1 Biomaterials Week 11 11/29/2010 Classes of Materials used in Medicine.

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Biomaterials Biomaterials Week 11Week 11

11/29/201011/29/2010

Classes of Materials used in Classes of Materials used in MedicineMedicine

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2.7 Bioresorbable and Bio2.7 Bioresorbable and Bioerodible materialserodible materials

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Introduction: Introduction: Bioresorbable and BioerodibleBioresorbable and Bioerodible

Degradable implant, no need to be Degradable implant, no need to be removedremoved

Temporary presenceTemporary presencePotential concern: toxicityPotential concern: toxicity

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Definition relating to the process Definition relating to the process or erosion and/or degradationor erosion and/or degradation

Used to indicate a given material eventuUsed to indicate a given material eventually disappear after having been introdually disappear after having been introduced into living organismced into living organismBiodegradationBiodegradationBioerosionBioerosionBioabsorptionBioabsorptionBioresorptionBioresorption

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DegradationDegradation

Chemical Chemical processprocessCleavage of covalent bondCleavage of covalent bondHydrolysisHydrolysisOxidative and enzyme mechanismOxidative and enzyme mechanism

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ErosionErosion

Physical change in size, shape, or mass of Physical change in size, shape, or mass of a devicea device

Consequence of degradation or simply Consequence of degradation or simply dissolutiondissolution

Erosion can occur without degradationErosion can occur without degradation Degradation can occur without erosionDegradation can occur without erosion Consensus Conference of the European Consensus Conference of the European

Society of Biomaterials: “biodegradation” Society of Biomaterials: “biodegradation” biological agents to cause the chemical biological agents to cause the chemical degradation of implanted devicedegradation of implanted device

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BiodegradableBiodegradable

Biodegradable polymer: Biodegradable polymer: water-insoluble polywater-insoluble polymermer that is that is convertedconverted under physiological con under physiological condition into dition into water-soluble materialswater-soluble materials without re without regard to specific mechanism involve in the erosgard to specific mechanism involve in the erosion procession process

Bioerosion: include both physical processes (dBioerosion: include both physical processes (dissolution) and chemical processes (backbone issolution) and chemical processes (backbone cleavage) cleavage)

Bioresorption and bioabsorption: Bioresorption and bioabsorption: Used interchangedUsed interchanged Polymer and its degradable product are removed bPolymer and its degradable product are removed b

y cellular activitiesy cellular activities

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Overview of current available Overview of current available degradable polymersdegradable polymers

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TABLE I Degradable Polymers and TABLE I Degradable Polymers and Representative Applications under InvestigationRepresentative Applications under Investigation

Degradable polymer Degradable polymer

Synthetic degradable Synthetic degradable polyesterspolyesters

Current major research applicationsCurrent major research applications

Poly(glycolic acid), poly(Lactic Poly(glycolic acid), poly(Lactic acid), and copolymersacid), and copolymers

Barrier membranes, drug delivery, Barrier membranes, drug delivery, guided tissue regeneration (in dental guided tissue regeneration (in dental applications), orthopedic applications applications), orthopedic applications , stents. staples, sutures, tissue , stents. staples, sutures, tissue engineeringengineering

Polyhydroxybutyrate (PHB), polPolyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV), and coyhydroxyvalerate (PHV), and copolymerspolymers

Long-term drug delivery, orthopedic Long-term drug delivery, orthopedic applications, stents, suturesapplications, stents, sutures

PolycaprolactonePolycaprolactone Long-term drug delivery, orthopedic Long-term drug delivery, orthopedic applications, staples, stentsapplications, staples, stents

PolydioxanonePolydioxanone Fracture fixation in non-load-bearing Fracture fixation in non-load-bearing bones, sutures, wound clipbones, sutures, wound clip

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Overview of current available Overview of current available degradable polymersdegradable polymers

Design, synthesis of new, degradable Design, synthesis of new, degradable biomaterials is currently an biomaterials is currently an important research challengeimportant research challenge

In tissue engineering: development In tissue engineering: development of new biomaterials that can provide of new biomaterials that can provide predetermined and controlled predetermined and controlled cellular response needed component cellular response needed component of most practical applications of of most practical applications of tissue engineeringtissue engineering

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RequirementsRequirements

Toxic component leached from the Toxic component leached from the implant (residual monomer, implant (residual monomer, stabilizers, polymerization initiator, stabilizers, polymerization initiator, emulsifiers, sterilization by-productemulsifiers, sterilization by-product

Potential toxicity of the degradation Potential toxicity of the degradation products and subsequent products and subsequent metabolitesmetabolites

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FDA approved biodegradable FDA approved biodegradable polymerspolymers

