
biomaterial that potentially cause morbidity on the patient such as disease trans-
mission, infection, inflammation due to reaction against foreign component,
dislodgment and wear, and also lack of donor (Muscolo et al. 2006; Bus et al. 2014;
Bus et al. 2015; Meehan et al. 2014; Illingworth et al. 2013).
Organ transplantation from donor to the recipient is a lifesaving therapy.
Transplantable organ are namely kidney, liver, heart, and lung. The technological
advancement in medical studies ensured transplantation to be safe and successful
procedures to maintain the life of the patient. Transplantation, however, might
cause several problems such as immune system process that would lead into chronic
rejection and destruction of the organ being transplanted, rendering the recipient to
consume lifelong immunosuppressant with risk of infection vulnerability and ten-
dency of tumor formation. The biggest and apparent problem of tissue and organ
transplantation is severe discrepancy between available donor and recipients who
need the organ, as shown by data from Organ Procurement and Transplantation
Network. Up to mid-2015, there are 122,648 total waiting list patient for life saving
organ transplant, 79,260 of them are on the active waiting list. On January until July
2015 18,048 transplantation procedure have been performed with 8,757 people as
donor. Its displeasing to see 22 patient died each day while waiting for donor
availability. There are 4 fold increase of organ demand in the last 20 years, followed
only by 2 fold increase of transplantation procedure.
Solution is needed to solve the problem of limited organ donor in transplantation
procedures. Tissue engineering might be one of the answers for that. In the late
1980, a meeting was held in Keystone, Colorado, sponsored by National Science
Foundation entitled Tissue Engineering which emphasize efforts in manipulating
tissue or combine it with prosthetic material to restore the function. The article
Functional Organ Replacement: The New Technology of Tissue Engineering
published in 1991 issue of Surgical Technology International recorded for the rst
time the term tissue engineering is used (Vacanti 2006; Vacanti and Vacanti
2014). In the following 25 years, tissue engineering has evolved rapidly not only by
using prosthesis or manipulating tissue, but by also integrating the use of cell and
protein as well. The denition of tissue engineering is still unclear and is often
mistaken for regenerative medicine. According to National Institute of Health US
Tissue engineering evolved from the eld of biomaterials development and refers
to the practice of combining scaffolds, cells, and biologically active molecules into
functional tissues. The goal of tissue engineering is to assemble functional con-
structs that restore, maintain, or improve damaged tissues or whole organs.
Regenerative medicine is a broad eld that includes tissue engineering but also
incorporates research on self-healingwhere the body uses its own systems,
sometimes with help foreign biological material to recreate cells and rebuild tissues
and organs. Other denition that is used to identify tissue engineering is the use
of a synthetic or natural biodegradable material, which has been seeded with living
cells when necessary, to regenerate the form and/or function of a damaged or
diseased tissue or organ in a human patient (Russell and Bertram 2014).
Tissue engineering is a combination of three component known also as tissue
engineering triad that is: cell, scaffold and proteins as signaling (Nerem and Schutte
2014; Moroni et al. 2015). The aim of tissue engineering is to create a living tissue
construction to substitute the damaged tissue or organ. The cells can be obtained
from stem cells or other progenitor cells or even fully differentiated cells. It might
be a mix of several types of cell, mostly known as primary cell with a partner cell.
The scaffolds can be manufactured from either synthetic biomaterial or natural
extracellular matrix. The scaffold is needed for fabrication of a replacement tissue
or as a delivery vehicle for the cells being used in a tissue engineering. There are
various types of signals, including growth factors and chemotactic factors. These
signals might be ones secreted by the cells employed (Nerem and Schutte 2014).
Tissue engineering works in replacement, repair and regeneration of the dam-
aged tissue. The oldest concept is to replace the tissue rather than repair or
regenerate it. Several procedure create a replacement tissue or organ outside of the
body which would be implanted within the body. Some of the initial successes were
in this category of replacement. This includes such skin substitutes as Integra, a
product of Integra Life Sciences and approved by Food and Drug Administration
(FDA) in 1996; Apligraf, a product of Organogenesis approved by FDA in 1997;
and Dermagraft, a product of Advanced Tissue Sciences approved by FDA in 1999.
Dermagraft is now sold by Advanced Biohealing which has been acquired by Shire
Medical. Using Integra as an example, the research on this approach was published
in a journal in 1982 however, as already noted, FDA approval did not come until
1996, a gap of 14 years. Furthermore, although all three of these skin substitutes
were developed as a replacement, these products act and categorized as wound
healing implants according to the regulation of the US FDA through the Center for
Devices and Radiological Health. Therefore they should be in the repair category
instead of replacement. Today these might well be regulated as biologics, and one
can only speculate about the length of time today that would be required for FDA
approval.
4.1 The Cells
Cell is one of major component in tissue engineering to create a fabricated con-

