Biomaterials: an introduction

Evolution of Biomaterial Science & Technology

1
st
generation (since 1950s)
G l Bi i t Goal: Bioinertness
2
nd
generation (since 1980s)
Goal: Bioactivity
3
rd
generation(since2000s) 3 generation (since 2000s)
Goal: Regenerate functional tissue
Some application of biomaterials
Application Types of Materials
- Skeletel system
J oint replacement(Hip, knee)
Bone plate
Bone cement
Artificial tendon andligment
Titanium , Stainless steel, PE
Stainless steel, Co-Cr alloy
PMMA
Hydroxylapatie Teflon Dacron
Artificial tendon and ligment
Dental implant
- Cardiovascalar sysem
Blood vessel prosthesis
Heart valve
Hydroxylapatie Teflon, Dacron
Titanium, alumina, calcium phosphate
Dacron, Teflon, Polyurethane
Reprocessed tissue, Stainless steel, Carbon
Silicone rubber teflon polyurethane
Catheter
- Organs
Artificial heart
Skin repair template
Artificial kidney
Silicone rubber, teflon, polyurethane
Polyurethane
Silicone-collage composite
Cellulose, polyacrylonitrile
Silicone rubber
y
Heart-lung machine
- Senses
Cochlear replacement
Intraocular lens
Contact lens
Silicone rubber
Platium electrodes
PMMA, Silicone rubber, hydrogel
Silicone-acrylate. Hydrogel
C ll h d l
Contact lens
Corneal bandage
Collagen, hydrogel
What is a Biomaterial?
A material intented to interface with
biological systemstoevaluate treat biological systems to evaluate, treat,
augment or replace any tissue, organ
or functionof thebody or function of the body.
Historically, biomaterials consisted of materials common in the
laboratories of physicians with little consideration of material laboratories of physicians, with little consideration of material
properties.
Early biomaterials : y
Gold: Malleable, inert metal (does not oxidize); used in dentistry
by Chinese, Aztecs and Romans--dates 2000 years
Iron brass: High strength metals; rejoin fracturedfemur (1775) Iron, brass: High strength metals; rejoin fractured femur (1775)
Glass: Hard ceramic; used to replace eye (purely cosmetic)
Wood: Natural composite; high strength to weight; used for limb
prostheses prostheses
and artificial teeth
Bone: Natural composite; uses: needles, decorative piercings
Sausage casing: cellulose membrane used for early dialysis (W
Kolff)
Other: Ant pincers. Central American Indians used to suture
wounds
A biomaterial
is a nonviable material used in a medical device intended to is a nonviable material used in a medical device, intended to
interact with biological systems.
1
is used to make devices to replace a part of a function of the
b d i f li bl i d h i l i ll body in a safe, reliable, economic, and physiologically
acceptable manner.
is any substance (other than a drug), natural or synthetic, that
treats, augments, or replaces any tissue, organ, and body
function.
The need for biomaterials stems from an inability to treat many
diseases, injuries and conditions with other therapies or procedures :
replacement of body part that has lost function (total hip, heart)
correct abnormalities (spinal rod)
improve function (pacemaker, stent)
assist in healing (structural pharmaceutical effects: sutures assist in healing (structural, pharmaceutical effects: sutures,
drug release)
HISTORY
Important dates Important dates
1860's: Lister develops aseptic surgical technique
early 1900's: Bone plates used to fix fractures
1930's: Introduction of stainless steel, cobalt chromium alloys
1938 : first total hip prosthesis (P. Wiles)
1940's: Polymers in medicine: PMMA bone repair; cellulose y p ;
for dialysis; nylon sutures
1952: Mechanical heart valve
1953: Dacron (polymer fiber) vascular grafts 1953: Dacron (polymer fiber) vascular grafts
1958: Cemented (PMMA) joint replacement
1960: first commercial heart valves
1970' PEO ( l th l id ) t i i t t thi fil 1970's: PEO (polyethyleneoxide) protein resistant thin film
coating
1976: FDA ammendment governing testing & production of
bi t i l /d i biomaterials /devices
1976: Artificial heart
EXAMPLES OF USES OF BIOMATERIALS
Organ/Tissue Examples
heart pacemaker, artificial val ve, artificial heart
t t l i t l l eye contact lens, intraocular lens
ear artificial stapes, cochlea implant
bone bone plate, intramedullary rod, joint bo e bo e p ate, t a edu a y od, jo t
prosthesis, bone cement, bone defect
repair
kidney dial ysis machine
muscle sutures, muscle stimulator
circulation artificial blood vessels circulation artificial blood vessels
skin artificial skin
endocrine encapsulated pancreatic islet cells

MATERIAL ATTRIBUTES FOR BIOMEDICAL
APPLICATIONS
Property Desirables
Biocompati bility Noncarcinogenic nonpyrogenic Biocompati bility Noncarcinogenic, nonpyrogenic,
nontoxic, nonallergenic, blood
compatible, non-inflammatory
Sterilizability Not destroyed by typical sterilizing
techniques such as autoclaving, dry
heat, radiation, ethylene oxi de
Physical characteristics Strength, elasticity, durability
Manufacturability Machi nable, moldable, extrudable

BIOCOMPATIBILITY
There is no general set of criteria, that if met, qualify a
material as being biocompatible
The time scale over which the host is exposed to the material
or device must be considered or device must be considered
material contact time
syringe needle 1-2 s syringe needle 1 2 s
tongue depressor 10 s
contact lens 12 hr - 30 days
bone screw / plate 3-12 months
total hip replacement 10-15 yrs
intraocul ar lens 30 + yrs
Biocompatibility
Biocompatibility:
Theabilityof amaterial toperformwithan The ability of a material to perform with an
appropriate host response in a specific
application application.
