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Biomaterials

Biocompatibility Biometallic materialsBiopolymersBioceramics

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Biocompatibility

The ability of a material to perform with an appropriate host response in a specific application

Examples of appropriate “host response”

Resistance to blood clotting.Resistance to bacterial colonisation“Uncomplicated” healing

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Biomedical Materials

Metals: Co-Cr alloys, Stainless steels, Titanium alloys.

Uses: Orthopaedics, Fracture fixation, Dental & Craniofacial reconstruction, Stents.

Ceramics: Alumina, Zirconia, Calcium Phosphate, Pyrolitic Carbon

Uses: Orthopaedics, Heart valves, Dental reconstruction.

Polymers: PE (LDPE, HDPE, UHMWPE), PU, PMMA.

Uses: Orthopaedics, Contact lenses, Catheters, Artificial tendons.

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Biomedical Materials

Hydrogels: Cellulose, Acrylic co-polymers.Uses: Drug delivery, wound healing.

Resorbables: Bioglass, HA, Polyglycolic acid, Polylactic acid, Polyesters.

Uses: Coatings, Sutures, Drug delivery, Tissue engineering.

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Evolution of Total Hip Replacement

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Polymer Composites in the body

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Categories of Biomaterials

• Bioactive Material• One that elicits a specific biological response at the

interface of the material, resulting in the formation of a bond between the tissues and the material.

• Bioinert Material• One that elicits minimal biological response.

• Bioresorbable Material• One that is gradually replaced by normal tissues, thereby

excluding possible long term effects.

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Implant Factors

Bulk propertiesChemical composition, structure and purity.

Surface propertiesSmoothness, CoF, geometry and hydrophilicity.

Mechanical propertiesMatch properties of component being replaced, e.g. Young’s modulus. Stability & fixation.

Long-term structural integrityDesign against fatigue and fracture loading, wear, plastic deformation, and corrosion.

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Host Factors

SpeciesSimulated tests in smaller species do not always capture response in humans

Age and health statusThe rate of tissue repair in the elderly is slower than the young

Immunological / metabolic statusSome patients are more immune than others

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Biocompatibility

Arises from differences between living and non-living materials.Trigger inflammation or foreign body response.Must be tested rigorously prior to implantation according to FDA (US) regulation.WW2: Validated biocompatibility of several materials including PMMA.

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Application of Biomaterials

OrthopaedicsArtificial joints (hips, knees, shoulders, wrists, IVD), fracture fixation, bone grafts.

CardiovascularHeart valves, pacemakers, catheters, grafts, stents.

Dental & CraniofacialEnamels, fillings, prosthetics, orthodontics.

Soft tissueWound healing, occular

SurgicalStaples, sutures, scalpels

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Orthopaedic implants

Total hip arthroplasty consists of the femoral stem and the acetabular cup

Artificial intervertebraldisc to restore the

flexibility of the spinal column.

Total replacement of

the knee has two major

types: fixed bearing and

mobile bearing

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Dental implants

Scanned image of the mandible showing the dental implant.

Osseointegration of dental implant body.

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Cardiovascular devices

Vascular grafts or stents to repair blocked arteries.

Artificial valve for the replacement of defective heart valves.

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Biocompatible dependability

Biocompatibility depends on the purpose of the implant:

Teflon Vascular Prosthesis:Inside must have blood-compatible surface, i.e. should not cause adhesion or clotting.Outside must firmly attach to surrounding fibrous tissue but must not cause fibrous hyperplexia

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Current Challenges

Biofixation and stability of an implantLong-term wear and debris generationIn-vivo degradation through complex bio-chemi-mechanical actionsInert materials do not elicit “pro-active”responses in the bodySolutions are often temporary for tissue replacement

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• Bulk & Surface Properties:-- directly influence or control “tissue interface dynamics”.-- can change over time, leading to changes in “t.i.d.”

• Interaction needs to be evaluated in both ways:-- Effect of implant on host tissue.-- Effect of host on implant.