struction to become a living tissue construction. The cells can be obtained from
stem cells or other progenitor cells or even fully differentiated cells. A stem cell is
dened as a cell that has the capacity for self-renewal and the potential to differ-
entiate into any cell type in the body. Self-renewal is the process by which stem
cells divide to make more stem cells, perpetuating the stem cell pool throughout
life. Self-renewal is division with maintenance of the undifferentiated state. This
requires cell cycle control and often maintenance of multipotency or pluripotency,
depending on the stem cell (Shenghui et al. 2009). Progenitor cell, however, has the
ability to generate the exact same cells of the tissue or organ from which it was
harvested without ability to change its attributes.
Stem cells have an important role in the process of tissue repair. Manipulating
stem cells for applications in tissue engineering and regenerative medicine has
caught a lot of attention. The differentiation potential of stem cells is described with
different functional terminologies (Samadikuchaksaraei et al. 2014).
Totipotent stem cells, i.e. the zygote and its descendants up to the eight-cell
stage in mammals, which can form the embryo and the trophoblast of the
placenta
Pluripotent stem cells, such as the inner cell mass of the blastocyst, embryonic
stem cells and reprogrammed cells, such as induced pluripotent stem (iPS) cells
that can differentiate into all the cells of the three embryonic germ layers
Multipotent stem cells, such as mesenchymal stem cells and several other adult
stem cells, which can differentiate into multiple cell lineages like osteoblast,
chondroblast and adipocyte, but not all the lineages derived from the three germ
layers
Bipotent stem cells such as mammary gland epithelial stem cells, which can
differentiate into two cell lineages such as myoepithelial and luminal cells
Unipotent stem cells such as spermatogonial stem cells that can differentiate into
only one mature cell lineage like male gamete.
Stem cell can be obtained from the patient themselves (autologous) or from
another person or donor (allogenic). Using autologous stem cell will diminish any
risk of disease transmission and ensure compatibility with the patient. There are
some disadvantages, however, such as decreasing potential of stem cells in elderly
patient and requiring harvest procedure, which is relatively easy but would still
potentially causing morbidity for the patient. Allogenic stem cells are obtained from
different individual. It is mainly used for the patient whose stem cells potential
decreased for any reason. Some risks must be taken into caution while using
allogenic stem cell such as disease transmission and rejection reaction from the
host.
Stem cells are classied into embryonic (human embryonic stem cells, hESCs)
and adult stem cells. The hESCs isolated in 1998 for the rst time from the inner
cell mass (ICM) of a pre-implantation human blastocyst in a landmark study by
Thompson et al. (Thomson et al. 1998). In theory, hESCs have the capability to
change into all tissues of the human body and may provide crucial therapeutic
treatment for various diseases. The only method of hESC harvest process in the late
1990s/early 2000s involved destruction of a human embryo, and it is considered by
some as the same of terminating a human life. Embryonic stem (ES) cells are
considered as immortal version of the ICM in culture; they retain high telomerase
activity and can continue to self-renew indenitely under appropriate culture con-
ditions. When injected into immune-decient mice, hESC form teratoma tumors
that contain derivatives of all three germ layers, the most typical ones being bone,
cartilage, neural rosettes and epithelium of the airways and gut (Klimanskaya et al.
2014). Yamanaka et al. discover that Induced pluripotent stem cells (iPS) is an
effort to make a mature cell into pluripotent cell (Takahashi and Yamanaka 2006).
Induced pluripotent stem cells (iPSCs) show similarities to embryonic stem cells
(ESCs) that are obtained from many somatic cell types and many animal species.
Due to accessibility of somatic cell origin, human iPSCs does not have any problem
regarding ethical issues that found in human ESCs due to their embryonic origin,
but also enable the easy production of patient-specic pluripotent stem cells.
Similar to human ESCs, human iPSCs are capable of massive proliferation in vitro
while retaining the developmental potential to differentiate into various types of
cells.
Adult stem cell can be obtained from bone marrow, adipose tissue, peripheral
blood, umbilical cord, placenta and from other tissues or organ of human bodies.
Adult stem cells have lower proliferation and differentiation potential compared to
human embryonic stem cells, therefore the risk of teratoma formation is consid-
erably low and diminish the ethical and religion controversy. The most researched
adult stem cells is the one obtained from bone marrow. Beside bone marrow, adult
stem cells is usually obtained from adipose tissue and umbilical cord. Adult stem
cells from organ are rarely used due to the difculty in harvesting and higher risk of
morbidity (Li et al. 2014).
The ideal stem cells in tissue engineering should be: easy to obtain in large
numbers, safe to implant, able to differentiate into the expected cells. It resulted in
limited types of stem cells which might be useful for tissue engineering.
Mesenchymal stem cells, hematopoietic stem cells, adipose stem cells, and skin stem
cells are easy to obtain and provided in large numbers. They are basically safe for the
patient, being harvested from matured tissues. Although pluripotent stem cells, such
as ES cells and iPS cells, are able to provide massive amount cells due to their
innite proliferative potential, one should remember their potential of causing tumor
formation, which often prevents their clinical application (Samadikuchaksaraei et al.
2014).
4.2 Scaffolds
Scaffold is an important part in tissue engineering that construct the compound in