Host response:
Th i f li i h The reaction of a living system to the
presence of a material
Biocompatibility
B=f(X
1
,X
2
......Xn)
WhereX: material design applicationetc Where X: material, design, application etc.
Medical Device
It does not achieve its principal intended
action in or on the human body by y y
pharmacological, immunological or
metabolic means, but it may be assisted in , y
its function by such means.
Classes of Biomaterials
Metals
stainless steel, cobalt alloys, titanium alloys
Ceramics
aluminum oxide, zirconia, calcium phosphates
Polymers
silicones, poly(ethylene), poly(vinyl chloride),
polyurethanes polylactides polyurethanes, polylactides
Natural polymers
collagen, gelatin, elastin, silk, polysaccharides g g p y
Biomaterials
Polymeric biomaterials
Bioceramics Bioceramics
Metallic biomaterials
Biocomposite
Biologically based (derived) biomaterials g y ( )
Polymerization
Condensation: A reaction occurs between
two molecules to form a larger molecule g
with the elimination of a smaller molecule.
Addition: A reactionoccursbetweentwo Addition: A reaction occurs between two
molecules to form a larger molecule without
theeliminationof asmaller molecule the elimination of a smaller molecule.
PolymericBiomaterials Polymeric Biomaterials
Advantages Disadvantages
Easy to make complicated
items
T il bl h i l &
Leachable compounds
Absorb water & proteins etc.
Tailorable physical &
mechanical properties
Surfacemodification
Surface contamination
Biodegradation
Diffi lt t t ili
Surface modification
Immobilize cell etc.
Biodegradable
Difficult to sterilize
Polymeric Biomaterials
PMMA PMMA
PVC
PLA/PGA PLA/PGA
PE
PP
PA
PTFE
PET
PUR
Sili Silicones
Bioceramic Bioceramic
Advantages Disadvantage
High compression
strength
High modulus
(mismatched with bone)
Wear & corrosion
resistance
Low strength in tension
Low fracture toughness
Can be highly
polished
Difficult to fabricate
Bioactive/inert
Bioceramics
Alumina
Zirconia(partiallystabilized) Zirconia (partially stabilized)
Silicate glass
C l i h h ( i ) Calcium phosphate (apatite)
Calcium carbonate
Metallic Biomaterials:
Advantages Disadvantages
High strength
Fatigue resistance
High moduls
Corrosion
Wear resistance
Easy fabrication
Metal ion sensitivity
and toxicity
Easy to sterilize
Shape memory
Metallic looking
Metallic biomaterials
Stainlesssteel Stainless steel
Co-Cr alloys
Ti
6
Al
4
V
Au-Ag-Cu-Pd alloys g y
Amalgam (AgSnCuZnHg)
Ni Ti Ni-Ti
Titanium
Surface modification (treatment)
Physical and mechanical treatment
Chemical treatment Chemical treatment
Biological treatment
Surface Properties of Materials
Contact angle (Hydrophilic & Hydrophobic)
Surface chemical analysis y
SEM (Surface morphology)
Deterioration of Biomaterials
Corrossion
Degradation Degradation
Calcification
M h i l l di Mechanical loading
Combined
General Criteriafor materials General Criteria for materials
selection
Mechanical and chemicals properties
Noundersirablebiological effects No undersirable biological effects
carcinogenic, toxic, allergenic or
immunogenic immunogenic
Possible to process, fabricate and sterilize
i h d d ibili with a good reproducibility
Acceptable cost/benefit ratio
Material Properties
Compresssive strength
Tensile strength
Surface tension
Hardness and density g
Bending strength
E-Modulus
y
Hydrophobic/philic
Water sorption/
Coefficient of thermal
expansion
p
solubility
Surface friction p
Coefficient of thermal
coductivity
Creep
Bonding properties gp p
Cell/tissue reaction to implant
Soft tissue
Hardtissue Hard tissue
Blood cells
The biological milieu
Atomic scale