Poly(lactic acid)Poly(lactic acid) Poly(glycolic acid)Poly(glycolic acid) PolydioxanonePolydioxanone PolycaprolactonePolycaprolactone Poly(PCPP-SA anhydride)Poly(PCPP-SA anhydride)

Table 1 provide an overview of some representative dTable 1 provide an overview of some representative degradable polymersegradable polymers

Structural formula is shown in Fig 1Structural formula is shown in Fig 1

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Polydioxanone (PDS)Polydioxanone (PDS) Poly (ether ester)Poly (ether ester) Ring-opening polymerizRing-opening polymeriz

ation of p-dioxanone moation of p-dioxanone monomernomer

Low toxicity monomerLow toxicity monomer Lower modulus than PLLower modulus than PL

A or PGAA or PGA Used in Used in

Monofilament sutureMonofilament suture Suture clipSuture clip Bone pinBone pin

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Poly(hydroxybutyrate) (PHB)Poly(hydroxybutyrate) (PHB) 聚羥基丁酯聚羥基丁酯 , poly, poly(hydroxyvalerate) (PHV) and copolymer(hydroxyvalerate) (PHV) and copolymer

Polyester from Polyester from microorganismmicroorganism

PHB: crystalline and PHB: crystalline and brittlebrittle

Copolymer PHB and Copolymer PHB and PHV acid: less PHV acid: less crystalline more flexiblecrystalline more flexible

Used: drug release, Used: drug release, suture, artificial skin suture, artificial skin and vascular graftsand vascular grafts

Slow degradation time Slow degradation time (500 days, 80 % (500 days, 80 % stiffness) stiffness)

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Polycaprolactone (PCL)Polycaprolactone (PCL) 聚己內酯多元聚己內酯多元醇醇

Semicrystalline polymeSemicrystalline polymerr

Degrade at lower pace Degrade at lower pace than PLAthan PLA

Used in drug release: aUsed in drug release: active for over 1 yearctive for over 1 year

Nontoxic and tissue-coNontoxic and tissue-compatible materialsmpatible materials

Used in wound dressinUsed in wound dressings, and degradable stags, and degradable stapleple

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PolyanhydridesPolyanhydrides Hydrolytic instabilityHydrolytic instability AliphaticAliphatic 脂肪族的脂肪族的 .. (an organic compound having an open-chain (an organic compound having an open-chain

structure) structure) polyanhydrides degrade: dayspolyanhydrides degrade: days Aromatic Aromatic (ring system (as benzene) containing usually multiple co(ring system (as benzene) containing usually multiple co

njugated double bonds) njugated double bonds) polyanhydrides degrade: yearspolyanhydrides degrade: years Aliphatic and aromatic copolymer: intermediaAliphatic and aromatic copolymer: intermedia

te ratete rate High degradation rate: degrade by surface witHigh degradation rate: degrade by surface wit

hout catalyst or excipients hout catalyst or excipients (inert substance (as gum arabi(inert substance (as gum arabic or starch) that forms a vehicle (as for a drug) )c or starch) that forms a vehicle (as for a drug) )

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PolyanhydridesPolyanhydridesReact with drug containing amino group React with drug containing amino group

or nucleophilic functional groupor nucleophilic functional groupReaction with nucleophile: limit the type Reaction with nucleophile: limit the type

of drug can be successfully incorporatedof drug can be successfully incorporatedAmine containing biomolecules could reAmine containing biomolecules could re

act with anhydride bond on the surfaceact with anhydride bond on the surface

Nucleophile: as an electron-donating Nucleophile: as an electron-donating reagentreagent

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PolyanhydridesPolyanhydridesExcellent biocompatibilityExcellent biocompatibilityDrug deliverDrug deliverPrepared by compression molding or miPrepared by compression molding or mi

croencapsulationcroencapsulation Insulin, bovine growth factors, angiogenInsulin, bovine growth factors, angiogen

esis inhibitor (herparin, cortisone) enzyesis inhibitor (herparin, cortisone) enzyme me

Nonviral vectors of delivering DNA in geNonviral vectors of delivering DNA in gene therapyne therapy

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Poly(ortho ester)Poly(ortho ester) Surface erosionSurface erosion Slab-like devices release Slab-like devices release

drug more constant ratedrug more constant rate Controlled-release drug Controlled-release drug

deliverydelivery Ortho ester link more stOrtho ester link more st

able in base than in acidable in base than in acid Control degradation by iControl degradation by i

ncorporated acidic and ncorporated acidic and basic excipients into polbasic excipients into polymer matrixymer matrix

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Poly(ortho ester)Poly(ortho ester)Surface erodability: incorporated with hiSurface erodability: incorporated with hi

ghly water-soluble drugs into polymeric ghly water-soluble drugs into polymeric matrix can result in swelling of polymer matrix can result in swelling of polymer matrixmatrix