two or three dimensional shape. Scaffolds will give structural support and shape for
new tissue construction in vitro and/or through the initial period after implantation
as cells expand, differentiate, and organize.(Stock and Vacanti 2001; Hollister and
Murphy 2011). Materials used in these differ from metals and ceramics, to natural
and synthetic polymers, as well as micro- and nanocomposites. When used in a
three dimensional shape, these materials are processed into micro- and/or nano-
porous cell carriers, typically known as scaffolds.
All biological materials for scaffold used in medical applications and regener-
ative medicine approaches are obtained from naturally materials produced by the
resident cells of each tissue and organ; specically, the extracellular matrix (ECM).
The composition of each ECM is specic depends on the tissue, highly dynamic,
and crucially important in organ and tissue development, homeostasis, and response
to injury. ECM is consists of separate components such as proteins, gly-
cosaminoglycans, glycoproteins, and small molecules or the intact matrix itself, can
be obtained and processed for use as scaffold materials. Individual ECM compo-
nents, such as collagen and bronectin, can be used to alter synthetic scaffold
materials to enhance their interaction and integration into host tissues, although they
have also been used to create both naturally derived scaffold materials and
combination products with synthetic materials as biohybrid devices (Pradhan and
Farach-Carson 2010; Kular et al. 2014).
Decellularized tissues or organs can be used as sources of biological ECM for
tissue engineering. The advanced research of tissue engineering has showed that
ECM components allow the use of xenogeneic materials (often porcine). Many
types of extracellular matrices have been tried successfully for tissue engineering in
animal models, and products incorporating decellularized heart valves, small
intestinal submucosa (SIS), and urinary bladder matrix have been approved for
human use. The use of decellularized matrices is preferred due to its ability to retain
the complex set of molecules and three dimensional structure of original ECM. The
right amount in which structural and signaling components are needed depends on
the choices of detergents and enzymes used and the washing conditions used to
clear these reagents. Despite many advantages, there are also concerns about the use
of decellularized materials. Those are potential for rejection reaction, disease
transmission, variability among preparations, and the inability to determine the
bioactive components of the material expected (Gilbert et al. 2006; Badylak et al.
2011).
Biomaterial synthetic scaffolds used to be implemented as temporary prosthetic
devices to ll the void spaces caused by necrosis or surgery. Current biomaterials
development aim to copy the function of natural extracellular matrix (ECM), which
can support cell adhesion, differentiation, and proliferation. Biomaterial scaffolds
should be designed considering the following requirements to be considered suc-
cessful in copying ECM. First, suitable biomaterials must be selected for certain
applications. This is the same with the effort to build up the target-specic bio-
logical scaffolds. Second, biomaterial scaffolds must be a highly open porous
structure with good interconnectivity, while possessing enough structural strength
for cellular in- or outgrowth. Third, the surface of modied scaffolds must be able
to support cellular attachment, proliferation, and differentiation. Fourth, substance
or cytokine releasing scaffolds are good for tempering tissue regeneration since
cytokines such as growth factors and other small molecules have important roles in
growing functional living tissues. Fullment of the above requirements will ensure
excellent biological scaffolds, therefore producing synergic effects on successful
tissue healing (Lee 2011).
There are signicant advantages in synthetic scaffolds that closely copy key
characteristic of the ECM, but it might be manufactured and reproduced more easily
than decellularized organs. Electrospinning has enabled the production of a new
generation of highly biocompatible micro- and nano-brous scaffolds from mate-
rials such as poly(epsilon-caprolactone), from diverse matrix proteins such as
collagen, elastin, brinogen, and silk broin, from polysaccharides, and from car-
bon nanobers (Lee et al. 2009; Szentivanyi et al. 2011). Electrospun materials
have approximately the same ber diameters with those found in native ECM
and display better structural strength than hydrogels. The electrospun scaffolds
can be manufactured using various nano-brous structures and can include
additional essential ECM components such as particular subtypes of collagen,
glycosaminoglycans, and laminin, either in the spun bers or as coatings, to pro-

