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www.rsc.org/materials | Journal of Materials Chemistry

Development of bone substitute materials: from biocompatible to

instructive

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Matilde Bongio, Jeroen J. J. P. van den Beucken, Sander C. G. Leeuwenburgh and John A. Jansen*
Received 22nd March 2010, Accepted 21st July 2010
DOI: 10.1039/c0jm00795a
Progress made in basic research in the last decades led to a tremendous increase in quality of clinically
applied bone substitute materials (polymers, ceramics and composites). The desired biological performance
of these materials has consequently shifted from a passive role where materials were merely accepted by the
body to an active role in which materials instruct their biological surroundings. Bone substitute materials
were traditionally based on bioceramics, that can be optimized in terms of composition, structure and
porosity. Now, polymers are increasingly gaining importance for use in medical applications due to their
high versatility. This review provides an overview of the evolution from 1st generation biotolerant and
bioinert materials via 2nd generation bioresponsive bone substitutes towards 3rd generation bioinstructive
bone substitute materials that possess inherent biological cues for bone regeneration.

1 General background
The change in living conditions during the twentieth century,
compared to the centuries that preceded it, has brought major
benefits to the welfare and health of mankind. However, the
increased life-expectancy, the dynamism of activities (e.g. transportation methods and sport activities), and the growing world
population lead to a substantial increase in patients who suffer
from damaged, malfunctioning or diseased tissues or body parts.
In view of bone tissue, these patients require safe and reliable bone
substitute materials, which are available in sufficient quantities
and possess the capacity to rapidly regenerate bone defects.
The conventional treatment approach for bone defects involves
bone grafting, which is a surgical procedure that utilizes a patients
own bone (autograft), removed from another site (e.g. hip or ribs)
or from a human donor (allograft) to fill up the defect. However,
the scarce amount of bone that can be safely harvested and the risk
of donor site morbidity limit the applicability of this approach.1
Consequently, an alternative strategy for bone grafting is required
in the form of synthetic materials that can promote bone regeneration. A large variety of synthetic materials for bone substitute
applications, (so-called biomaterials) have already been investigated for the reconstruction of bone defects. Generally, these
materials can be categorized into three groups: ceramics, polymers
and composites. Ceramic materials have a long history as bone
implant coatings and bone substitute materials owing to their
unique properties, including biocompatibility, bioactivity and
osteoconductivity. Major drawbacks for the application of
ceramics are the relatively slow degradation and poor mechanical
properties. Although ceramics are still emerging as bone substitute materials, an increasing trend is seen towards the fabrication
of polymer-based materials to obtain biodegradable and more
versatile bone substitute materials that can be adjusted to specific
Department of Biomaterials (309), Radboud University Nijmegen Medical
Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail:
j.jansen@dent.umcn.nl; Fax: +31-24-3614657; Tel: +31-24-3614006
This paper is part of a joint Journal of Materials Chemistry and Soft
Matter themed issue on Tissue Engineering. Guest editors: Molly
Stevens and Ali Khademhosseini.

This journal is The Royal Society of Chemistry 2010

requirements. Additionally, combinations of ceramics and polymers (i.e. ceramic/polymer composites) have been developed to
combine the advantageous properties of both materials within
a single bone substitute material.
The aim of the present review is to provide an overview of the
past and present bone substitute materials, and to highlight
current developments in this multidisciplinary field. For reasons
of convenience, a list of the abbreviations used throughout the
paper is presented in Table 1.

Bone substitute materials

2.1 Past and present bone substitute materials: evolution and

current commercially available products.
Evolution of bone substitute materials. Reviewing the classical
concepts and considering the evolution of materials science until
today, the definition of a biomaterial has evolved from
Table 1 List of abbreviations
BMP
hrBMP
BCP
BMA
hBMSCs
CPC
DBM
ECM
FGF
HA
NF
OPF
PCL
PEG
PGA
PLA
PLEOF
PLGA
PPF
TIPS
SMP
SME
VEGF

Bone morphogenetic protein

Human recombinant bone morphogenetic protein
Biphasic calcium phosphate
Bone marrow aspirate
Human bone marrow stromal cells
Calcium phosphate cement
Demineralized bone matrix
Extracellular matrix
Fibroblast growth factor
Hydroxyapatite
Nanofibrous
Oligo (poly (ethylene glycol) fumarate)
Poly-e-caprolactone
Poly(ethylene glycol)
Poly(glycolic acid)
Poly(lactic acid)
Poly(lactide-co-ethylene oxide- co-fumarate)
Poly(lactic-co-glycolide acid)
Poly(propylene fumarate) (PPF)
Thermally induced phase preparation
Shape memory material
Shape memory effect
Vascular endothelial growth factor

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a non viable material used in a medical device, intended to interact

with biological systems to a substance that has been engineered
to take a form which, alone or as part of a complex system, is used
to direct, by control of interactions with components of living
systems, the course of any therapeutic or diagnostic procedure, in
human or veterinary medicine.2 These alterations in definition
are accompanied by a shift in conceptual ideas on biomaterials
and the expectations of their biological performance, which both
have changed in time. In view of bone substitute materials, the
shift in expectations on biomaterial performance is chronologically described below.
The search for appropriate materials as bone substitute
materials to repair and reconstruct bone defects due to trauma
or disease began in the early part of the 20th century. At that
time, selection was restricted to materials that seemed (i) suitable to fill bone defects, and (ii) tolerated by the biological
environment. However, before the advent of modern immunology, many of these early attempts were pathogenic or toxic
and triggered rejection, adsorption, or inflammatory responses.
These first insights established the basis for the development of
a continuing progress within the field of biomaterials science.
Concurrently, other ongoing developments in several disciplines, from molecular biology and chemistry to computer
science and engineering, have contributed to a significant
acceleration towards understanding of biological processes and
biomaterials.3 In this review, the historical development of bone
substitute materials is divided in three consecutive generations,
the characteristics of which are not always confined to one
specific generation but represent the optimization of requirements during this evolution (Table 2).
The 1st generation biomaterials, the so-called traditional
materials, included inert and tolerant biomaterials, which were
designed to withstand physiological stress without, however,
stimulating any specific cellular responses.4,5 Despite the longterm integrity, the inability of the body to adapt to these materials determined high probability of failure.
Consequently, attention shifted from tolerant and inert
1st generation biomaterials towards responsive 2nd generation biomaterials that were able to elicit biological responses.6
In particular, huge emphasis has been placed on synthetic
biomaterials that encompassed bioactive properties (i.e.
actively interacting with surrounding bone tissue to establish
a direct bond between the synthetic material and bone),7
osteointegration (i.e. healing process of implant placed within
the bone)8 and osteoconductive properties (i.e. the capacity to
guide bone-forming tissue on a surface or down into
pores).9,10 Another revolutionary step for these 2nd generation
biomaterials was the development of biodegradable materials,
which allows the gradual replacement of a bone substitute