Tissue - Biomaterials Interface

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Sequence of Host Reactions

• The sequence following implantation is:• Injury• Acute inflammation• Chronic inflammation• Granulation tissue• Fibrosis / fibrous capsule development

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Injury

• Implantation causes injury – placing a biomaterial in an in vivo environment requires injection, insertion or surgical implantation.

• Extent of injury varies with implant procedure.

• Response to injury is activated – to maintain homeostasis.

• Host reacts to the biomaterial• Tissue dependent• Organ dependent• Species dependent

• Immediately after injury:• Fluid, proteins, blood escape

from vascular system into injured tissue.

Humeral replacement with CoCrMo alloy stem.

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Inflammation

• Reaction of vascularized living tissue to injury.

• Serves to contain, neutralise, dilute or wall off injurious agent.

• Sets into motion series of events that lead to healing and reconstitute the implant site by:• Regeneration of native

parenchymal cells.• Formation of fibroblastic

scar tissue.• Or combination of both.

“A basic way in which the body reacts to infection, irritation or other injury, the key feature being redness, warmth, swelling and pain. It is a type of nonspecific

immune response.”

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Inflammation

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Acute Inflammation

Relatively short-lived (minutes to days), depending on extent of injury.Key features:

Exudation of fluid and plasma proteins.Emigration of Leukocytes.Phagocytosis occur following activation of neutrophils and macrophages.

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Phagocytosis

Three-step process:Recognition of injurious agent and neutrophilattachment.Engulfment.Killing or degradation.

Amount of enzymes released depends on size of implant; larger particles induce larger amounts of enzyme release.

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Chronic Inflammation

Prolonged inflammation where there is tissue destruction, active inflammation and attempts at healing.Key features:

Tissue destructionInfiltration by Macrophages, lymphocytes.Repair by granulation tissues laying down fibrous tissue.

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Macrophages

“Big eaters”Originate from specific white blood cells -monocytes.They are phagocytes –digest foreign substance by releasing degradativeenzymes (lysozymes).Macrophages multiply (mitosis) and serve as progenitor to the giant cell.

A macrophage of a mouse stretching its arms to engulf two

particles, possibly pathogens

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Granulation Tissue

Derives its name from the pink, soft granular appearance on the surface of healing wounds.Hallmark of healing inflammation.Key features:

Proliferation of new small blood vessels.Fibroblasts.Foreign-body Giant Cells.

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Foreign Body Giant Cells

Formed by the fusion of monocytes and macrophages in an attempt to phagocytose the material.

Polyethylene flakes (shiny globular material) surrounded by foreign body giant cell reaction and histiocytes.

Polyethylene flakes (shiny linear material) surrounded by foreign body giant cell reaction.

Methylmethacralate debris (linear webs) surrounded by giant cells.

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End-stage healing response

Repair of implant sites can involve 2 distinct phases:

Regeneration –replacement of injured tissue by parenchymalcells of the same type.Replacement by connective tissue that constitutes the fibrous capsule.

Fibrous tissue could be the end-stage healing response after implantation.

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Biological Evaluation

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Initial Evaluation

Skin – Electrodes, external prostheses, fixation tapes, compression bandages, monitors of various types.Mucosal membrane – contact lenses, urinary catheters, intravaginal and intratestinal devices, bronchoscopes, dental prostheses, orthodontic devices.Breached – Ulcer, burn.

Blood path indirect – Blood administration sets.Tissue communicating – Dental cements, Skin staples.Circulating blood – Intravascular catheters, dialyzers.

Tissue/bone implant device –Replacement joints, Pins & Plates, Replacement tendons, Breast implants, Artificial larynx.Blood – Heart valves, vascular grafts, internal drug delivery catheters.

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Initial EvaluationCytotoxicity – the state of being toxic to cells.

Measured through assays (e.g: occular assay for contact lenses)

Sensitization – Development of an allergic reaction to a chemical.

Starts with mild response, may worsen.

Irritation – Assessment of localisedreaction of tissue to leachable substances.

Systemic Toxicity – Poisoning of the whole system, rather than poisoning a single organ.