mote cell adhesion, growth, and differentiation (Ayres et al. 2010; Shin et al. 2012).
One of the method in producing articial scaffold for tissue engineering is
bioprinting. 3D bioprinting is the process of generating custom cell patterns
using 3D printing technologies, where cell function and viability are preserved
within the printed construct. The 3D bioprinting is applied to regenerative medicine
to ll the need for tissues and organs in suitable shape for transplantation. It
involves additional modications, such as the choice of materials, cell types, growth
and differentiation factors, and technical challenges related to the sensitivities of
living cells and the construction of the tissues. Addressing these modications
requires the integrated effort from several elds such as engineering, biomaterials
science, cell biology, physics and medicine. The 3D bioprinting has already been
used for the generation and transplantation of several tissues, including multilay-
ered skin, bone, vascular grafts, tracheal splints, heart tissue and cartilaginous
structures (Murphy and Atala 2014).
4.3 Development of Tissue Engineering in Indonesia
The development of tissue engineering in Surabaya is centered at Dr. Soetomo

General HospitalFaculty of Medicine University Airlangga, beginning with
usage of natural biomaterial from the Surabaya Cell and Tissue Bank. Natural
biomaterial application has helped many patients that require tissue reconstruction
procedure. On several occasion, these procedure might not yield satisfactory result
due to the nature of material being transplanted which are not a living tissue. In
massive bone allograft, for instance, the incorporation between the donor and
recipient bone are limited only in the contact surface area, while the middle part of
the allograft is still considered as dead bone tissue. Consequently, fracture in the
middle of the allograft might occur in the future. The fact that it takes longer time to
heal compared to the normal tissue should be taken into consideration in performing
such procedures. To overcome all of that problems, we need some life constructions
that use good cell, mature cell, and stem cells.
Tissue engineering triad that consist of cells, biomaterial as scaffold and protein
as signaling (Fig. 9.8) has similar biologic feature compared to the ideal bone graft
that is osteogenesis (possess cells that can produce new bone tissue), osteoinductive
(protein to stimulate host cell to produce new bone tissue) and osteoconductive
(scaffold as frame for the new bone cell and tissue).
Tissue engineering using stem cells composite along with biomaterial scaffold
might become a solution, since the transplanted construction is a living construc-
tion. The earliest research in 2008 was bone engineering by using bovine HAp as
bone scaffold for bone marrow mesenchymal stem cells (BM-MSCs) in critical size
defect reconstruction on rabbit as shown in Fig. 9.9 (Ferdiansyah 2010). It was then
followed by tendon engineering research using tendon allograft and cartilage
engineering research using processed bovine cartilage as scaffold for bone marrow
Fig. 9.8 Similarity in the concept of tissue engineering and bone engineering
Fig. 9.9 Bone engineering practice: a Bone marrow aspiration, b culture of stem cells, c bovine
HAp, d SEM image of bovine HAp, e stem cells growth inside the bovine HAp, f radiograph
shows the healing of critical size defect of ulnar bone of rabbit. (Adapted from Ferdiansyah 2010)
mesenchymal stem cells (BM-MSCs) as shown in Fig. 9.10 (Suroto 2011). The rst
research of tissue engineering in Surabaya showed good products rather than just
using only biomaterial.
The above research has triggered more research on stem cells, therapies based on
stem cell, and tissue engineering in Indonesia. In order to facilitate the growth of
stem cell research in Surabaya, the Surabaya Regenerative Medicine and Stem
Center (SRMSC) was founded in 2011 with a collaboration with Dr. Soetomo
General Hospital, the Faculty of Medicine, and the Institute of Tropical Disease,
Airlangga University. The SRMSC has two laboratories: (1) in the Institute of
Fig. 9.10 Tendon engineering in practice: a, b Culture of bone marrow mesenchymal stem cells,
c tendon allograft, d SEM image of tendon allograft, e stem cells grow inside tendon allograft,
f application of tendon engineering. (Adapted from Suroto 2011)
Tropical Disease focuses on basic research, animal and disease model, stem cell
banking and stem cell education; (2) in Dr. Soetomo General Hospital focuses on
natural production of biomaterial, culture and isolation on stem cell for clinical trial,
stem cell banking, education for stem cell, and tissue engineering. Now, the
SRMSC has done thousands of stem cell researches and has graduated twenty-two
doctors on stem cell studies. In 2014, Dr. Soetomo General Hospital got appointed
by Indonesian Ministry of Health as the centre of stem cell educations, researches,
and services in Indonesia.
Acknowledgment The authors acknowledge the supports from Dr. Soetomo General Hospital,
Surabaya and the Indonesian Ministry of Health. We thank Dr. Hermawan, Laval University for
the discussion and revision during the preparation of this chapter.
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Indonesian Perspective on Biomaterials
and Medical Devices
Ferdiansyah Mahyudin, Sulistioso Giat Sukaryo,