material by bone tissue without limiting the regenerative

process.11
These advanced properties of synthetic bone substitute materials provided the basis for a progression towards the demand for
more powerful biomaterials to be used for the reconstruction of
bone defects, and more specifically those for application in
compromised clinical situations (e.g. critical-sized defect
scenarios, osteoporotic patients, patients with impaired wound
healing due to diabetes, etc.). Hence, these advances have
resulted in the onset of 3rd generation biomaterial development,
in which biomaterials can instruct the biological healing
process. The more recent developments and the novel requirements of 3rd generation bone substitute materials will be outlined in more detail below.
The main properties and the respective definitions for a bone
substitute material are listed in Table 3.
Current commercially available bone substitute materials. In
modern orthopedic and dental applications, several inorganic
and organic bone substitute materials, including ceramics,
demineralized allografts, polymers and composites have gained
popularity thanks to their availability, cost-effectiveness and
biological performance. Since the past decade, a growing range
of synthetic scaffolds for bone regeneration has become
commercially available with widespread usage.12 Currently, the
major segments in bone substitute market belong to the 2nd
generation bone substitute materials (Table 4). These bone
substitute materials are prepared in various physical forms, such
as powders, granules, dense blocks, putties, pastes, gels and
porous scaffolds, depending on the components and treatment.
In 2008, the fastest growing bone graft substitute material was

Table 3 Definitions of properties relevant for a bone substitute material

Requirement

Definition

Biocompatibility

The ability to perform with an appropriate host

response in a specific situation131
The ability to form a direct chemical bond with
bone and thus a uniquely strong biomaterialstrong interface132
The healing process of implant placed within the
bone8
The capacity to guide bone-forming tissue on
a surface or down into pores9
The ability to gradually vanish and leave space for
new tissue growth without hindering the
regeneration process11
The ability to induce bone formation by
influencing the differentiation or maturation of
stem cells into bone-forming cells9

Bioactivity
Osteointegration
Osteoconduction
Biodegradability
Osteoinduction

Table 2 Evolution of three biomaterial generations and the corresponding material characteristics and biological performances
Generation

Material characteristics

Tissue responses

Examples

1st

Tolerant, inert

Fibrous tissue encapsulation

2nd
3rd

Responsive
Instructive

Bone bonding, osteoconduction, degradation

Bone bonding, osteoconduction/induction,
angiogenesis, biomolecules delivery, degradation

Titanium and its alloys, alluminia, zirconia, porous

ceramics, thermoplastic polymers
Bioglass
Tissue engineered biomaterials, smart biomaterials,
biomimetic biomaterials

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Composition

This journal is The Royal Society of Chemistry 2010

DBM suspended in gelatin carrier
DBM suspended in a hydrogel carrier
DBM and CCC suspended in
a hydrogel carrier
DBM putty
DBM plus reverse phase medium
Total bone matrix, 100% preformed
DBM combined with glycerol carrier
DBM particles and cancellous chips
DBM fibers and cancellous chips
rhBMP-2 protein on an absorbable
collagen sponge
DBM in Type-1 bovine collagen and
sodium alginate
DBM in porcine gelatin
DBM in sodium hyaluronate carrier
DBM combined with Glycerol

Optefil

Optecure

Optecure + CCC

Accell 100
Accell Connexus
Accell TBM
Optium DBM

IC Graft Chamber

Cellect DBM
INFUSE Bone Graft

DBM combined with a starch carrier

DBM combined with
natural gelatin carrier
DBM combined with glycerol
rhBMP-7 with type 1 bone collagen

Grafton Plus
BioSet

VIAGRAF
OP-1 Implant

Osteofil DBM
DBX
Grafton

Progenix DBM Putty

DBM and cortical cancellous

chips suspended in gelatin carrier

Heat sensitive copolymer with DBM

DBM in a lecithin carrier

Biphasic calcium phosphate

Calcium phosphate
Calcium phosphate
b-Tricalcium phosphate
Tricalcium phosphate

Opteform

MasterGraft Granules
Norian SRS
Norian SRS Fast Set Putty
chronOS
CELLPLEX
Organic matrix-based bone substitutesb
AlloFuse
InterGro

Inorganic matrix-based bone substitutesa

ProOsteon 500R
Coralline-derived HA/CC composite
CONDUIT TCP Granules
100% b-TCP
OpteMx
HA/TCP biphasic combination

Product

Injectable paste and moldable strips

Paste, putty mix and strip
Formable putty, injectable gel, putty
mixed with chips, flexible
sheets and matrix
Paste
Injectable paste, injectable putty,
strips and blocks with cortical
cancellous chips
Putty, paste, gel, crunch and flex
Lyophilized powder reconstituted
to form wet sand

Ready to use injectable putty

Injectable gel and putty

Paste, putty and mix with HA/CC
composite granules
Formable putty or dry powder ready to
be hydrated with autologous
diluents or saline
Injectable bone paste, dry powder
ready to be hydrated with blood or
saline
Dry mix kit delivered with or buffered
saline mix with patients autogenous
bone graft or autologous diluents
Dry mix kit delivered with buffered
saline or mix with patients
autogenous bone graft or
autologous diluents
Injectable putty
Injectable putty
Various sized strips
Formable putty (bone fibers) and
injectable gel (bone particles)
Lyophilized and packaged in various
sizes within a delivery chamber
Provided in a specialized cartridge
Multiple kit sizes

Granular or block
Granules
Granules, sticks, rounded wedges,
wedges and cylinders in several sizes
Granules
Injectable paste
Moldable putty
Granules, blocks and wedges
Various sized granules

Form

Table 4 Summary of typical commercially available bone substitute materials until 2009133

X
X

X
X
X

X
X

X
X
X
X

X
X

X
X
X
X
X

X
X
X

Osteoconduction

X
X

X
X

X
X
X

X
X

X
X
X
X

X
X

X
X
X
X
X

X
X
X

Resorbability

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X
X

X
X

X
X
X

X
X

X
X
X
X

X
X

Osteoinduction

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J. Mater. Chem., 2010, 20, 87478759 | 8749


b-TCP - b-tricalcium phosphate, HA/CC - Hydroxyapatite/camcium carbonate. b CCC - Cortical cancellous chips, DBM - Demineralized bone matrix.