The increase amount of water imbedded The increase amount of water imbedded into the matrix can cause “bulk erosioninto the matrix can cause “bulk erosion” instead of “surface erosion” ” instead of “surface erosion”

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Poly(ortho ester)-preparationPoly(ortho ester)-preparationTrans-esterification of 2,2’-dimethoxyfTrans-esterification of 2,2’-dimethoxyf

uran with a diol uran with a diol (a compound containing two hydroxyl (a compound containing two hydroxyl groups )groups )

Acid-catalyzed addition reaction of diols Acid-catalyzed addition reaction of diols with diketeneacetal: with diketeneacetal:

3rd generation: soft and viscous liquids, 3rd generation: soft and viscous liquids, drug delivery, can be injectable formdrug delivery, can be injectable form

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Poly(amino acid) and pseudo- Poly(amino acPoly(amino acid) and pseudo- Poly(amino acid)id)

Protein composed of amino acids, obviouProtein composed of amino acids, obviouss

Amino acid side chains offer sites for the aAmino acid side chains offer sites for the attachment for drugs, cross-linking agents, ttachment for drugs, cross-linking agents, pendent pendent (something suspended)(something suspended) groups (used to groups (used to modify the physiomechanical properties modify the physiomechanical properties of the polymerof the polymer

Low toxicity Low toxicity Early application: suture, artificial skin suEarly application: suture, artificial skin su

bstitutes, drug delivery system bstitutes, drug delivery system

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Drugs attached to side chains, via a spacer Drugs attached to side chains, via a spacer unit that distances the drug from the backunit that distances the drug from the backbonebone

Poly(L-lysine) with methotrexate and pepPoly(L-lysine) with methotrexate and pepstatinstatin

Poly(glutamic acid) with adriamycinPoly(glutamic acid) with adriamycinAppear attractive: few practical applicatioAppear attractive: few practical applicatio

nnHighly insoluble and nonprocessibleHighly insoluble and nonprocessible

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Pronounce tendency to swell in Pronounce tendency to swell in aqueous aqueous

Difficult to predict drug release rateDifficult to predict drug release rateSo far, no approved by FDASo far, no approved by FDA

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pseudo- Poly(amino acid)pseudo- Poly(amino acid) Backbone-modified “pseudo” poly(amino aBackbone-modified “pseudo” poly(amino a

cid)cid) Polyester from N-protected trans-4-hydroxyl-Polyester from N-protected trans-4-hydroxyl-

L-proline and a polyiminocarbonate derived frL-proline and a polyiminocarbonate derived from tyrosine dipeptideom tyrosine dipeptide

Easy process by solvent or heatEasy process by solvent or heat High degree biocompatibilityHigh degree biocompatibility Tyrosine-derived polycarbonates are high-streTyrosine-derived polycarbonates are high-stre

ngth materials: degradable orthopedic implanngth materials: degradable orthopedic implantsts

Poly (DTE carbonate): bone conductivity (bone Poly (DTE carbonate): bone conductivity (bone grow directly along the polymeric implantgrow directly along the polymeric implant

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pseudo- Poly(amino acid)pseudo- Poly(amino acid) Reduce the number of interchain hydrogen bonReduce the number of interchain hydrogen bon

dd AA polymerized via repeated amide bonds leadiAA polymerized via repeated amide bonds leadi

ng strong interchain hydrogen bondingng strong interchain hydrogen bonding Hydrogen bonding leading to 2nd structure: α-hHydrogen bonding leading to 2nd structure: α-h

elices and β-pleated sheetselices and β-pleated sheets In pseudo- Poly(amino acid): half on the amide In pseudo- Poly(amino acid): half on the amide

bonds are replaced by other linkage (such as cabonds are replaced by other linkage (such as carbonate, ester, or iminocarbonate bonds)rbonate, ester, or iminocarbonate bonds)

Lower tendency to form hydrogen bondsLower tendency to form hydrogen bonds Better processibility and loss of crystallinityBetter processibility and loss of crystallinity

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PolycyanocrylatesPolycyanocrylates Bioadhesive Bioadhesive Methyl Polycyanocrylates: commonly usedMethyl Polycyanocrylates: commonly used Spontaneous polymerization at room temperaSpontaneous polymerization at room tempera

ture in the presence of waterture in the presence of water Toxicity and erosion rate: depend on alkyl Toxicity and erosion rate: depend on alkyl (having (having

a monovalent organic group and especially one Ca monovalent organic group and especially one CnnH2H2nn+1 (as methyl) )+1 (as methyl) )