Widowati Siswomihardjo and Hendra Hermawan
Abstract Indonesia is an emerging country with population about 255 million in

2015 and 40 % of this population is in their productive age. The countrys nominal
GDP for 2015 is about 900 billion USD with 5 % annual growth and general
government debt stays at 26 % of GDP. The government has put healthcare service
as one of the strategic program in the 20152019 National Development Plan along
with a new effective national healthcare nancing scheme. Indonesia is a big market
for medical products with a market value about 800 million USD in 2015 and
estimated to reach 1.2 billion USD in 2019. The government has set policies and a
clear roadmap for assuring the availability and distribution of medical devices by
fostering local production, improving the quality of local products and tightening
the surveillance to the pre- and post-market devices. The challenge lies on unifying
the countrys experts to mutually collaborate under a strong leadership on the same
interest toward the national independency in producing effective yet low cost
medical devices.
Keywords Biomaterials Indonesian government Market Medical devices

Policy Regulation
F. Mahyudin (&)
e-mail: ferdyortho@yahoo.com
S.G. Sukaryo
National Nuclear Energy Agency of Indonesia, Yogyakarta, Indonesia
e-mail: giat_s@batan.go.id
W. Siswomihardjo
e-mail: widowati@ugm.ac.id
H. Hermawan (&)

