Biomaterials: an introduction

Evolution of Biomaterial Science & Technology

• 1st generation (since 1950s)G l Bi i tGoal: Bioinertness

• 2nd generation (since 1980s)Goal: Bioactivity

• 3rd generation (since 2000s)3 generation (since 2000s)Goal: Regenerate functional tissue

Some application of biomaterialsApplication Types of Materials

- Skeletel system• Joint replacement(Hip, knee)• Bone plate• Bone cement• Artificial tendon and ligment

• 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 rubbery

• 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 lContact lens• Corneal bandage

• Collagen, hydrogel

What is a Biomaterial?A material intented to interface with biological systems to evaluate treatbiological systems to evaluate, treat, augment or replace any tissue, organ

or function of the bodyor function of the body.

Historically, biomaterials consisted of materials common in the laboratories of physicians with little consideration of materiallaboratories of physicians, with little consideration of material properties.

Early biomaterials :yGold: Malleable, inert metal (does not oxidize); used in dentistry by Chinese, Aztecs and Romans--dates 2000 yearsIron brass: High strength metals; rejoin fractured femur (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 prosthesesprosthesesand artificial teethBone: Natural composite; uses: needles, decorative piercingsSausage 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 tois 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 llbody 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: suturesassist in healing (structural, pharmaceutical effects: sutures, drug release)

HISTORYImportant datesImportant dates

1860's: Lister develops aseptic surgical techniqueearly 1900's: Bone plates used to fix fractures1930's: Introduction of stainless steel, cobalt chromium alloys1938 : first total hip prosthesis (P. Wiles)1940's: Polymers in medicine: PMMA bone repair; cellulose y p ;for dialysis; nylon sutures1952: Mechanical heart valve1953: Dacron (polymer fiber) vascular grafts1953: Dacron (polymer fiber) vascular grafts1958: Cemented (PMMA) joint replacement 1960: first commercial heart valves1970' PEO ( l th l id ) t i i t t thi fil1970's: PEO (polyethyleneoxide) protein resistant thin film coating1976: FDA ammendment governing testing & production of bi t i l /d ibiomaterials /devices1976: Artificial heart

EXAMPLES OF USES OF BIOMATERIALS

Organ/Tissue Examples

heart pacemaker, artificial valve, artificial heart

t t l i t l leye 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 tprosthesis, bone cement, bone defect repair

kidney dialysis machine

muscle sutures, muscle stimulator

circulation artificial blood vesselscirculation artificial blood vessels

skin artificial skin

endocrine encapsulated pancreatic islet cells

MATERIAL ATTRIBUTES FOR BIOMEDICAL APPLICATIONS

Property Desirables

Biocompatibility Noncarcinogenic nonpyrogenicBiocompatibility Noncarcinogenic, nonpyrogenic,

nontoxic, nonallergenic, blood

compatible, non-inflammatory

Sterilizability Not destroyed by typical sterilizing

techniques such as autoclaving, dry

heat, radiation, ethylene oxide

Physical characteristics Strength, elasticity, durability

Manufacturability Machinable, moldable, extrudable

BIOCOMPATIBILITYThere 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 consideredor device must be considered

material contact time

syringe needle 1-2 ssyringe 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

intraocular lens 30 + yrs

Biocompatibility

• Biocompatibility: The ability of a material to perform with anThe ability of a material to perform with an appropriate host response in a specific applicationapplication.

• Host response: Th i f li i hThe reaction of a living system to the presence of a material

Biocompatibility

• B=f(X1,X2......Xn)• Where X: material design application etcWhere X: material, design, application etc.

Medical Device

• It does not achieve its principal intended action in or on the human body by y ypharmacological, immunological or metabolic means, but it may be assisted in , yits function by such means.

Classes of BiomaterialsMetals

• stainless steel, cobalt alloys, titanium alloysCeramics

• aluminum oxide, zirconia, calcium phosphatesPolymers

• silicones, poly(ethylene), poly(vinyl chloride), polyurethanes polylactidespolyurethanes, polylactides

Natural polymers• collagen, gelatin, elastin, silk, polysaccharidesg g p y

Biomaterials

• Polymeric biomaterials• Bioceramics• Bioceramics• Metallic biomaterials• Biocomposite• Biologically based (derived) biomaterialsg y ( )

Polymerization

• Condensation: A reaction occurs between two molecules to form a larger molecule gwith the elimination of a smaller molecule.

• Addition: A reaction occurs between twoAddition: A reaction occurs between two molecules to form a larger molecule without the elimination of a smaller moleculethe elimination of a smaller molecule.

Polymeric BiomaterialsPolymeric BiomaterialsAdvantages Disadvantages

• Easy to make complicated itemsT il bl h i l &

• Leachable compounds• Absorb water & proteins etc.