Disadvantages: Disadvantages: monomer very reactive component, toxicmonomer very reactive component, toxic Degradation release formaldehyde: intense inflamDegradation release formaldehyde: intense inflam

mation mation

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Polyphosphazenes:Polyphosphazenes: Backbone: nitrogen-phosphorus bondsBackbone: nitrogen-phosphorus bonds Interface between inorganic and organic Interface between inorganic and organic

polymerspolymers High thermal stabilityHigh thermal stability Formation of controlled drug deliveryFormation of controlled drug delivery Claim to be biocompatible Claim to be biocompatible

Chemical structure provide a readily accessible Chemical structure provide a readily accessible “pendent” chain“pendent” chain

Various drugs, peptide, biological compounds Various drugs, peptide, biological compounds can be attached and release via hydrogelscan be attached and release via hydrogels

Used in skeletal tissue regeneration Used in skeletal tissue regeneration Vaccine design Vaccine design

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Poly(glycolic acid) (PGA) and Poly(glycolic acid) (PGA) and poly(latic acid) (PLA) copolymerspoly(latic acid) (PLA) copolymers

Most used in bioerodible polymersMost used in bioerodible polymers PGA: simplest linear aliphatic polyesterPGA: simplest linear aliphatic polyester

First synthetic absorbable suture (Dexon)First synthetic absorbable suture (Dexon) 2-4 weeks: lose mechanical strength 2-4 weeks: lose mechanical strength Bone pin (Biofix)Bone pin (Biofix)

Copolymer PGA +PLA (hydrophobic)Copolymer PGA +PLA (hydrophobic) Suture (Vicryl)Suture (Vicryl) PGA- crystalline; lose crystallinity be copolymerPGA- crystalline; lose crystallinity be copolymer PLA- Chiral PLA- Chiral (( 分子呈分子呈 )) 對掌性的對掌性的 ; molecule not superimp; molecule not superimp

osable on its mirror site osable on its mirror site

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Semi-crystalline L-PLA in high mechanical Semi-crystalline L-PLA in high mechanical strength & toughness, suture or strength & toughness, suture or orthopedicorthopedic

Best advantage: safe, nontoxic, Best advantage: safe, nontoxic, biocompatible (copolymer can be brought biocompatible (copolymer can be brought to market in less time, lower cost)to market in less time, lower cost)

Current products: Current products: suturesuture GTR membrane for dentistryGTR membrane for dentistry Bone pinsBone pins Implantable drug delivery system Implantable drug delivery system

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Investigated in: Investigated in: vascular & urological stentsvascular & urological stents Skin substitutesSkin substitutes Scaffold for tissue engineeringScaffold for tissue engineering Tissue reconstructionTissue reconstruction

Unsolved issues:Unsolved issues: Most cell do not attach to PGA & PLA surface, Most cell do not attach to PGA & PLA surface,

poor substrate for cell growth; for tissue poor substrate for cell growth; for tissue engineering used is debatableengineering used is debatable

Degradation product strong acid accumulate at Degradation product strong acid accumulate at implant site, delayed inflammatory responseimplant site, delayed inflammatory response

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Applications of synthetic, Applications of synthetic, degradable polymers as degradable polymers as

biomaterialsbiomaterials

Classification of degradable Classification of degradable medical implantsmedical implants

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Classification of degradable medical Classification of degradable medical implantsimplants

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Classification of degradable medical Classification of degradable medical implantsimplants

5 main type of degradable implants:5 main type of degradable implants:A temporary support deviceA temporary support deviceA temporary barrierA temporary barrierAn implantable drug delivery systemAn implantable drug delivery systemThe tissue engineering scaffoldThe tissue engineering scaffoldThe multifunctional implantThe multifunctional implant

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A temporary support deviceA temporary support device Healing wound, broken bone, damaged Healing wound, broken bone, damaged

blood vesselblood vessel Suture, bone fixation (bone nail, screws, Suture, bone fixation (bone nail, screws,

plates), vessel graftsplates), vessel grafts Degradable implant would provide Degradable implant would provide

temporary, mechanical support until natural temporary, mechanical support until natural tissue heals and regains its strengthtissue heals and regains its strength

Adjust the degradation rate of the Adjust the degradation rate of the temporary support device to the healing of temporary support device to the healing of the surrounding tissue represents one of the surrounding tissue represents one of the major challenges in the design of such the major challenges in the design of such devicesdevices

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A temporary support deviceA temporary support device

Suture: most successfulSuture: most successfulPGA-DexonPGA-DexonFirst routine use of a degradable polymeFirst routine use of a degradable polyme

r in a major clinical applicationr in a major clinical application90:10 PGA/PLA (Vicryl) were developed90:10 PGA/PLA (Vicryl) were developedPolydioxanone (PDS) Polydioxanone (PDS)

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Temporary barrier Temporary barrier

Medical adhesion preventionMedical adhesion prevention Adhesion formed between two tissue sections by Adhesion formed between two tissue sections by clottclott

ing blood in extravascular tissueing blood in extravascular tissue space followed by inf space followed by inflammation and fibrosis.lammation and fibrosis.