Molecular scale Molecular scale
Cellular level
Ti Tissue
Organ
System
Organism Organism
pH in humans
Gastric content 1.0
Urine 45-60 Urine 4.5 6.0
Intracellular 6.8
I i i l 70 Interstitial 7.0
Blood 7.17-7.35
Sequenceof local eventsfollowing Sequence of local events following
implantation in soft tissue
Injury
Actuteinflammation Actute inflammation
Granulation tissue
F i b d i Foreign body reaction
fibrosis
Soft tissueresponsetoanimplant Soft tissue response to an implant
Actut (mins to hrs)
Cell type: Leukocytes
Function: Recognition, engulfment and degradation
(killing)
Chronic (days to months) Chronic (days to months)
Cell types: Macrophages, monocytes and
lymphocytes.
G l ti ti f ti (3 5 d ) Granulation tissue formation (3-5 days)
Cell types: Endothelial cells (forming blood
vesssels), fibeoflasts (forming connnective tissue) ) ( g )
Foreign body reaction (days to life time)
Cell types: Foreign body giant cells, Macrophages,
fibroblasts fibroblasts
Fibrosis & Fibrous encapsulation
Cell type: Fibroblasts
Bioactive and Osteointegration
A chemical bonding between bone and
material will be formed. (Bioactive, ( ,
Hydroxylapatite)
A direct contact between bone and implant
(Osterintegration titanium) (Osterintegration, titanium)
Blood material interaction
Hemolysis (red cells)
Coagulation(Platelets) Coagulation (Platelets)
Test Hierarchies (for blood-contacting device)
Cell culture, cytotoxicity (Mouse L929 cell line)
Hemolysis (rabbit or human blood)
Mutagenicity (Ames test)
Systemic injection, acute toxicity (Mouse)
S iti ti (G i i ) Sensitization (Guinea pig)
Pyrogenicity (Rabbit)
Intramuscular implantation(Rat rabbit) Intramuscular implantation (Rat, rabbit)
Blood compatibility
Long-term implatation. g p
Standards
Test methods
Materialsstandards Materials standards
Device standards
P d d d Procedure standards
ISO 10993 and EN 30993
ISO 10993-1: guidance on selection of tests
ISO 10993-2: Animal welfare requirements
ISO 10993-3: Test for genotoxicity, carcinogenicity and reproductive toxicity
ISO 10993-4: Selection of tests for interactions with blood
ISO 10993-5: Tests for cytotoxicity: In vitro methods
ISO 10993-6: Test for local effects after implantation
ISO10993 7 Eth l id t ili ti id l ISO 10993-7: Ethylene oxide sterilization residuals
ISO 10993-8: Clinical investigation
ISO 10993-9: Degradation of materials related to biological testing
ISO10993-10: Testsfor irritationandsensitization ISO 10993 10: Tests for irritation and sensitization
ISO 10993-11: Tests for systemic toxicity
ISO 10993-12: Sample preparation and reference materials
........
Testing of Biomaterials
Physical and mechanical
Biological Biological
In vitro assessment
i i in vivo assessment
Functional assessment
Clincal assessment
Biomaterials applications
Dental implant
Tooth fillings g
Vascular implants
Drug delivery, bone fixing pine, suture g y, gp ,
Bone defect fillings
Hipjoint prosthesisboneplate Hip joint prosthesis bone plate
Scaffolds for tissue engineering
Contanct lens Contanct lens
3-principles in dental implant design:
Initial retention Initial retention
Anti-rotation mechanics
N h d No sharp-edges
Tooth fillings materials: Tooth fillings materials:
Amalgam
Dental composite
Ceramics Ceramics
Other metals
General criteria for tooth filling materials
Non irritation to p lp and gingi al Non-irritation to pulp and gingival
Low systemic toxicity
Cariostatic
Bonding to tooth substance without marginal leakage
Not dissolved or erode in saliva
M h i l h i d l hi Mechanical strength, wear resistance, modules matching.