Subchronic Toxicity – Adverse effects as a result of repeated dosing of a chemical.

Genotoxicity – Assessment for chromosomal damage.

Implantation – Effect of foreign materials inserted into tissues/organs with a purpose of treatment.

Haemocompatibility – Blood compatibility

Can influence inflammation response.

Biomedical Metals

Stainless steel

Longest history among metallic materials being used for implants.Highly corrosion resistance due to the dense film of Cr2O3 (Cr content >11%) on the surface.

Plates & screws for orthopedic fracture fixation.

Microstructure

Categorised according to the crystalline phase:

Ferritic (BCC)Relatively cheap, less corrosion resistant, less ductile than Austenitic SS.

Austenitic (FCC)High in Ni (FCC) and low C content.Highest corrosion resistance, used for endosseusimplants.

Martensitic (BCT)Contain relatively high C content (1%)Formed through rapid coolingHigh strength, high hardness, used as medical surgery tools (knives, clips, etc.)

Composition Map of SS

Chemical composition (mainly Ni & Cr) determines the type of Stainless Steels.

Types of SS used in Biomedical

The first ever used contained 18%Cr and 8%Ni (SS type 302).Later add small amount of Mo & Si (SS type 316).

Mo enhances resistance when Cl ion is present (body fluids).

C content is further reduced from 0.08wt% to 0.03wt% (SS type 316L) in order to further improve corrosion resistance.

Type Fe C Cr Ni Mo Mn302 bal 0.15 18 9 - 2304 bal 0.08 19 9 - 2316 bal 0.08 17 12 2.5 2316L bal 0.03 17 12 2.5 2

Microstructure of 316L

Two main features that affect performance are:Grain size (< 100μm)Shape

Equiaxed in annealed condition (isotropic)Elongated in a cold-worked condition (anisotropic)

Equiaxed grains of SS316L in annealed condition.

Various implant types made of SS316L.

Mechanical Properties of 316L

Low C content – not heat treatable.Use cold-working to improve strength.

Type Treatment E (GPa) σy (MPa) σtensile(MPa)

Ductility (%)

316L Annealed 190 172 485 40

Cold-worked 190 690 860 12

316 Annealed 190 205 515 40

Cold-worked 190 690 860 12

Cobalt-based Alloy

Better corrosion resistance and wear resistance than Stainless Steel, but heavier.Three types are commonly used for medical implants (C content = 0.25wt%):

CoCrMo (F75 or Stellite 21) (Cast or P/M)CoCrWNi (F90 or Stellite 25) (Wrought)CoNiCrMoTi (F562 or MP35N)

Cr increases corrosion resistance and provides solid solution strengthening.Mo produce finer grains and provide solid solution strengthening.W & Ni added to improve machinability and fabrication properties.

Co-Cr Phase Diagram

MicrostructureVaries significantly with processing.Casting

Co-rich ε-phase with interdendritic carbides.Relatively large grains, low strength.

WroughtObtained through hot forging, improve mechanical properties.

Microstructure of cast CoCrMo(left) and wrought CoCrMo (right).

Artificial Intervertebral Disc (IVD) with top and bottom plates made of CoCrMo

Mechanical Properties

Higher E and σ than SS.Lower ductility.Better wear resistance.

Alloys Treatment E (GPa) σy (MPa) σtensile (MPa) Ductility (%)

CoCrMo Cast 248 450 655 8

CoCrMo Wrought 248 827 1172 12

CoNiCrMo Annealed 228 241-448 793-1000 50

Titanium alloysIncreasingly used in medical implants due to excellent biocompatibilities, corrosion resistance, and low density.TiO2 form on the surface – excellent protection from corrosion.

Ti64 is widely used as endosteal implants (elbow – left, shoulder –centre), as well as artificial limbs (right).

Polymorphs of Titanium

Titanium is polymorphicα-Ti (HCP) at low temp.β-Ti (BCC) at high

temperature.α stabilising elements – Al, O,

N, Ga.β stabilising elements – Mo, V,

W, Ta.At RT, can have 3 different Ti:

α single phase, α+β dual phase, β single phase.