Cause pain, functional impairment, and problems duriCause pain, functional impairment, and problems during subsequent surgeryng subsequent surgery

Surgical adhesions: caused of morbidity, and represenSurgical adhesions: caused of morbidity, and represent one of the most significant complications of a wide rt one of the most significant complications of a wide range of surgical procedures such as ange of surgical procedures such as cardiac, spinal, ancardiac, spinal, and tendond tendon surgery surgery

Investigated for sealing of breaches of the lung tissue Investigated for sealing of breaches of the lung tissue that cause leakage that cause leakage

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Temporary barrierTemporary barrier

Skin reconstruction: artificial skinSkin reconstruction: artificial skin Artificial, degradable collagen/glycosaminoglyArtificial, degradable collagen/glycosaminogly

can matrix that is placed on top of the skin lesican matrix that is placed on top of the skin lesion to stimulate the regrowth of a functional deon to stimulate the regrowth of a functional dermisrmis

Degradable collagen matrix with preseeded huDegradable collagen matrix with preseeded human fibroblastsman fibroblasts

Goal: stimulate the regrowth of the functional Goal: stimulate the regrowth of the functional dermisdermis

Used in the treatment of burns and other deep Used in the treatment of burns and other deep skin lesions and represent an important applicskin lesions and represent an important application for temporary barrier type devicesation for temporary barrier type devices

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An implantable drug delivery An implantable drug delivery devicedevice

By necessity a temporary deviceBy necessity a temporary deviceThe device will eventually run out of The device will eventually run out of

drug or the need for the delivery of a drug or the need for the delivery of a specific drug is eliminated once the specific drug is eliminated once the diseased is treateddiseased is treated

Most widely investigated application Most widely investigated application of degradable polymers of degradable polymers

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An implantable drug delivery An implantable drug delivery devicedevice

Poly(latic acid) and poly(glycolic acid) have an extensiPoly(latic acid) and poly(glycolic acid) have an extensive safety profile based on their use as sutureve safety profile based on their use as suture

Formulation of implantable controlled release devicesFormulation of implantable controlled release devices Implantable, controlled release formulation based on Implantable, controlled release formulation based on

copolymers of lactic acid and glycolic acid have alreacopolymers of lactic acid and glycolic acid have already become available.dy become available.

Polyanhydride in the formulation of an intracranialPolyanhydride in the formulation of an intracranial 頭頭蓋蓋 , implantable device for administration of BCNU to , implantable device for administration of BCNU to patients suffering from glioblastomapatients suffering from glioblastoma 神經膠母細胞瘤神經膠母細胞瘤 mmultiformae, a usually lethal form of brain cancerultiformae, a usually lethal form of brain cancer

a malignant rapidly growing astrocytoma of the central nervous system and usually of a cerebral hemisphere -- called also glioblastoma mul.ti.for.me

Carmustine or BCNU (= "bis-chloronitrosourea") is a mustard gas-related α-chloro-nitrosourea compound used as an alkylating agent in chemotherapy

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Tissue engineering scaffoldTissue engineering scaffold

Degradable implantDegradable implant that is designed to act as an that is designed to act as an artificial extracellular matrixartificial extracellular matrix by providing by providing space space for cells to growfor cells to grow into and recognize into functional into and recognize into functional tissuetissue

Man madeMan made implantable prostheses do implantable prostheses do not function not function as well as the native tissue as well as the native tissue

Or maintain the functionality of native tissue over Or maintain the functionality of native tissue over long periods of timelong periods of time

Interdisciplinary field that utilizes degradable Interdisciplinary field that utilizes degradable polymers, among other substrates and biologics, polymers, among other substrates and biologics, to develop treatments that will allow the body to to develop treatments that will allow the body to heal itself without the need for permanently heal itself without the need for permanently implanted, artificial prosthetic devices implanted, artificial prosthetic devices

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Ideal case, a tissue engineering scaffold is implanted to Ideal case, a tissue engineering scaffold is implanted to restore lost tissue function, maintain tissue function, or restore lost tissue function, maintain tissue function, or enhance existing tissue functionenhance existing tissue function

Can take the form of feltlike material obtained from kniCan take the form of feltlike material obtained from knitted or woven fibers or from fiber meshestted or woven fibers or from fiber meshes

Various procedures be used to obtain foams or spongeVarious procedures be used to obtain foams or spongess

Pore interconnectivityPore interconnectivity is a key properties: as cells need is a key properties: as cells need to be able to migrate and grow throughout the entire scto be able to migrate and grow throughout the entire scaffoldaffold