Calstrux

8750 | J. Mater. Chem., 2010, 20, 87478759

CopiOs Bone Void Filler

Sponge and paste

X
Moldable putty

X
X
X


MasterGraft Matrix
MasterGraft Putty
Vitoss

Compression resistant block

Moldable putty
Putty, strip, flow, morsels and shapes

X
X
X

X
Strip and putty

 80% highly purified B-TCP

 20% highly purified type-1 collagen
Calcium phosphate and collagen
Calcium phosphate and collagen
 100% b-TCP
 80% b-TCP/20% collagen
Tricalcium phosphate with carboxy methelcellulose
Dibasic calcium phosphate and Type I
collagen

DBM putty

Puros Demineralized Bone Matrix

Inorganic/Organic matrix-based bone
substitutes
HEALOS Bone
Graft Replacement
Integra Mozaik

X
Variety of strip sizes

Bovine bone
CopiOs Cancellous Bone Graft

Mineralized collagen matrix

X
X
X

X
X

Lyophilized powder reconstituted

to form putty
Cancellous chips, cancellous cubes
and wedges
Putty
rhBMP-7 with type 1 bone collagen

OP-1 Putty

Form
Composition
Product

Table 4 (Contd. )

Osteoconduction

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Resorbability

Osteoinduction

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demineralized bone matrix (DBM) allograft (data from European Markets for Dental Bone Graft Substitutes and Other
Biomaterials 2009, Published Sep 2009 by iData Research, Inc.:
www.mindbranch.com). DBM possesses acknowledged osteoconductive and osteoinductive properties.13 Nevertheless,
different methods of preparation, carrier, sterilization techniques, storage, and donor specifications determine significant
differences in osteogenic potential between the product formulations.14,15 DBM is produced alone (Accell 100, PurosDBM)
or in combination with osteocompatible carriers, such as glycerol
(Optium DBM, Grafton), gelatin (Opteform, Optefil
OsteofilDBM, BioSet), collagen (Progenix DBM Putty),
lecithin (InterGro) and hyaluronic acid (DBX), which are all
intended to increase the handling properties of DBM by turning
it into a putty or paste without reducing the osteoconductive
properties. The success of DBM is mainly due to cost-effectiveness and availability from human tissue banks.13
Within the bone substitute material market, ceramics also hold
a prominent position. Biocompatibility and osteoconductive
properties provide ceramics with desirable qualities as implant
materials for different applications throughout the body,
covering all areas of the skeleton, such as bone fillers, treatment
of bone defects, fracture treatment, orthopedics, and craniomaxillofacial reconstruction.16,17
Although limited in extent, few current commercially available
bone substitute materials belong to 3rd generation biomaterials.
The limited number of currently commercially available 3rd
generation biomaterials for bone substitute include materials
endowed with high porosity and interconnectivity to allow
attachment of bone-forming cells, nutrient/oxygen infiltration
and vascularization, and high resorbability that permits better
imaging and visualization of the healing process (e.g. CopiOs
Bone Void Filler). In addition to osteoconductive properties, the
supplementation of bone substitute materials with an autologous
bone marrow aspirate (BMA) can provide osteoinductive properties necessary for bone ingrowth. Finally, also growth factors,
such as recombinant human bone morphogenetic protein 2
(rhBMP-2) and rhBMP-7 (or Osteogenic protein 1, (OP-1)), have
been incorporated into scaffolds (INFUSE Bone Graft, OP-1
Implant and OP-1 Putty) to be released in a temporally and
spatially controlled manner and to confer osteoinductive properties by actively recruiting stem cells from surrounding tissue
and blood, initiating the bone formation process.

2.2 Current development for 3rd generation bone substitute

materials
Despite recent achievements, the majority of 3rd generation
synthetic bone substitute materials is at research or test level and
many improvements are still necessary before application in
a clinical setting becomes feasible. Biomaterials science is an
interdisciplinary field, in which many experts (e.g. mechanical
engineers, material scientists, chemists, biologists, medical
doctors, and surgeons) collaborate, expanding knowledge about
composition, microstructure, properties, biological performance
and ability to control these characteristics. Material researchers
can now analyze and manipulate material properties in ways that
were hard to imagine just a few years ago.
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structures to allow bone ingrowth as well as biodegradability for

a rapid turn-over to newly-formed osseous tissue.21 The stiffness
and strength should be appropriate to offer an environment
suitable for cell growth and, in the same time, allow the material
itself to withstand the tractional forces and adapt to changes of
surrounded tissue.18 Fig. 1 shows the possible strategies that can
be adopted to achieve these instructive goals for the design of
ideal 3rd generation bone substitute materials suitable for
medical applications.

Fig. 1 Current strategies to achieve 3rd generation bone substitute

material requirements.

The next step for the development of 3rd generation bone

substitute materials will consist of the integration of more farreaching and powerful requirements into higher-level systems
that instruct the biological surroundings into a desired response
upon implantation. Indeed, future bone substitute materials will
intervene actively to instruct the physiological environment
toward desired biological responses (e.g. bone formation and
blood vessels formation), for a real integration of the materials
within the native bone.18 Hence, up-to-date approaches to meet
these requirements include drug delivery systems as well as
bioactive molecule carriers capable of triggering new bone tissue
formation.19,11 Challenges in the field of bone substitute materials
are to create gene-based or, even more ambitious, cell-based
scaffolds to act as an additional source in vivo and to facilitate the
remodeling process. However, the scarce availability of autologous cells, risks of cell transplantation and several impediments
of 3D scaffolds, such as biophysical complexity and cell-matrix
interactions, make this strategy still too difficult to define in
practice as well as time-, money- and labor-consuming.20
Besides biochemical composition, there is growing appreciation of the importance of other properties, including mechanical
performance, mechanical durability and physical properties in
guiding biological responses and providing the best chance for
success. A bone substitute material should supply both sufficient
mechanical stability to maintain structural integrity throughout
the period of bone remodeling and interconnected porous

2.2.1 Ceramic-based materials. Ceramic materials began to

gain extreme popularity for biomedical applications in the late
1960s. The huge advance in knowledge and technology during
the course of the last 40 years brought ceramics to be universally
appreciated in terms of biocompatibility, osteoconductivity and
bioactivity due to the close chemical and structural resemblance
to the mineral phase of bone tissue.22 The historical landmarks of
the development of ceramics for biomedical applications over the
past four decades are summarized in Table 5.
Currently, the most common types of calcium phosphate
ceramics used as synthetic materials are porous hydroxyapatite
(HA), b-tricalcium phosphate (b-TCP), their derivatives and
their combinations, such as biphasic calcium phosphate ceramics
(BCP).11,19 Calcium phosphate ceramics have consistently
demonstrated an excellent tissue response in vivo, but some
drawbacks of crystalline calcium phosphates, such as inherent
brittleness and relatively slow degradation, limit their clinical
application as synthetic bone substitute materials.23
Current strategies for the fabrication of 3rd generation
ceramic-based bone substitute materials will be discussed below
according to modern requirements (as listed in Fig. 1) that are
indispensable for a successful regeneration of bone tissue.
Osteoinduction. Although the exact mechanism of osteoinduction by calcium phosphate bioceramics is largely unknown,24
the induction of bone formation at non-osseous sites in animals
without the addition of any osteoinductive biomolecules is
demonstrated to be feasible with calcium phosphate
ceramics.25,26 These calcium phosphate materials have included
synthetic porous hydroxyapatite, coral derived hydroxyapatite,
a-tricalcium phosphate, b-tricalcium phosphate, biphasic
calcium phosphate, a-pyrophosphate and b-pyrophosphate
ceramics, calcium phosphate cements and calcium phosphatecontaining biomaterials coatings.24 Their intrinsic osteoinductive
capacity was proposed to be related to several design parameters
(e.g. topography, geometry, composition, macroporosity and