Chemical compositionCP Titanium (interstitial elements) is commonly used because most corrosion resistant.Ti-6Al-4V ELI is also widely used due to its strength.

% Impurity Min tensile strength

Min yield strength

Oxygen Fe MPa

240

345

450

655

Ti-6Al-4V ELI 0.10 0.20 890 825

MPa

Ti grade 1 0.18 0.20 170

Ti grade 2 0.25 0.30 275

Ti grade 3 0.35 0.30 380

Ti grade 4 0.40 0.50 485

Materials

α + β alloys

High strength and formabilityContain 4-6 wt% of β-stabilisers – substantial amounts of βretained during quenching from β to α + β phase.Most popular alloy is Ti-6Al-4V

Al reduces density, stabilises & strengthens α.V provides a more ductile β phase for hot working.Strength 110GPa, creep resistance at 300OC, fatigue resistance and castability.

Microstructure of Ti-6Al-4V

Biomedical Polymers

Categories

NaturalUsed because similar structure to human tissues.Biodegradable.E.g.: Collagen, Alginate, Chitin & Chitosan.

SyntheticNon-degradable.Used as implants, drug delivery, tissue scaffolds.E.g.: PE, PMMA, Polyester, PC, Polyamides, PU, Polysulfones, PEEK.

Polyethylene

HDPE and UHMWPE are frequently used.Very inert.Used as bone and cartilage substitute.Minimal inflammatory and foreign body response.HDPE is used in medical tubing and as porous scaffolds – tissue ingrowth into the implant.HDPE also used for Craniofacial applications – nasal reconstruction, ear reconstruction.

Medical tubing (top) and porous scaffold (bottom).

UHMWPEProduced as powder and must be consolidated under elevated temperatures and pressures due to its high melt viscosity.Due to UHMW, only compression moulding can be used for production (cannot use IM, Extr., Blow Moulding).Due to its low Thermal Conductivity, processing time is long to ensure uniform heating and cooling rates.Direct compression moulding has been used to manufacture acetabular cup liner, tibial knee inserts and patellar component.

Long entangled chains of UHMWPE (top) and various implants for human

joints (bottom).

Properties of UHMWPE

High abrasion resistance, Low friction, High impact strength, excellent toughness, low density, ease of fabrication.Very attractive as bearing surfaces in arthroplasty.Wear is still a problem – cause osetolysis.

Wear of UHMWPE tibial insert.

PMMA

Used primarily as bone cement.Consists of two parts – solid in a packet & liquid in a vial.When the two part mixed, the viscosity of the mixture will increase, and will become dough in a few minutes.The dough will harden in another few minutes.

PET

Belong to the Polyester family which have ester linkage connecting the polymers.

It has very good mechanical properties.PET fibers are used as sutures, internal patches, pledglets, ligamentous prosthesis, artificial blood vessels, heart valve sewing cuffs, etc.

O

O

C Various suturing techniques (top) and closing of wound via sutures

(bottom).

PC

Have carbonate linkages in their polymer chains

O

O

C O

Used to make components for oxygenator for open heart surgery, venous reservoir, arterial filter.Sterilisable, ease of processing, clarity.

Oxygenator for Open Heart Surgery.

Polyamides

Have amide linkages in their polymer chains.

O

C N

Have amide linkages in their polymer chains.Nylon-66 was the first Polyamides ever synthesized.Nylon-66/Nylon-6 have been used as surgical sutures.

Nylon sutures (top) and the surgical procedure in the treatment of

glaucoma using sutures (bottom).

Polyurethanes

Have urethane linkages in their polymer chains.

Excellent fatigue resistance.Used as blood contacting materials –totally implantable artificial heart, left Ventricular Assist Devices (VADs), pacemaker lead insulators.

O

O

C NSchematic of pacemaker system

(top) and a pacemaker set (bottom).

Biomedical Ceramics

CategoriesBioactive

Calcium Phosphate.