Open pore structureOpen pore structure May be preseeded with cells in vitro prior, followed by tMay be preseeded with cells in vitro prior, followed by t

he safe resorption of scaffold materialhe safe resorption of scaffold material

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Guided tissue regeneration (GTR): Guided tissue regeneration (GTR): traditionally used in dentistrytraditionally used in dentistry

Scaffold encourage the growth of Scaffold encourage the growth of specific type of tissuespecific type of tissue

Treatment of periodontal disease, Treatment of periodontal disease, favor new bone growth in the favor new bone growth in the periodontal pocket over soft tissue periodontal pocket over soft tissue ingrowths ingrowths

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Tissue engineering scaffoldTissue engineering scaffold Challenges in the design of tissue Challenges in the design of tissue

engineering scaffold is the need to engineering scaffold is the need to adjust adjust the rate of scaffold degradation to rate of the rate of scaffold degradation to rate of tissue healingtissue healing

Polymer may need to function on the order Polymer may need to function on the order of days to monthsof days to months

For bone: scaffold must For bone: scaffold must maintain some maintain some mechanical strengthmechanical strength to support the bone to support the bone structure while new bone is formedstructure while new bone is formed

Premature degradation of the scaffoldPremature degradation of the scaffold material can be as detrimental to the material can be as detrimental to the healing process as remains intact for healing process as remains intact for excessive period of time excessive period of time

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Future use of tissue engineering Future use of tissue engineering scaffolds has the potential to scaffolds has the potential to revolutionize the way aging, trauma, revolutionize the way aging, trauma, and disease-related loss of tissue and disease-related loss of tissue function can be treatedfunction can be treated

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Multifunctional devicesMultifunctional devices

Combining several functions as one Combining several functions as one single devicesingle device

These applications envision the These applications envision the combination of combination of several functions several functions within the same devicewithin the same device and require and require the design of custom-made materials the design of custom-made materials with narrow range of predetermined with narrow range of predetermined materials propertiesmaterials properties

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Ultrahigh-strength poly(lactic acid) biodegradUltrahigh-strength poly(lactic acid) biodegradable bone screwsable bone screws and bone nails opens the po and bone nails opens the possibility of combining the “mechanical suppossibility of combining the “mechanical support” function of the device with a rt” function of the device with a “site-specifi“site-specific drug delivery”c drug delivery” function; function;

A biodegradable A biodegradable bone nailbone nail that holds the fract that holds the fractured bone in place can simultaneously stimulaured bone in place can simultaneously stimulate the growth of new bone tissue at the fracturte the growth of new bone tissue at the fracture site by slowly e site by slowly release bone growth factors threlease bone growth factors throughoutroughout its degradation process its degradation process

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Biodegradable stents for implantation into corBiodegradable stents for implantation into coronary arties onary arties

Stents are designed to Stents are designed to mechanically prevent tmechanically prevent to collapse and restenosiso collapse and restenosis (Recurrence of stenosis (Recurrence of stenosis <<A constriA constriction or narrowing of a duct or passage>ction or narrowing of a duct or passage> after corrective surgery on a heart v after corrective surgery on a heart valve)alve) of arteries that have been opened by ballo of arteries that have been opened by balloon angioplastyon angioplasty

Ultimately, the stents could Ultimately, the stents could deliver an antiinfldeliver an antiinflammatory or antithrombogenic agentammatory or antithrombogenic agent directly directly to the site of vascular injury to the site of vascular injury

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Multifunctional devicesMultifunctional devices Most important multifunctional device for future appliMost important multifunctional device for future appli

cations is cations is a tissue engineering scaffold that also serve a tissue engineering scaffold that also serve as a drug delivery systemas a drug delivery system for cytokines, growth hormo for cytokines, growth hormones, or other agents that directly nes, or other agents that directly affect cells and tissuaffect cells and tissue within the vicinity of the implanted scaffolde within the vicinity of the implanted scaffold

E.g. bone regeneration scaffold that is placed within a E.g. bone regeneration scaffold that is placed within a bone defect to allow the regeneration of bone while rebone defect to allow the regeneration of bone while releasing bone morphogenic protein (BMP) at implant sleasing bone morphogenic protein (BMP) at implant site.ite.

The release of BMP has been reported to stimulate boThe release of BMP has been reported to stimulate bone growth and therefore has potential to accelerate thne growth and therefore has potential to accelerate the healing ratee healing rate

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The process of bioerosionThe process of bioerosion

Transformation from solid into water-soluble Transformation from solid into water-soluble materials materials

Associated withAssociated with Macroscopic change in appearanceMacroscopic change in appearance PhysiomechanicalPhysiomechanical Physical processPhysical process

Swelling Swelling DeformationDeformationStructural disintegrationStructural disintegrationWeight lossWeight lossDepletion of drugDepletion of drugLoss of functionLoss of function

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Factors that influence the rate of Factors that influence the rate of bioerosionbioerosion

Although the solubilization of intact polymer aAlthough the solubilization of intact polymer as well as several distinct mechanisms of chemis well as several distinct mechanisms of chemical degradation have been recognized as possical degradation have been recognized as possible causes for the observed bioerosion of a solble causes for the observed bioerosion of a solid, polymeric implant, virtually all currently avid, polymeric implant, virtually all currently available implant materials erode because of the ailable implant materials erode because of the hydrolytic cleavagehydrolytic cleavage of the polymer backbone of the polymer backbone (mechanism III in Fig. 2). (mechanism III in Fig. 2).