Table 5 Chronological order of important milestones in the development of ceramics for biomedical applications during the past 40 years
Date

Event

Pioneers

1960s

Characterization of carbonate substituted HA (CHA) for biomedical

application
Bioglass
First bone bonding in bioactive glass ceramics
Apatite-wollastonite (A-W) glass-ceramic
Plasma-sprayed hydroxyapatite implants
Calcium phosphate bone cements
Use of hydroxyapatite (HA) for implantation
Use of calcium phosphate as a filler in polymer-matrix composites

LeGeros R.Z.134

1967
Early 1970s
1982
1980s
1980s
1980s1990s
1980s1990s

This journal is The Royal Society of Chemistry 2010

Hench L.L.135
Hench L.L.136,137
Kokubo T.138
De Groot K.139
Ferdandez E.,140,141 Chow L.C.142
De Groot K., Jarcho M., Driessens F., Bonfield W.143
Bonfield W.144

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nano/microporosity) that allow entrapment and concentration of

bone inducing substances and/or immature bone-forming cells
from the biological surroundings onto the ceramic surface.2729
Besides intrinsic osteoinductive activity of bioceramic materials, engineered osteoinductivity can be introduced by grafting
bioactive proteins, osteoinductive growth factors30 and/or boneforming cells31,32 into the traditional bioactive materials. When
cell binding-proteins, which allow cell attachment, are absorbed
(e.g. fibronectin,28 vitronectin,33 fibrinogen and trombin34) or
covalently or physicochemically incorporated (e.g. type I
collagen35,36) onto the surface of bioceramics, these have been
shown to improve the biological properties of these hybrid/
composite materials.
The most important growth factors in bone formation and
healing are bone morphogenetic proteins (BMPs), belonging to
the transforming growth factor (TGF)-b-superfamily. The
primary function of BMPs is to induce the maturation of bone
forming-cells through the binding to specific cell receptors. As
a result, intracellular signaling will direct a gene-specific response
that will transform the immature cell into a bone-forming cell.
Several studies have demonstrated the powerful capacity of
BMPs incorporated into bioceramic materials to provoke
modification in the behavior of immature bone forming-cells,
which are recruited to the site of injury and enhance new bone
formation.37,38
The delivery or presentation of growth factors to the biological
surrounding is a critical step for engineered osteoinductive
ceramics. Enrichment with growth factors can be based on
simple adsorption,39,40 but more sophisticated entrapment
approaches have been proposed, predominantly with the aim to
prolong and intensify the exposure of the biological surroundings to these factors.41,42
The relatively high-strength and osteoconductive calcium
phosphate cements (CPC), either in prefabricated blocks or
injectable formulations, have been shown to be an effective
delivery vehicle for growth factors to promote bone regeneration.
Prefabricated block ceramics are commonly loaded with growth
factors by adsorption,39,43 while growth factor loaded-polymeric
microspheres (e.g. PLGA44 or gelatin38) can be incorporated
inside injectable CPC as delivery vehicles. The clinical relevance
of such microsphere structures is that these matrices can serve as
appropriate carriers to control the release and maintain therapeutic levels of diffusible growth factors at the repair site.
Angiogenesis. Scaffolds not only provide a substrate onto
which host cells can grow, but they can also be used to guide
tissue formation, such as bone (see previous section) and
vascular structures that provide nutrient and oxygen supply.45
The exact requirements for a scaffold to induce or promote
vascular tissue formation are still in part unsolved. Challenges
in bone substitute materials research address to promote
angiogenesis either by matching angiogenic growth factors,
endothelial cells (i.e. cells that line the inner side of the blood
vessels), or other biological components to a tissue engineered
construct, or by defining an appropriate porosity within a scaffold. Recently, the constant release at low concentrations of
vascular endothelial growth factor (VEGF) from biphasic
calcium phosphate (BCP) ceramics has been shown to be
beneficial for blood vessel in-growth and thus for bone
8752 | J. Mater. Chem., 2010, 20, 87478759

formation.46 Alternatively, inorganic copper ions incorporated

within calcium phosphate scaffolds showed angiogenetic
potential and represent an attractive alternative to the use of
costly and complex proteinaceous factors.47
Besides having an important effect on osteoinductive properties, interconnecting macroporosity and microporosity of the
scaffold are essential to allow vascularization. Pore size must be
sufficient to provide efficient in vivo blood vessel formation
within bioceramic scaffolds.19
Mechanical properties. The development of ceramic bone
substitute materials that show both good biological and
mechanical performance is desired. However, the major shortcoming of bioceramics relates to their inherent poor mechanical
properties (i.e. brittleness) and non-matching to the elastic
behavior of bone tissue. Different strategies, including sintering
methods and biocomposite materials with polymers, can be
adopted to confer favorable mechanical performance of
ceramic scaffolds without compromising the biological properties.
Sintering procedures, in which a granular material is subjected to
a thermal treatment with the purpose of increasing its strength,
appear to be of major importance to produce bioceramics with
appropriate mechanical properties.19 Sintering temperature is
correlatedtodifferentscaffoldparameters,suchasdensity,porosity,
grain size, chemical composition and strength. In a recent study,
hydroxyapatite disks with four different porosities sintered at
different temperatures (900, 1100, 1200 or 1250  C) showed distinct
mechanical properties, including elastic modulus and hardness.
Indeed, with increasing sintering temperature, the bulk density,
grain sizes and elastic modulus increased whilst the total porosity
decreased.48
Alternatively, in order to improve the mechanical properties of
calcium phosphate bioceramics, ceramic-polymer composites
have been synthesized.49 Composites can combine the advantages of both materials, namely (i) strength via a ceramic phase,
and (ii) toughness and plasticity via a polymer phase. In analogy
with living bone, which is a composite matrix of mainly collagen
and biomineral (bone apatite crystals),27 the incorporation of
polymer components within ceramic materials can provide
improved elastic behavior of the bone substitute material.
Substantial research efforts have already been focusing on the
development of ceramic-polymer composites for bone graft
applications, in which the major challenge relates to obtaining
a good chemical and/or physical bond between the polymer and
the ceramic phase. The most commonly used resorbable
synthetic polymers in combination with ceramics materials are
saturated poly-a-hydroxy esters, including (poly(lactic acid)
(PLA) and poly(glycolic acid) (PGA), their copolymer (poly(lactic-co-glycolide) (PLGA) and poly-e-caprolactone (PCL).
These polymers can be mixed with ceramic scaffolds using
different methods, such as porogen leaching, gas expansion,
emulsion drying and, more recently, freeze-drying via thermally
induced phase separation (TIPS).50
Biodegradability. Development of bone substitute materials
for the regeneration of living tissues leads to the requirement for
higher resorbability, especially when combined with the release
of pharmaceuticals to enhance tissue regeneration. Although
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bioresorbable ceramics are gradually degraded in bony defects,