1 Indonesia, Facts and Figures
Indonesia is the largest archipelagic country with 17,508 islands spreading over a
5,271 km distance from East to West and 2,210 km from North to South with ve
biggest islands namely Sumatra, Java, Kalimantan, Sulawesi and Papua. It is
located over the equator line between Asia and Australia with total land area of
1,904,569 km2 or about 5 million km2 total territorial claim including the sea. The
country declared its independence on 17 August 1945 after three centuries-long
tireless ght against the Dutch colonialization and started their nation building 5
years later after winning the heroic post-independence war against the Dutch mil-
itary aggression attempting to recolonialize Indonesia (Reid 1974).
Indonesian nominal GDP for 2015 is estimated at 895.677 billion USD with 5 %
annual growth or by considering the purchasing power parity the total GDP stands
at 2.840 trillion USD or 11,135 USD per capita (IMF 2015). Its economic activity
remains signicant thanks to a contribution of commodities sector even though the
value of production and exports has been affected by global recession in recent
years. The declining public debt in Indonesia since the late 1990s has strengthened
the economys resilience, maintaining favorable scal and debt positions compared
with its peers. Indonesian general government debt stays at 26 % of GDP at end
2014 and current gross funding needs of around 4 % of GDP a year are much lower
than the median of other emerging market economies such as Brazil, Malaysia and
Turkey (IMF 2015).
The 2011 census reported Indonesian population was 237,424,363 and estimated
to be 255,461,700 in 2015, making Indonesia the 4th country with the largest
population in the world (Statistics Indonesia 2015). About 40 % of this population
is in their productive age. Indonesian ethnic composition varies very widely as the
country has hundreds of ethnic and cultural diversity. However, more than half of
the population are dominated by two largest ethnics, the Javanese (41 % total
population) and the Sundanese (15 % total population). Both of them are the native
of Java, the most populated island in Indonesia, home for approximately 60 % of
the total population of Indonesia. In general the population consists of 50.3 % male
and 49.7 % female with the current life expectancy stands at 72 years old (Ministry
of Health et al. 2013).
In 2013, Indonesia has 11 cities with population over 1 million, with Bogor City
is quickly approaching the 12th. Jakarta, the national capitol, is not just the most
populated city in Indonesia, it is also the most populated city in Southeast Asia and
the 13th most populated city on earth. The ofcial metropolitan area, known as
Jabodetabek, is the second largest in the world, and the metropolis suburbs
extend even further. The entire area has a population surpassing 28 million, which
makes it one of the largest conurbations on earth. It is also one of the fastest
growing cities on earth, growing faster than Beijing and Bangkok, with population
density in the city reaches 15,342 people per square kilometer (Ministry of
Health et al. 2013).
Indonesian Perspective on Biomaterials and Medical Devices 237
All of the above facts, in turn, affect the population health and healthcare service
in Indonesia which at some points touch the aspects in biomaterials and medical
devices as shown in previous chapters. In recent years, the Indonesian authorities
have embarked on an initiative towards universal social insurance, including for
health insurance and old-age security. The initiative began in 2004 with enactment
of the Law on the National Social Security System, followed in 2011 by a law
establishing a single social insurance administrator for health care, or BPJS Health
(Badan Penyelenggara Jaminan Sosial Kesehatan). Under this framework, the
government began implementing a universal health insurance system in January
2014, consolidating several public health insurance schemes, and is nanced
through contribution payments and aims at covering the entire population by 2019
(IMF 2015).
2 Challenge and Opportunity
It has been shown in previous chapters that the large population creates some
challenges in providing basic healthcare services, notably dental care
(Chap. Biomaterials in Dentistry). In addition, the concentrated population in
main Indonesian cities has created chronic crowd trafcs dominated by motorcyles
that in turn contributes to high trafc accidents causing a high incidence of trau-
matic bone fractures (Chap. Biomaterials in Orthopaedics). These examples show
a challenge related to providing adequate quantity of medical products in dentistry
and orthopaedics which can be turn into opportunities of producing local, effective
and low-cost biomaterials and medical devices. At some points, this opportunity
can be also related to utilization of abundant Indonesian natural resources for even
producing innovative biomaterials with strong local taste and self-sustainability
(Chaps. Naturally Derived Biomaterials and Its Processing, Biocompatibility
Issues of Biomaterials, Biomaterials in Dentistry, and Tissue Bank and Tissue
Engineering).
Currently, Indonesia is merely a big market for imported medical products with a
market value about 800 million USD in 2015 and estimated to 1.2 trillion USD in
2019. This market is dominated by diagnostic imaging, medical consumable
products and implants. The Indonesian medical device market remains one of the
fastest growing, with a compound annual growth rate of 14.6 % to 2019 (BMI
Research 2015). The expansion of the health insurance programme, increased
government spending on healthcare and infrastructure development projects will
further spearhead growth.
The Government realizes that medical devices are important component in the
healthcare service where their production relies strongly with the technology and
economic strength of the country. They are considered as one of most valuable
trading commodities with big social impact, therefore with the opening of ASEAN
free-trade zone in 2015, the capability of producing medical devices locally
becomes a strategic issue in Indonesia. According to a survey by the Ministry of
Health, it is revealed that only 6 % of medical devices are produced locally and the
rest of 94 % are imported. This number is far below compared to the percentage of
local products in the neighboring countries such as Malaysia (10 %), Vietnam
(13 %), India (18 %) and Thailand (33 %), indicating a high dependence of
Indonesia toward import (Hariyanti 2015).
Locally-owned domestic production mainly consists of the manufacture of basic
items, such as surgical gloves, bandages, orthopaedic aids and hospital furniture,
but a few local manufacturer produces orthopaedic implants competing some
medium grade imported products (Chap. Biomaterials in Orthopaedics). One of
the main challenge to local manufacturing of medical devices is the Government
regulation itself that incurs 15 % taxes to imported raw materials while applies tax
holiday to imported ready to use medical products. However, the actual market
price for imported implants is always more expensive compared to similar products
produced locally. This could be related to high overhead fee, shipping fee and
promotional fee that at the end must be included in the selling price in Indonesia.
Therefore, local products can be more competitive up to 60 % when those three
factors are excluded. However, the next challenge is acquiring the technology of
medical devices manufacturing and setting up manufacturing plants whereas the
investment cost is high and increases as the level of technological content (added
value) of the devices increases.
Indonesia is not lack of experts in medical devices and its manufacturing. They
spread in many universities, research institutes and governmental instutions, such as
those who contributed to the writing of this book. The country is not lack of
potential investors either as there is always a number of rich Indonesians listed in
yearly Forbes billionaires list. The total wealth of the 2015 Forbes list of 50
Indonesian richest business persons reaches 89.84 billion USD (Forbes 2015). The
challenge is to unify those experts to mutually collaborate on the same interest
toward the national autonomy (independency) in producing medical devices under
an effective leadership. The Government should trigger the investment during the
early research and development phase and when the potential become evidence,
private investors will naturally be attracted.
3 Government Policy
3.1 Regulation
Indonesian Government have put healthcare service as one of the strategic program
in the 20152019 National Development Plan. Along with creating strategic mis-
sions such as increasing access to healthcare service for all 255 million population,
the authorities developed an effective national healthcare nancing scheme that
ensures, among all, the avalaibility of drugs and medical devices (Table 1). The
Ministry of Health has set a policy for assuring the availability and distribution of
medical devices by fostering local production, improving quality of local medical
Table 1 Classication of medical devices according to the Indonesian Ministry of Health