We therefore limit the following discussion to We therefore limit the following discussion to solid devices that bioerode because of the solid devices that bioerode because of the hydhydrolytic cleavage of the polymer backbone.rolytic cleavage of the polymer backbone.

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In this case, the main factors that determine the In this case, the main factors that determine the overall rate of the erosion process are overall rate of the erosion process are the chemical stability of the hydrolytically the chemical stability of the hydrolytically

susceptible groups in the polymer backbone the susceptible groups in the polymer backbone the hydrophilic/hydrophobic character of the repeat hydrophilic/hydrophobic character of the repeat units, units,

the morphology of the polymer, the morphology of the polymer, the initial molecular weight an molecular weight the initial molecular weight an molecular weight

distribution of the polymer, distribution of the polymer, the device fabrication process used to prepare the the device fabrication process used to prepare the

device, device, the presence catalysts, additives, or plasticizers, the presence catalysts, additives, or plasticizers,

and and the geometry (specifically the surface area to the geometry (specifically the surface area to

volume ratio) of the implanted device.volume ratio) of the implanted device.

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The susceptibility of the polymer backbone toward The susceptibility of the polymer backbone toward hyhydrolytic cleavagedrolytic cleavage is probably the most fundamental p is probably the most fundamental parameter. arameter.

Generally speaking, Generally speaking, anhydridesanhydrides 失水酸失水酸 tendtend to hydroly to hydrolyzed faster than zed faster than ester bondsester bonds that in turn hydrolyze fast that in turn hydrolyze faster than amide bonds. er than amide bonds.

Thus, polyanhydrides will tend to degrade faster than Thus, polyanhydrides will tend to degrade faster than polyesters that in turn will have a higher tendency to polyesters that in turn will have a higher tendency to bioerode than polyamides. bioerode than polyamides.

Based on the known susceptibility of the polymer bacBased on the known susceptibility of the polymer backbone structure toward hydrolysis, it is possible to makbone structure toward hydrolysis, it is possible to make predictions about the bioerosion of a given polymeke predictions about the bioerosion of a given polymer.r.

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However, the However, the actual erosion rateactual erosion rate of a solid pol of a solid polymer cannot be predicted on the basis of the ymer cannot be predicted on the basis of the ppolymer backbone structureolymer backbone structure alone. alone.

The observed erosion rate is strongly dependeThe observed erosion rate is strongly dependent on the ability of water molecules to penetrant on the ability of water molecules to penetrate into the polymeric matrix. te into the polymeric matrix.

The hydrophilic versus hydrophobic character The hydrophilic versus hydrophobic character of the polymer, which is a function of the strucof the polymer, which is a function of the structure of the ture of the monomeric starting materialsmonomeric starting materials, can t, can therefore have an overwhelming influence on therefore have an overwhelming influence on the observed bioerosion rate. he observed bioerosion rate.

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For instance, the erosion rate of polyanhydrides cFor instance, the erosion rate of polyanhydrides can be slowed by about three orders of magnitude an be slowed by about three orders of magnitude when the when the less hydrophobic sebacic acidless hydrophobic sebacic acid is replace is replaced by the more d by the more hydrophobic bis(carboxy phenoxy)hydrophobic bis(carboxy phenoxy)propanepropane as the monomeric starting material. as the monomeric starting material.

Likewise, devices made of poly(glycolic acid)Likewise, devices made of poly(glycolic acid) 羥基羥基乙酸乙酸 erode faster than identical deviceserode faster than identical devices made of made of the more the more hydrophobic poly(lactic acidhydrophobic poly(lactic acid), although ), although the ester bonds have about the same chemical rethe ester bonds have about the same chemical reactivity toward water in both polymers.activity toward water in both polymers.

sebacic acid sebacic acid a crystalline dicarboxylic acid Ca crystalline dicarboxylic acid C1010HH1818OO44 used espec used especially in the manufacture of synthetic resinsially in the manufacture of synthetic resins

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The observed bioerosion rate is further influenced by tThe observed bioerosion rate is further influenced by the morphology of the polymer. he morphology of the polymer.

Polymers can be classified as either semicrystalline or Polymers can be classified as either semicrystalline or amorphous. amorphous.