there is still need for ceramic scaffolds with higher resorbability.
From a material point of view, the degradation speed of calcium
phosphate ceramics depends on composition,51 crystallinity,
porosity and preparation conditions. Modulation of these
parameters improves the biodegradability of ceramic materials
and facilitates new bone to invade the defect site.
Modern strategies, including nanotechnology, have demonstrated the ability to reproduce superior structural properties
compared to currently used implants, by creating materials that
mimic the natural nanostructure of bone tissue.52 For instance,
nanocrystalline calcium phosphates have demonstrated faster
degradation and enhanced bone cell functions compared to
micron grain size calcium phosphate.53
Porosity and interconnected pores within the scaffolds are also
essential components that are introduced within bioceramic
materials in order to enhance resorbability.54 Especially, generating pores in injectable matrices is a current topic of research, in
which investigators are examining fast-degrading particles that
can dissolve within a short time after injection and hardening,
leaving a porous but rigid structure behind.55 It has been
reported that the optimal pore size for successful cell infiltration
and bone tissue ingrowth is 100350mm.56 A number of fabrication techniques have been developed over the years for
manufacturing porous bioceramics, according to the various
physical forms (e.g. block, granular form, putty or paste).19 The
most common techniques are incorporation of pore-creating
additives (porogens),57,54,56 such as naphthalene, H2O2, polymeric microspheres, or foaming methods.58 Habraken et al.
conducted research on incorporation of different types of polymeric microspheres (e.g. gelatin59,60 and PLGA61,62) within
calcium phosphate cement to induce porosity, through the
degradation of the polymeric microspheres, and to improve the
degradation rate of the materials. The main advantage of these
materials is that they degrade hydrolytically, resulting in
a breakdown of the polymer chain, hence leading toward
a controllable (bio)degradation. However, control of degradation rate is a contributing factor to the success of bone substitute
materials. High porosity and a too fast degradation rate may
result in the loss of the surface that is needed for further facilitation of bone formation. Therefore, an optimal balance between
high surface reactivity and a low dissolution rate is required to
regulate the in vivo bioresorbability of calcium phosphate
ceramics.
Handling properties. The clinical application of bone substitute materials requires optimal handling properties for reliable

Fig. 2 Examples of injectable bone substitute materials: (A) CPC

injection for maxillary sinus floor elevation in a goat model; (B) hydrogel
applied in the medullar cavity of tibia in a guinea pig model.

This journal is The Royal Society of Chemistry 2010

and safe clinical application. Preparation of the bone substitute

materials and implantation at the defect site should be simple,
fast, and standardized under all conditions without surgeondependent variations.
The current ceramic bone substitute materials are mainly
available in dense or porous blocks or granules. However,
ceramics in the hardened form are not easy to handle and to
maintain in the surgical sites thus leaving empty spaces between
bone tissue and filling material. Moreover, surgeons need to fit
the surgical site around the implant or to carve the graft to the
desired shape, increasing the probability of bone loss, trauma to
the surrounding tissue and surgical time.
Moldability of ceramic-based bone substitute has been introduced with the development of putty-like materials, that can be
quickly sculptured during surgery in situ to provide intimate
adaptation to the contours of defect surfaces.63 Additives, such as
accelerants, cohesion promoters, and fluidificants have been used
to improve workability, and setting and hardening properties.64
For instance, the combination of fibrin glue with ceramic granules has been used as a strategy to stabilize the material at the
implantation site and produce a composite that can be molded
into the defect without leaving empty spaces.65,66
Even more sophisticated is the introduction of injectability
with the development of calcium phosphate cement (CPC) paste
that can be easily applied into the bone defects by using a syringe
(Fig. 2A). The injectability of CPC is also of critical importance
for use in minimally invasive techniques. The advantages of an
injectable CPC include: (i) shortening the surgical operation
time; (ii) minimizing the damaging effects of large muscle
retraction; (iii) achieving optimal defect filling; (iv) reducing
postoperative pain and scar size; (v) achieving rapid recovery;
(vi) reducing cost.63 CPC consists of a powder containing one or
more solid compounds of calcium and/or phosphate salts and
a cement liquid that can be water or an aqueous solution.67 The
powder and the liquid are mixed in an appropriate ratio prior to
implantation to form a paste that subsequently hardens at body
temperature within several minutes.55 Once injected, CPC form
a low-crystallinity hydroxyapatite that can be adsorbed over
time.
2.2.2 Polymer based-materials. Polymers are increasingly
gaining interest for the development of scaffolds for tissue
engineering and regenerative medicine applications compared to
other bone substitute materials, such as ceramics, because of
their versatility in terms of chemical and physical properties.52
Polymer based-materials mainly boast design flexibility associated with a wide range of mechanical properties that make these
materials to be easily manipulated into desired shapes and
structures and to be degraded at a controlled rate in concert with
tissue regeneration.68 In addition, polymers can be easily sterilized without causing any chemical change and have the capacity
to incorporate biological matrix components.
The polymeric materials used in the biomedical field and, more
specifically, in tissue engineering are of natural or synthetic
origin. Natural polymers are categorized into proteinaceous
polymers (e.g. collagen, gelatin, silk) and polysaccharidic polymers (e.g. chitosan, alginate, starch, and hyaluronic acid derivatives).69 Due to their extracellular matrix (ECM)-like properties
suitable for cell survival and function, and low toxicity, natural
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polymers are attractive materials for designing biocompatible,