Class Consequence of failure or Requirement for approval Example
misuse
I Will not cause signicant Assessment is focused on Toothbrush, mask, dental
medical problem product and its quality flos, bandage, icebag,
sunglasses (without
ordonance), etc.
IIa Can cause signicant Requires complete AC powered
medical problem to assessment but clinical test is dinamometer, reflex
patient but not serious unnecessary hammer, wheelchair, etc.
(life threatening)
IIb Can cause very Requires complete Contact lenses,
signicant medical assessment, including risk ophthalmic laser, etc.
problem to patient but not analysis and safety proof but
serious without clinical test
III Can cause serious Requires complete Ventricular bypass device,
medical problem to assessment, including risk orthopaedic implants,
patient or operator analysis and safety proof and silicon gel lled breast,
clinical test etc.
products and surveillance to the pre- and post-market medical devices. Another
policy was enacted to strengthen national independency in fullling the need for
pharmaceutical products and medical devices. One of the policy is the 2009 Law on
Health that sets a strict standard on safety, efcacy and quality of pharmaceutical
products and medical devices, pointing out on their affordability (Law 36 2009).
A monetary ne up to 100,000 USD can be charged to individual who produces
medical devices that dont meet the standard or illegally distributes any kind of
medical product.
3.2 Roadmap for Medical Devices Development
The Government has a strong vision toward national independency on high quality
medical devices produced based on a rigorous research and development program.
Since 2014, serious efforts have been made to fulll the demand of medical devices
by local industry by facilitating investment in this sector, increasing the variety and
quality of local medical devices, giving incentive to local industries and reducing
import. The authorities enforce a regulation in prioritizing the use of local products
while redene stringent regulation for import such as the prohibition of using the
state budget to subsidize import. The Indonesian Ministry of Research, Technology
and Higher Education, have launched a multi-years grant scheme to Indonesian
researchers for conducting research and development on biomaterials and medical
devices utilizing optimum local content, and encourage collaboration with local
industries.
Table 2 Indonesian roadmap for medical devices development (20142022)

Stage Period Aim
I 20142016 Optimizing current medium-low technology of local medical devices
industry
Increasing number of production facilities for medical devices
Increasing use of local medical devices
Setting up research and development in medical devices technology
Initiating collaboration among industry, university and the Government
II 20172019 Developing research-based medium-high technology for medical devices
Increasing number of production facilities with standardization from ISO
13485:2003 and good manufacturing practice of medical devices
Increasing research and development activities in medical devices
technology
Increasing availability of local raw materials
Decreasing number of imported medical devices distribution yet
maximize the use of local products
Increasing export of medical devices
III 20202022 Achieving national independency on research-based high technology
medical devices
Increasing number of production facilities with standardization from ISO
13485:2003 and good manufacturing practice of medical devices
Increasing investment in medical devices industry
Decreasing number of imported medical devices distribution
Optimizing export of medical devices
Finally, the Indonesian Ministry of Health has launched a medium-term (8 years)

roadmap for realizing the above vision. This roadmap is divided into three stages as
described in Table 2 (Permenkes 86 2013).
One of actual example of national projects conducted under this roadmap is the
research and development of coronary stents, a small implant used to open coronary
artery occlusion. About 10 % of Indonesian population is elderies having potential
cardiovascular problem and the prevalence of cardiovascular patients in Indonesia was
around 530,000 in year 2013 (Ministry of Health Information Center 2013). All
coronary stents used to treat Indonesian patients are imported, soaring the cost of stent
implantation to exceed most of health insurance coverage limit (Tontowi et al. 2013).
The Indonesian Ministry of Research, Technology and Higher Education has appointed
Gadjah Mada University to lead a research and development on coronary stent which
was started in 2013 under a Triple Helix model of university-government-industry
interaction. The team have been conducting an interdisciplinary research covering
materials and engineering aspect of stents till in vitro study and planned in vivo and
clinical trials (Tauq et al. 2015; Tontowi et al. 2015).
Apart of this roadmap, examples of other research and development resulting into
commercially produced biomaterials and medical devices have been briefly exposed
in previous chapters. These include the GAMA-CHA human bone apatite composite
for bone substitution developed at Gadjah Mada University (Chap. Biocom-
patibility Issues of Biomaterials), Bio-hydrox bovine hydroxyapatite scaffolds and
various type of stainless steel bone plates developed at Airlangga University in
collaboration with the Indonesian Agency for the Assessment and Application of
Technology (Chap. Biomaterials in Orthopaedics).
Finally, we would like to conclude that all favorable factors permitting the
achievement of the national vision toward independency on medical devices evi-
dently present. The high demand for medical devices has become the Governments
concern reflected in the new policy of universal public healthcare insurance. The
enthusiastic Indonesian biomaterials scientists nd a place in the roadmap of
medical devices development, where their creativity will continue to transform the
actual challenge and opportunity into innovating effective and low-cost medical
devices.
Acknowledgment We acknowledge the supports from the Ministry of Health and the Ministry of
Research, Technology and Higher Education.
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BMI Research. (2015). Indonesia medical devices report. http://store.bmiresearch.com/indonesia-