At body temperature (37°C) amorphous polymers with At body temperature (37°C) amorphous polymers with Tg above 37°C will be in a glassy state, and polymers Tg above 37°C will be in a glassy state, and polymers with a with a Tg below 37°C will in a rubbery stateTg below 37°C will in a rubbery state. .

In this discussion it is therefore necessary to consider In this discussion it is therefore necessary to consider three distinct morphological states: three distinct morphological states: semicrystalline, semicrystalline, amorphous—glassy, and amorphous—glassy, and amorphous—rubbery.amorphous—rubbery.

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In the crystalline state, the polymer chains are In the crystalline state, the polymer chains are densely packed and organized into crystalline densely packed and organized into crystalline domains that domains that resist the penetration of waterresist the penetration of water. .

Consequently, Consequently, backbone hydrolysis tendsbackbone hydrolysis tends to o to occur in the ccur in the amorphous regionsamorphous regions of a semicrystal of a semicrystalline polymer and at the surface of the crystalliline polymer and at the surface of the crystalline regions. ne regions.

This phenomenon is of particular importance tThis phenomenon is of particular importance to the erosion of devices made of o the erosion of devices made of poly(L-lactic poly(L-lactic acid) and poly(glycolic acid)acid) and poly(glycolic acid) which tend to hav which tend to have high degrees of crystallinity around 50%.e high degrees of crystallinity around 50%.

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Another good illustration of the influence of the polymAnother good illustration of the influence of the polymer morphology on the rate of bioerosion is provided ber morphology on the rate of bioerosion is provided by a comparison of poly(L-lactic acid) and poly(D, L-lacty a comparison of poly(L-lactic acid) and poly(D, L-lactic acid): ic acid):

Although these two polymers have chemically identicAlthough these two polymers have chemically identical backbone structures and an identical degree of hydal backbone structures and an identical degree of hydrophobicity, devices made of rophobicity, devices made of poly(L-lactic acid) tend tpoly(L-lactic acid) tend to degradeo degrade much more much more slowlyslowly than than identical devices midentical devices made of poly(D, L-lactic acid). ade of poly(D, L-lactic acid).

The slower rate of bioerosion of poly poly(L-lactic aciThe slower rate of bioerosion of poly poly(L-lactic acid) is due to the fact that this d) is due to the fact that this stereoregular polymerstereoregular polymer is is semicrystalline, while the racemicsemicrystalline, while the racemic 外消旋外消旋 (( 體體 )) 的的 poly(D, poly(D, L-lactic acid) is an amorphous polymer.L-lactic acid) is an amorphous polymer.

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Likewise, a polymer in its Likewise, a polymer in its glassy stateglassy state is is less peless permeable to waterrmeable to water than the same polymer whe than the same polymer when it is in its rubbery state. n it is in its rubbery state.

This observation could be of importance in casThis observation could be of importance in cases where an amorphous polymer has a glass tres where an amorphous polymer has a glass transition temperature that is not for above bodansition temperature that is not for above body temperature (37°C). y temperature (37°C).

In this situation, water sorption into the polymIn this situation, water sorption into the polymer could lower its Tg below 37°C, resulting in er could lower its Tg below 37°C, resulting in aabrupt changes in the bioerosionbrupt changes in the bioerosion rate. rate.

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The The manufacturing processmanufacturing process may also have a si may also have a significant effect on the erosion profile. gnificant effect on the erosion profile.

For example, Mathiowitz and co-workers (MatFor example, Mathiowitz and co-workers (Mathiowitz et al., 1990) showed that hiowitz et al., 1990) showed that polyanhydridpolyanhydride microspherese microspheres produced by produced by melt encaspulatimelt encaspulationon were very dense and eroded slowly, wherea were very dense and eroded slowly, whereas when the same polymers were formed into s when the same polymers were formed into microspheres by microspheres by solvent evaporationsolvent evaporation, the micr, the microspheres were very porous (and therefore morospheres were very porous (and therefore more water permeable) and eroded more rapidly.e water permeable) and eroded more rapidly.

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The preceding examples illustrate an important technThe preceding examples illustrate an important technological principle in the design of bioeroding devices: ological principle in the design of bioeroding devices:

The bioerosion rate of a given polymer is not an unchaThe bioerosion rate of a given polymer is not an unchangeable property, but depends to a very large degree ngeable property, but depends to a very large degree on readily controllable factors such as on readily controllable factors such as the presence of plasticizers or additives, the presence of plasticizers or additives, the manufacturing process, the manufacturing process, the initial molecular weight of the polymer, and the initial molecular weight of the polymer, and the geometry of the device.the geometry of the device.

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To be continuedTo be continued

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1 Biomaterials Week 11 11/29/2010 Classes of Materials used in Medicine.

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