biodegradable and bioactive scaffolds. Nevertheless, natural
polymers suffer from disadvantageous properties, including low
mechanical strength and high degradation rates that limit their
use for bone tissue replacement.
On the other hand, synthetic polymers are appealing, and have
a number of advantages over both natural polymers and other
bone substitute materials. The chemical versatility of synthetic
polymers permits the fabrication of materials and scaffolds in
different forms as well as with variation in porosity and pore
sizes, degradation kinetics and mechanical properties. Although
synthetic polymers do not possess functional groups to stimulate
cell adhesion, such groups can be easily introduced by the
incorporation of bioactive molecules or protein sequences able to
induce specific cellular responses. Moreover, synthetic polymer
production can also be more easily scaled-up than natural
polymers.70 The most frequently used biodegradable synthetic
polymers for scaffolds in bone tissue engineering approved by the
FDA are saturated poly-a-hydroxy esters, including (poly(lactic
acid) (PLA) and poly(glycolic acid) (PGA), as well as (poly(lactic-co-glycolide) (PLGA) copolymers.71
Hydrogels. In addition to solid polymeric bone substitute
materials, hydrogel-forming polymers are an emerging and
physiologically relevant class of biomaterials. Hydrogels are
a network of crosslinked polymer chains, which are able to swell,
but not to dissolve, in aqueous solution.72 These properties
confer native tissue-like viscoelasticity and provide a suitable
physiologic micro-environment to house cells until the onset of
ECM production by these cells.73 As early as 1960, hydrogels
started to be used as biomaterials due to their major advantages,
such as biocompatibility, permeability and ductile physical
properties.74 However, only in the last 510 years hydrogel
research has undergone sharp development, in which research
interest has shifted from conventional prefabricated hydrogels,
whose implantation requires large incisions (cuts), to injectable
formulations that rapidly allow gelation under physiological
conditions once injected into the body.75 Besides a minimallyinvasive implantation procedure, these types of materials allow
the incorporation of pharmaceutical agents by simply mixing
them before injection.76 Following gelation, these gel-like
matrices release their content at the target site triggering tissue
regeneration.

According to the mechanism of the crosslinking reaction,

hydrogels can be classified into two main categories: (i) chemically crosslinked hydrogels and (ii) physically crosslinked
hydrogels.77 The so-called chemical gels are crosslinked by
chemical interactions, including covalent (irreversible) or ionic
(reversible) bonds,78 through the action of crosslinking agents
under thermal,79 redox80 or photoinitiating81 (i.e. visible or UV
light) conditions or enzymatic reactions.82,83 Chemical hydrogels
have relatively strong and stable mechanical properties.
However, high concentrations of initiators and crosslinking
agents may compromise cell viability and be detrimental for
surrounding tissues as a result of side-effect reactions. Unlike
chemically crosslinked hydrogels, physical hydrogels lack
crosslinking agents and thus polymerize spontaneously through
a number of non-covalent interactions under physical stimuli,
such as changes in temperature, pH, electric field, salt or ionic
environment.77 For this reason, physical hydrogels can also be
called self-assembling hydrogels.84
Similar to ceramic based-materials, advanced strategies are
being explored for the development of 3rd generation polymerbased materials. An overview of these strategies is provided
below, listed by the criteria indicated in Fig. 1.
Osteoinduction. New generation polymeric-based materials
are engineered to direct the host cells to adhere to and degrade
the synthetic matrix, and ultimately to regenerate new bone at
the defect site. Release of biological signals from polymeric
scaffolds or gene therapy, based on the localized delivery of
naked DNA plasmid encoding osteoinductive proteins, are the
current strategies to achieve these goals.
Foremost, cell adhesion to the ECM or to a scaffold, through
binding between specific cell membrane receptors and corresponding cell-adhesion-molecules, is an imperative requirement
for survival and cell-cycle progression of certain types of cells, i.e.
anchorage-dependent cells, which include bone-forming cells.8587
Cell adhesion is a 4-step process that includes (1) initial cell
attachment, (2) cell spreading, (3) cytoskeletal organization and
(4) confocal adhesion formation. Cell attachment and cell
adhesion are often used indistinctly, however, from the definition it is evident that the first is just one part of the entire
process.88 Although some hydrogels show appropriate structural
characteristics suitable for a scaffold, they do not contain celladhesion-molecules and, hence do not support cell survival. To

Table 6 Hydrogel functionalizations with different adhesive peptides

Hydrogel

Synthetic sequence

Origin

Functions

Ref.

PEG

RGD

Fibronectin, vitronectin, collagen

145

PEODA
OPF
pHEMA
OPF

RGD
GRGD
RGDSK
DVDVPDGRGDSLAYG

Fibronectin, vitronectin, collagen

RGD derived peptide
RGD derived peptide
Osteopontin

PLEOF

KIPKA SSVPT ELSAI STLYL

Bone morphogenetic protein-2

P(NIPAAm-co-AAc)

FHRRIKA

Heparin binding domain

PEGDM

RGDS and Heparin

Osteoblast adhesion, proliferation and

mineralization
Osteoblast differentiation and mineralization
Osteoblast adhesion
Osteoblast adhesion and proliferation
Osteoblast adhesion, proliferation, migration
and differentiation
Osteoblast adhesion, proliferation and
differentiation
Osteoblast adhesion, spreading and
mineralization
Osteoblast viability and differentiation

8754 | J. Mater. Chem., 2010, 20, 87478759

146
94
147
91,93
96
148
97

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overcome this drawback, several modifications of design

parameters have been made by chemical or physical entrapment
of biological cues, ranging from inorganic minerals, such as
calcium phosphate nanocrystals,89 to adhesive long or short
ECM peptide sequences, derived from natural proteins. The
resulting materials, containing biomimetic components, ensure
cell-matrix interaction in order to control cell behavior and,
subsequently, promote bone tissue growth. One successful
strategy to improve the viability and activity of bone-forming
cells in hydrogel scaffolds is the use of small peptides that activate receptor-mediated cellular responses. The most commonly
used peptide is the amino acid triplet RGD (Arg-Gly-Asp),
which is the predominant ligand for cell-surface receptors (i.e.
integrins) to achieve cell attachment. The RGD-sequence is
abundantly present in many proteins that can be found in the
extracellular matrix (e.g. fibronectin, laminin, fibrinogen,
collagen). The RGD-sequence and other amino acid sequences,
such as IKVAV and YIGSR from laminin, REDRV and LDV
from fibronectin and DGEA from collagen I, have been covalently coupled to different types of hydrogel polymers that lack
cellular adhesion72 (Table 6). Among synthetic hydrogels,
poly(ethylene glycol) (PEG)- based polymer gels have been
used abundantly because of their proven safety and FDA
approval.90 However, due to inherent cell repellent properties (as
a result of poor protein adsorption) PEG-based hydrogels have
been functionalized through the incorporation of cell-binding
peptides to modulate cell adhesion, morphology and migration.9194
The adhesion to synthetic peptide sequences is not always
associated with changes in cytoskeletal organization and cellular
behavior and thus in cell-cycle progression. More essential,
models that ensure not only cell attachment but also succession
of all the downstream biological pathways involved in cell
function activation are required.85,86 According to the above
consideration, synergism between adhesive proteins and selection of bioactive molecules may be necessary to stimulate desirable biological events.95 In a recent study, an RGD-sequence and
a peptide derived from recombinant human bone morphogenetic
protein (rhBMP-2) have been grafted in Poly(lactide-co-ethylene
oxide- co-fumarate) (PLEOF) hydrogel. While RGD-sequences
mediated cellular adhesion to the hydrogels, BMP-peptide
promoted maturation of bone-forming cells and mineralization.96 Next to RGD-sequences, another extensive class of cell
binding domains, as used to enhance cell adhesion into polymer
based-materials, is represented by heparin, due to its intrinsic
ability to enhance the osteogenic activity of some growth factors
involved in bone formation.97
The delivery of osteoinductive agents, such as the abovementioned BMPs98,99 or other novel osteogenic proteins (e.g.
Nell-1),100 has significantly enhanced the bone regenerative
capacity of materials in animal models. However, the main
concern of researchers is how to deliver these molecules at the
appropriate site and how to maximize the therapeutic potential
and efficacy. An effective strategy involves the encapsulation of
osteoinductive factors within micro- or nanoparticles, subsequently incorporated in the scaffold to be released to the local
microenvironment in a controlled fashion by diffusion and/or
scaffold erosion or degradation mechanisms.101 Although growth
factor delivery has demonstrated to be a promising strategy, this
This journal is The Royal Society of Chemistry 2010