Calcium phosphate grown in an organic matrix. The sample is highly porous and the walls between the pores are composed of ~ 50 nm sized subunits.

BioinertAl2O3, Si3N4.

Alumina Ball

Calcium-phosphate

Only two are stable at body fluid & temp.:

Brushite: CaHPO.2H2O at pH < 4.2Hydroxyapatite: Ca10(PO4)6(OH)2> 4.2

TCP {Ca3(PO4)2} & TTCP {Ca4P2O9} formed @ higher temperatures.

SEM image of TCP

Dental implant made of Brushite

HydroxyapatiteGood biological stability.Form hydroxy-carbonate apatite (HCA) layer on the surface when implanted.HCA is similar in composition and structure to the mineral phase of bone.Widely used in powder and bulk forms.Weak in load-bearing applications – used as coating.

Morphological variant of HA at 10.6x magnification (left) and 50.6x magnification (right)

Furlong Hip Stem coated with HA.

Structure & Chemistry of HA

Chemically similar to the mineral component of bone.Excellent biocompatibility with hard and soft tissues.

Mineral Phase (70%)Organic Phase (20%)Water (10%)

Composition of Bone:Mineral – HA 95%, Mg, Na, K, Fl, Cl.Organic – Matrix, Collagen, Proteins.Water.

Synthesis of HA powder

Categorised into two types:Dry Chemical MethodsWet Chemical Methods

Morphology, stoichiometry, crystallinityvary with processing methods.

Dry Chemical Methods

Reactions between Ca and P in solid-state:

Raw Ca compound are milled, mixed, compressed, and sintered above 950OC.Require high temperature and long sintering time.

6CaHPO4 + 4Ca(OH)2 Ca10(PO4)6(OH)2 + 6H2O

or

3Ca3(PO4)2 + Ca(OH)2 Ca10(PO4)6(OH)2 + H2O

Wet Chemical Methods

Three major types of WCM:Hydrothermal reactionsHydrolysisPrecipitation

Produce fine particle size and low cost.

Hydrothermal reactionsReaction in the presence of aqueous solvents and mineralisation under high P and T.

6CaHPO4 + 4CaCO3 Ca10(PO4)6(OH)2 + 6H2O + 4CO2

HydrolysisRequire low T (< 100OC)Hydrolysis of other CaP (DCPD, DCP, TCP, ACP, CaCO3, etc.)Produce Ca deficient HA which is more soluble in bone.Highly non-stoichiometric, hydrolysis at low T require longer time period (hours, days).

3Ca3(PO4)2 + H2O Ca9(HPO4)(PO4)5OH

Precipitation

Involves the following reactions:

10Ca(OH)2 + 3H3(PO4)2 Ca10(PO4)6(OH)2

Or

10Ca(NO3)2 + 6(NH4)2HPO4 + 2NH4OH Ca10(PO4)6(OH)2 + 14NH3 + 10H2O + 20NO2.

Low processing T (24-94OC)Crystallinity depends on the concentrations of the reactants and pH of the reaction.

Mechanical Properties

Highly dependent on porosity, grain size, and impurities of HA.Properties comparable to hard tissue:

E = 35-120GPaσbend = 38-250MPaσcompr = 120-900MPaσtensile = 38-300MPa

Not normally used in load bearing applications due to its brittle nature.

Bone cell growing on the surface of HA.

Alumina

Bioinert ceramic, high corrosion and wear resistance – good for joint replacement.Properties:

σflex = 400MPaE = 380GPaHardness = 9/10

Moh’s

Processing

Bauxite (Al ore) contains large quantities of Al2O3.Bauxite impurities include Fe2O3 and SiO2.Bayer process for purification:

Fe2O3 does not dissolve – remove through filtering.SiO2 dissolves into Si(OH)6

2-.

Al2O3 + 3H2O + 2NaOH + heat → 2NaAl(OH)4

2Al(OH)3 + heat → Al2O3 + 3H2O

Upon cooling, Al(OH)3 precipitates.

Q & A