• Tailorable physical & mechanical properties

• Surface modification

• Surface contamination• Biodegradation

Diffi lt t t iliSurface modification• Immobilize cell etc.• Biodegradable

• Difficult to sterilize

Polymeric BiomaterialsPMMA• PMMA

• PVC• PLA/PGAPLA/PGA• PE• PP• PA• PTFE• PET• PUR

Sili• Silicones

BioceramicBioceramicAdvantages 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 (partially stabilized)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• Stainless steel• Stainless steel • Co-Cr alloys• Ti6Al4V• Au-Ag-Cu-Pd alloysg y• Amalgam (AgSnCuZnHg)• Ni Ti• Ni-Ti• Titanium

Surface modification (treatment)

• Physical and mechanical treatment• Chemical treatmentChemical treatment• Biological treatment

Surface Properties of Materials

• Contact angle (Hydrophilic & Hydrophobic)• Surface chemical analysisy• SEM (Surface morphology)

Deterioration of Biomaterials

• Corrossion• DegradationDegradation• Calcification

M h i l l di• Mechanical loading• Combined

General Criteria for materialsGeneral Criteria for materials selection

• Mechanical and chemicals properties• No undersirable biological effectsNo undersirable biological effects

carcinogenic, toxic, allergenic or immunogenicimmunogenic

• Possible to process, fabricate and sterilize i h d d ibiliwith a good reproducibility

• Acceptable cost/benefit ratio

Material Properties

• Compresssive strength• Tensile strength

• Surface tension• Hardness and densityg

• Bending strength• E-Modulus

y• Hydrophobic/philic• Water sorption/

• Coefficient of thermal expansion

psolubility

• Surface frictionp• Coefficient of thermal

coductivity• Creep• Bonding propertiesg p p

Cell/tissue reaction to implant

• Soft tissue• Hard tissueHard tissue• Blood cells

The biological milieu

• Atomic scale• Molecular scaleMolecular scale• Cellular level

Ti• Tissue• Organ• System• OrganismOrganism

pH in humans

• Gastric content 1.0• Urine 4 5-6 0Urine 4.5 6.0• Intracellular 6.8

I i i l 7 0• Interstitial 7.0• Blood 7.17-7.35

Sequence of local events followingSequence of local events following implantation in soft tissue

• Injury• Actute inflammationActute inflammation• Granulation tissue

F i b d i• Foreign body reaction• fibrosis

Soft tissue response to an implantSoft tissue response to an implant• Actut (mins to hrs)

Cell type: LeukocytesFunction: 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, fibroblastsfibroblasts

• Fibrosis & Fibrous encapsulationCell 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• Materials standardsMaterials 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

ISO 10993 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• ISO 10993-10: Tests for irritation and sensitizationISO 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 • BiologicalBiological

In vitro assessmenti iin vivo assessmentFunctional assessmentClincal assessment

Biomaterials applications

• Dental implant• Tooth fillingsg• Vascular implants• Drug delivery, bone fixing pine, sutureg y, g p ,• Bone defect fillings• Hip joint prosthesis bone plateHip joint prosthesis bone plate • Scaffolds for tissue engineering• Contanct lens• Contanct lens

3-principles in dental implant design:• Initial retentionInitial retention• Anti-rotation mechanics

N h d• No sharp-edges

Tooth fillings materials:Tooth fillings materials:

• Amalgam• Dental composite• CeramicsCeramics• 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 compoundsCa P compounds• Applications:

Bone fillers/HA-coatings/In situ setting cement/tooth paste/drug tablets

Hip joint prosthesis

• Ceramic head• Metallic stemMetallic stem• Polymeric socket

C i b• Composite bone cement

Requirements for Soft Tissue Adhesive

• Biodegradable• Fast spread on wet (wound) surfaceFast spread on wet (wound) surface• Adequate working time

Ad b di h• Adequate bonding strength• Hemostasis• Biocompatible

Contact lens

• Optical properties• Chemical stabilityChemical stability• Oxygen transmissibility

R i li id/ i d i i• Resistance to lipid/protein deposition• Easy to clean

Drug deliveryDrug delivery(Slow/Controlled release)

• Most effective and low toxi dose• A constant dosage over a long periodA constant dosage over a long period• Local treatment

E h dl d ff i• Easy to handle and cost-effective

Classification ofClassification ofslow release system

• Diffusion controlled • Water penetration controlledWater penetration controlled • Chemically controlled

P d h i• Pendant chain systems• Regulated system (Magnetic or ultrasound)

Sterilization Methods

•Moist heat (121-125oC, 15-30 min)

•EO (CH CH O)•EO (CH2CH2O)

•Radiation (60Co & Electron Beam)

•Dry heat > 140oC

•Others (UV, Ozone X-ray etc)

Silicone Applications

•Orthopedics (small joints)

Silicone Applications

Orthopedics (small joints)

•Extracorpreal Equipment (Dialysis, heart bypass manchines, blood oxygenator)

•Aesthetic implantp

•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 andcement 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 , gmacroporous 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; 352–379.

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.

Requirements of a Scaffold usedRequirements of a Scaffold used for tissue engineering

• Easy cell penetration, distribution, proliferation• Permeability of culture mediumy• In vivo vascularization (once implanted)• Maintenance of cell phenotypesp yp• Adequate mechanical properties• Controlled biodegradationControlled biodegradation• Ease of fabrication