medical-devices-report.html.
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Hariyanti, D. (2015). Ternyata 94 % alat kesehatan masih impor (The fact is 94 % of medical
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Advanced Structured Materials

Biomaterials and Medical

ISSN 1869-8433 ISSN 1869-8441 (electronic)

Library of Congress Control Number: 2016930548

Springer International Publishing Switzerland 2016

Printed on acid-free paper

This Springer imprint is published by SpringerNature

Structure and Properties of Biomaterials . . . . . . . . . . . . . . . . . . . . . . . 1

About the Editors

Ferdiansyah Mahyudin is lecturer and head of the

Hendra Hermawan is assistant professor at the

interest focuses on metals for biomedical applications. He serves as an

About the Contributors

Sri Estuningsih is a veterinarian and lecturer at the Faculty of Veterinary

conservative dentistry, minimally invasive dentistry, and composite materials.

Lukas Widhiyanto is lecturer at the Department of Orthopaedics and

Sulistioso Giat Sukaryo, Agung Purnama and Hendra Hermawan

Keywords Biomaterials Ceramic Metal Polymer Property Structure

In general understanding, biomaterials is dened as any substance, other than a

S.G. Sukaryo (&)

Springer International Publishing Switzerland 2016 1

Fig. 1 Diagram of multidisciplinary contribution to biomaterials

The early generation of biomaterials was designed to be inert, hence providing

Metals are exploited as biomaterials mainly due to their superior mechanical

2.1 Structure and Properties

Fig. 4 Illustration of two crystal structures: a HCP, and b FCC

Table 1 General applications of metals as biomaterials

Table 2 Properties of some metallic biomaterials

2.2 Stainless Steels

2.3 Co-Cr Alloys

2.4 Ti and Its Alloys

2.5 Other Metallic Biomaterials

A polymer is a macromolecule composed of many repeated subunits. It has a broad

3.1 Chain Structure

Fig. 7 Illustration of semi

Rethwisch 2014). The magnitude of the crystalline regions within a polymer is

3.2 Thermal and Mechanical Properties

Table 3 Comparison of thermoplastic and thermoset polymers

Fig. 8 The influence of temperature to the tensile behavior of poly(methyl methacrylate)

polymers depend on the strain rate, temperature, and environmental conditions.

Table 4 Mechanical properties of some polymers (Kalpakjian 2008)

3.3 Examples of Most Used Polymeric Biomaterials

4.1 Bonding and Structure

Fig. 9 The illustration of sliding in ceramics

The characteristics of ceramics is determined by the characteristics of its

4.2 Processing and Properties of Ceramics

specic types of ceramics. In alumina, the degradation may cause a preferential

4.3 Type of Bioceramics and Their Use

Fig. 10 Examples of dental implants made of bioceramics (Courtesy of Faculty of Dentistry,

Composites are combination of two different types of material or more without

Acknowledgment We acknowledge the nancial supports from Indonesian Ministry of Research,

Raden Dadan Ramdan, Bambang Sunendar

Keywords Biomaterials Biomimetic Coral Natural Precipitation Sol-gel

R.D. Ramdan (&) B. Sunendar

Springer International Publishing Switzerland 2016 23

In one denition, a biomaterial is any substance (other than a drug) or combination

Fig. 1 The Indonesian archipelago (Google)

2 Natural Source of Ceramic Biomaterials

Ceramic biomaterials (bioceramics) have been used as active biomaterials for

Fig. 3 a Achatina fulica snail, b its shell, c HAp powders

3 Synthesis of Naturally Derived Bioceramics

3.1 Hydroxyapatite Powders

One important bioceramics that is progressively developed by many researchers is

Fig. 4 Flow chart of HAp synthesis from achatina fulica shells