application can be limited by protein purification, short in vivo

stability, low activity and prohibitive costs. Another attractive
route to control the release of molecules stimulating bone growth
at the site of interest is gene therapy via a DNA plasmid vector
that integrates into the cells residing in the tissue. Thereby, the
delivery of plasmid DNA promotes local protein production by
the transfected cells.102 The success of therapeutic gene delivery,
however, requires a system that both guarantees high level of
transfection efficiency and long-term gene expression to produce
physiological responses that lead to tissue formation.103 This has
been shown in the context of a cranial critical-sized defect model
in which PEI-condensed plasmid DNA encoding for BMP-4
from macroporous PLGA scaffolds enhanced bone regeneration.
This system provided a platform that potentially allows immature bone-forming cells or other cell types (e.g. fibroblasts)
surrounding the defect area to migrate into the defect site and to
be transfected by the plasmid DNA associated with the scaffold.104 In another study, naked DNA plasmid encoding for
vascular endothelial growth factor (pVEGF165) has been incorporated into collagen/calcium phosphate scaffolds and has
shown a significant increase in bone formation upon implantation in an intra-femoral mouse model.105 Hence, DNA-presenting polymeric surface gains long-term osteoinductivity by
affecting the behavior of the cells that come in to contact with the
material.
Angiogenesis. As mentioned above, angiogenesis plays
a pivotal role in skeletal development and bone fracture
repair.45 Growth factor therapy as well as gene delivery from
polymeric scaffolds are under evaluation and development to
promote angiogenesis and thus to actively stimulate bone
regeneration.
Approaches involving single growth factor release by polymeric vehicles (e.g. collagen106 or gelatin microparticles107) that
allow for a localized and controlled delivery in the bone wound
healing environment, have shown promising results on the
formation of blood vessels. Although vascular endothelial
growth factor (VEGF) is an important initiator of angiogenesis,
the delivery of VEGF alone may lead to immature and leaky
vasculature with poor function.108 Therefore, dual release
approaches provide a more powerful tool to study and manipulate a wide array of developmental and regenerative processes.
The addition of both fibroblast growth factor-2 (FGF-2) and
VEGF to collagenheparin scaffolds led to an increased angiogenesis and blood vessel maturation at an earlier time point than
with either FGF-2 and VEGF alone.109 Similarly, the interplay of
VEGF and BMP-2 released from gelatin microparticles confined
within porous poly(propylene fumarate) (PPF) scaffold resulted
in a synergistic response to produce increased bony bridging and
bone formation within a rat critical size defect model compared
to delivery of BMP-2 alone.110 In another experiment, PLGA
scaffolds containing combinations of condensed plasmid DNA
encoding for BMP-4, VEGF, and human bone marrow stromal
cells (hBMSCs) significantly enhanced bone formation compared
to any single factor or combination of two factors.111
More interestingly, therapeutic angiogenesis might be further
improved by the sequential release of growth factors delivered
by a biodegradable polymer, which achieves distinct release
kinetics for each factor. A composite consisting of BMP-2
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loaded-PLGA microspheres embedded in a PPF scaffold surrounded by a VEGF loaded-gelatin hydrogel (microspheres/
PPF/gelatin composites) was implanted in a subcutaneous and
femoral defect of rat model and used for the sequential release
of the growth factors. The study demonstrated a significant
contribution of VEGF to subcutaneous bone formation induced
by BMP-2, whereas no effects of VEGF were observed in the
bony defect.112
Mechanical properties. The use of synthetic or natural polymer
matrices with low mechanical properties and fast degradation
kinetics results in bone substitute materials with high biological
activity but poor structural properties, in particular low strength
and stiffness.18 Polymers with better mechanical properties can
be fabricated by altering design parameters or by incorporating
organic or inorganic reinforcements within the polymeric matrix
that increase strength and toughness.
Anseth indicated several parameters that influence the
mechanical properties of hydrogels: (i) the polymer composition, (ii) the cross-linking density and (iii) the degree of
swelling.113 However, it must be considered that changes of
these parameters in the polymer will affect not only the
mechanical properties but also other general material behavior.
Temenoff and co-workers showed the possibility of altering
crosslinking density and therefore mesh size (i.e. the free space
between cross-linked macromolecules) of oligo (poly (ethylene
glycol) fumarate) (OPF) hydrogels by changing the molecular
weight of the polymeric chains.114 As a consequence, even
physical properties such as water-adsorbable performance,
mechanical strength, degradability and diffusivity were affected.
Nevertheless, matching all the qualities suitable for both a given
application and environmental conditions requires many
attempts and efforts as some properties may affect others.115
For example, hydrogels with high mechanical strength provide
more stability, however swelling and diffusion are limited. On
the other hand, lower mechanical strength guarantees higher
swelling and thus a better molecular trafficking, oxygen supply
and nutrient/waste transport. Therefore, it is imperative to find
a compromise between mechanical properties, swelling and
mass transport properties.116
Besides altering crosslinking density, a variety of processing
technologies have been developed to fabricate porous 3D polymeric scaffolds for bone regeneration. These techniques mainly
include solvent casting and particulate leaching, gas foaming,
emulsion freeze-drying, electrospinning, rapid prototyping, and
thermally induced phase separation (TIPS). Further details on
the fabrication of polymeric scaffolds are available elsewhere.68
Other strategies to increase the mechanical properties of polymeric based-materials involve (i) blending polymer with other
polymer(s) or (ii) reinforcement of the polymer matrix by
minerals or, more recently, by carbon nanotubes117 or carbon
nanoparticles.118
Polymeric microspheres embedded within PLGA matrix have
shown to tailor compressive strength as well as porosity and
interconnectivity of a polymeric scaffolds.119 Likewise, polymer
based-composites, such as nanocrystallites of inorganic biological compounds dispersed within polymer matrices or on the
surface of the composites, can be designed to improve the
mechanical performance and tissue integration and to provide
8756 | J. Mater. Chem., 2010, 20, 87478759