Good aesthetic properties
Thermal propertiesy (expansion &conductivity) Thermal propertiesy (expansion & conductivity)
Minimal dimensional changes on setting and adequate
working time and radio opacity
Calcium phosphate-based bioceramic
Bone
Ca-P compounds CaP compounds
Applications:
Bone fillers/HA-coatings/In situ setting
cement/tooth paste/drug tablets
Hip joint prosthesis
Ceramic head
Metallicstem Metallic stem
Polymeric socket
C i b Composite bone cement
Requirements for Soft Tissue Adhesive
Biodegradable
Fast spreadonwet (wound) surface Fast spread on wet (wound) surface
Adequate working time
Ad b di h Adequate bonding strength
Hemostasis
Biocompatible
Contact lens
Optical properties
Chemical stability Chemical stability
Oxygen transmissibility
R i li id/ i d i i Resistance to lipid/protein deposition
Easy to clean
Drugdelivery Drug delivery
(Slow/Controlled release)
Most effective and low toxi dose
A constant dosageover alongperiod A constant dosage over a long period
Local treatment
E h dl d ff i Easy to handle and cost-effective
Classificationof Classification of
slow release system
Diffusion controlled
Water penetrationcontrolled Water penetration controlled
Chemically controlled
P d h i Pendant chain systems
Regulated system (Magnetic or ultrasound)
Sterilization Methods
Moist heat (121-125
o
C, 15-30 min)
EO(CH CH O) EO (CH
2
CH
2
O)
Radiation (
60
Co & Electron Beam)
Dry heat > 140
o
C
Others (UV, Ozone X-ray etc)
SiliconeApplications
Orthopedics(small joints)
Silicone Applications
Orthopedics (small joints)
Extracorpreal Equipment (Dialysis, heart
bypass manchines, blood oxygenator)
Aesthetic implant p
Spine

Calcium phosphate cement (CPC) is a synthetic bone graft material that was invented
in 1986 by L. C. Chow and W. E. Brown, scientists at the American Dental Association.
The cement is a white powder consisting of equimolar amounts of ground
Ca4(PO4)2O (tetracalcium phosphate, TTCP) and CaHPO4 (dicalcium phosphate
anhydrous, DCPA). When mixed with water, the material forms a workable paste
which can be shaped during surgery to fit the contours of a wound. The cement
hardens within 20 min allowing rapid closure of the wound. The hardening reaction,
which forms nanocrystalline hydroxyapatite (HA) as the product, is isothermic and
occurs at physiologic pH so tissue damage does not occur during the setting reaction.
CPC was FDA approved for the treatment of non-load-bearing bone defects in 1996.
HA is the primary inorganic component of natural bone which makes the hardened
cement biocompatible and osteoconductive. Over time, CPC is gradually resorbed and cement biocompatible and osteoconductive. Over time, CPC is gradually resorbed and
replaced with new bone. Because CPC is brittle, it is used for non-load-bearing
applications such as dental and cranio-facial applications. CPC has two significant
advantages over pre-formed, sintered ceramics. First, the CPC paste can be sculpted
during surgery to fit the contours of the wound. Second, the nanocrystalline
hydroxyapatite structure of the CPC makes it osteoconductive causing it to be
gradually resorbed and replaced with new bone. Recent work with CPC has focused
on improving mechanical properties, making premixed cements, making the cement p g p p , g p , g
macroporous and seeding cells and growth factors into the cement.
Invention of CPC: Brown WE, Chow LC (1986) A new calcium phosphate water setting
cement. Brown PW, ed. Cements Research Progress. Westerville, OH: American
Ceramic Society; 352379.
CPC Review: Friedman CD, Costantino PD, Takagi S, Chow LC. (1998)
BoneSourceTM hydroxyapatite cement: a novel biomaterial for craniofacial skeletal
tissue engineering and reconstruction. J Biomed Mater Res (Appl Biomater) 43:428-
432, 1998.
Image Copyright 2007 by Wright Medical Technology, Inc. Used with permission.
Requirementsof aScaffoldused Requirements of a Scaffold used
for tissue engineering
Easy cell penetration, distribution, proliferation
Permeability of culture medium y
In vivo vascularization (once implanted)
Maintenance of cell phenotypes p yp
Adequate mechanical properties
Controlledbiodegradation Controlled biodegradation
Ease of fabrication