a suitable microenvironment that mimics the host tissues inorganic phase.89;120

Liu et al. fabricated nanofibrous (NF)-gelatin/apatite
composite scaffolds to mimic both physical architecture and
chemical composition of natural bone ECM. Firstly, thermally
induced phase separation (TIPS) was integrated with porogen
leaching technique to fabricated (NF)-gelatin scaffolds with well
defined micropores. Subsequently, bone-like apatite was incorporated onto the surface of NF-gelatin scaffolds. The resulting
biomimetic scaffolds showed high porosity, interconnectivity
and good mechanical strength.121
Biodegradability. Biodegradable polymers as bone substitute
materials need to possess appropriate degradation rates to match
new tissue formation under physiological conditions and nontoxic and neutral degradation products. The degradation of
a polymer occurs (i) by absorption of water followed by hydrolysis of the unstable bonds (hydrolytic degradation), (ii) by
metabolic (i.e. cellular or enzymatic) pathways or (iii) dissolution. The resulting non-toxic degradation products are metabolized and more easily excreted from the body compared to
ceramics.71
As illustrated for mechanical properties, biodegradability is
influenced by design factors of polymers, including polymeric
composition, molecular weight, the ratio of contents, pH, crystallinity and hydrophobicity.122 Therefore, control over these
parameters determine the degradability and the tissue reaction
that ultimately regulate bone formation. However, some polymers degrade too fast compared to the formation of new tissue,
hindering the bone healing process. Degradation can be slowed
down by chemical modifications. However, such modifications
can lead to tissue toxicity and decrease biocompatibility.
It has been only five years since stimuli-responsive nanostructured polymer materials have been developed. These
sophisticated materials, also called smart materials, display
a dramatic physicochemical change in response to small changes
in their environment such as temperature, pH, solvent, magnetic
field, ions, pressure, light, and magnetic fields.123 For example,
degradable hydrogels have been designed by the addition of
photolabile groups (e.g. nitrobenzyl ether-derived moiety124 or
photoreactive acrylate group125) attached to the backbone of
hydrophilic chains. Chemical and physical properties of these
materials are tunable spatially and temporally with UV light even
in the presence of entrapped cells. Gel degradation is externally
triggered and directed upon light exposure by photolytic
cleavage and removal of photosensitive macromolecules that
compose the gel.
Moreover, the development of smart biodegradable polymerbased injectable drug delivery systems has gained wide attention
over the past few years. Drug-loaded biodegradable polymers are
two-component systems (drug and polymer), which exhibit two
functionalities: the capability of drug molecules to gradually
escape from the matrix for a controlled release, and the ability of
the matrix to subsequently degrade for complete secretion from
the body. The application of these modern delivery systems
allows a decreased body drug dosage with concurrent reduction
in possible undesirable effects common to most forms of systemic
delivery, maintain drug level in the therapeutic window and
improve patient compliance and comfort.126
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Handling properties. The key advantages of polymers which

make them preferable to other bone substitute materials are
tunable physical properties that give excellent clinical characteristics. Indeed, polymer-based materials can be easily manipulated into various forms such as beads, micro/nanoparticles,
and gels under mild conditions. In particular, injectable formulations, required to increase the scope of minimally invasive
procedures, provide the ability to take shape of the cavity in
which they are placed and can thus fill irregular defects75
(Fig. 2B). Another category of stimuli-responsive materials in the
forefront of polymer science for medical application is represented by shape-memory materials (SMPs).127 These class of
actively moving polymers change shape on demand in response
to an external stimulus. The shape-memory effect (SME) is based
on a suitable polymer network architecture in combination with
a programming technology.128 In the future, these materials will
be introduced into bone defects by minimally invasive procedures through a small incision leading to benefits for a more
gentle treatment and reduction of costs in health care.

3 Conclusion and final remarks

The research on synthetic bone substitute materials has undergone explosive growth over the past 40 years due to an increasing
collaboration between experts from different scientific disciplines. Despite this explosive growth, the translation of scientific
knowledge on bone substitute materials has resulted in only a few
commercially-available bone substitute products that are
predominantly based on bioceramics and demineralized bone
matrix (DBM). However, the development of synthetic bone
substitute materials for commercial exploitation is in the initial
phase of a revolutionary leap, in which novel concepts account
for the generation of materials with instructive capacities.
The 1st generation biomaterials were generally based on
tolerant and inert materials that were only capable to withstand
anticipated physiological stress while being passively accepted by
the body. Although these materials provided an effective
immediate solution for many patients, their long-term performance was often insufficient. The increasing research efforts on
the determination of mechanisms causing biomaterial failure,
and the progress in the development of biomaterials that
interact with the biological surroundings led to 2nd generation
biomaterials. Because these biomaterials allow cell-surface
interactions, they are responsive to external stimuli that promote
direct bone-bonding and osteoconduction. The novel concepts
for the generation of 3rd generation materials with instructive
capacities are based on the combination of scientific knowledge
and clinical needs. Scientifically, huge progress has been made
toward the development of intelligent materials with unique
properties regarding biological performances (e.g. osteoinduction and angiogenesis), mechanical properties, degradation
capacity and porosity characteristics. Especially, the almost
unlimited possibilities of polymeric materials will offer valuable
advantages. Furthermore, novel strategies for the delivery of
growth factors will aid to orchestrate biological responses
through the controlled temporal and spatial release of these
factors. Although associated with major safety and regulatory
issues, even concepts based on combinations of cells or genes
with materials will evolve toward clinical applicability.
This journal is The Royal Society of Chemistry 2010

The widening of the classical view of bone substitute materials will certainly have a positive impact on medicine, industry
and more importantly on their clinical application. However,
at present there is a large gap between the state-of-the-art in
the field of materials science and the use of materials in clinical
practice. The progression from laboratory concept to
commercial application in patients faces several challenges
including long and often undefined regulatory approval pathways, high translational costs, assessing appropriate risk/
benefit and cost/benefit ratios, and appropriate matching of
technology and application. Moreover, it should be emphasized that bone substitute materials ultimately are employed to
address needs that the patient perceives in terms of rehabilitation, comfort and convenience.129 Biomedical innovation is
heading now into minimally invasive and quicker procedures,
fewer hospital visits including shorter stays and reduced
complications.
Despite the recent advances, future progress in engineering
disciplines (for example computer-aided design) together with
an increased understanding of the processes through which
inorganic and organic macromolecules self-assemble into
organized architectures and complex forms will allow for the
design of new materials with tailored structures at both the
micro- and the nano-domain level. Such sophisticated materials, so called bio-inspired, will be built to mimic nature not
through presenting active fragments reproduced exactly from
biological molecules, but rather through presenting sensor
activities to monitor their function and interact with the biological systems.130

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