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

2. 2 2.7 Bioresorbable and Bioerodible materials

3. 3 Introduction: Bioresorbable and Bioerodible Degradable implant, no need to be removed Degradable implant, no need to be removed Temporary presence Temporary presence Potential concern: toxicity Potential concern: toxicity

4. 4 Definition relating to the process or erosion and/or degradation Used to indicate a given material eventually disappear after having been introduced into living organism Used to indicate a given material eventually disappear after having been introduced into living organism Biodegradation Biodegradation Bioerosion Bioerosion Bioabsorption Bioabsorption Bioresorption Bioresorption

5. 5 Degradation Chemical process Chemical process Cleavage of covalent bond Cleavage of covalent bond Hydrolysis Hydrolysis Oxidative and enzyme mechanism Oxidative and enzyme mechanism

6. 6 Erosion Physical change in size, shape, or mass of a device Physical change in size, shape, or mass of a device Consequence of degradation or simply dissolution Consequence of degradation or simply dissolution Erosion can occur without degradation Erosion can occur without degradation Degradation can occur without erosion Degradation can occur without erosion Consensus Conference of the European Society of Biomaterials: “ biodegradation ” biological agents to cause the chemical degradation of implanted device Consensus Conference of the European Society of Biomaterials: “ biodegradation ” biological agents to cause the chemical degradation of implanted device

7. 7 Biodegradable Biodegradable polymer: water-insoluble polymer that is converted under physiological condition into water-soluble materials without regard to specific mechanism involve in the erosion process Biodegradable polymer: water-insoluble polymer that is converted under physiological condition into water-soluble materials without regard to specific mechanism involve in the erosion process Bioerosion: include both physical processes (dissolution) and chemical processes (backbone cleavage) Bioerosion: include both physical processes (dissolution) and chemical processes (backbone cleavage) Bioresorption and bioabsorption: Bioresorption and bioabsorption: Used interchanged Used interchanged Polymer and its degradable product are removed by cellular activities Polymer and its degradable product are removed by cellular activities

8. 8 Overview of current available degradable polymers

9. 9 TABLE I Degradable Polymers and Representative Applications under Investigation Degradable polymer Synthetic degradable polyesters Current major research applications Poly(glycolic acid), poly(Lactic acid), and copolymers Barrier membranes, drug delivery, guided tissue regeneration (in dental applications), orthopedic applications, stents. staples, sutures, tissue engineering Polyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV), and copolymers Long-term drug delivery, orthopedic applications, stents, sutures Polycaprolactone Long-term drug delivery, orthopedic applications, staples, stents Polydioxanone Fracture fixation in non-load-bearing bones, sutures, wound clip

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12. 12 Overview of current available degradable polymers Design, synthesis of new, degradable biomaterials is currently an important research challenge Design, synthesis of new, degradable biomaterials is currently an important research challenge In tissue engineering: development of new biomaterials that can provide predetermined and controlled cellular response needed component of most practical applications of tissue engineering In tissue engineering: development of new biomaterials that can provide predetermined and controlled cellular response needed component of most practical applications of tissue engineering

13. 13 Requirements Toxic component leached from the implant (residual monomer, stabilizers, polymerization initiator, emulsifiers, sterilization by-product Toxic component leached from the implant (residual monomer, stabilizers, polymerization initiator, emulsifiers, sterilization by-product Potential toxicity of the degradation products and subsequent metabolites Potential toxicity of the degradation products and subsequent metabolites

14. 14 FDA approved biodegradable polymers Poly(lactic acid) Poly(lactic acid) Poly(glycolic acid) Poly(glycolic acid) Polydioxanone Polydioxanone Polycaprolactone Polycaprolactone Poly(PCPP-SA anhydride) Poly(PCPP-SA anhydride) Table 1 provide an overview of some representative degradable polymers Table 1 provide an overview of some representative degradable polymers Structural formula is shown in Fig 1 Structural formula is shown in Fig 1

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18. 18 Polydioxanone (PDS) Poly (ether ester) Poly (ether ester) Ring-opening polymerization of p- dioxanone monomer Ring-opening polymerization of p- dioxanone monomer Low toxicity monomer Low toxicity monomer Lower modulus than PLA or PGA Lower modulus than PLA or PGA Used in Used in Monofilament suture Monofilament suture Suture clip Suture clip Bone pin Bone pin

19. 19 Poly(hydroxybutyrate) (PHB) 聚羥基丁酯, poly(hydroxyvalerate) (PHV) and copolymer Polyester from microorganism Polyester from microorganism PHB: crystalline and brittle PHB: crystalline and brittle Copolymer PHB and PHV acid: less crystalline more flexible Copolymer PHB and PHV acid: less crystalline more flexible Used: drug release, suture, artificial skin and vascular grafts Used: drug release, suture, artificial skin and vascular grafts Slow degradation time (500 days, 80 % stiffness) Slow degradation time (500 days, 80 % stiffness)

20. 20 Polycaprolactone (PCL) 聚己內酯多元醇 Semicrystalline polymer Semicrystalline polymer Degrade at lower pace than PLA Degrade at lower pace than PLA Used in drug release: active for over 1 year Used in drug release: active for over 1 year Nontoxic and tissue- compatible materials Nontoxic and tissue- compatible materials Used in wound dressings, and degradable staple Used in wound dressings, and degradable staple

21. 21 Polyanhydrides Hydrolytic instability Hydrolytic instability Aliphatic 脂肪族的. (an organic compound having an open-chain structure) polyanhydrides degrade: days Aliphatic 脂肪族的. (an organic compound having an open-chain structure) polyanhydrides degrade: days Aromatic (ring system (as benzene) containing usually multiple conjugated double bonds) polyanhydrides degrade: years Aromatic (ring system (as benzene) containing usually multiple conjugated double bonds) polyanhydrides degrade: years Aliphatic and aromatic copolymer: intermediate rate Aliphatic and aromatic copolymer: intermediate rate High degradation rate: degrade by surface without catalyst or excipients (inert substance (as gum arabic or starch) that forms a vehicle (as for a drug) ) High degradation rate: degrade by surface without catalyst or excipients (inert substance (as gum arabic or starch) that forms a vehicle (as for a drug) )

22. 22 Polyanhydrides React with drug containing amino group or nucleophilic functional group React with drug containing amino group or nucleophilic functional group Reaction with nucleophile: limit the type of drug can be successfully incorporated Reaction with nucleophile: limit the type of drug can be successfully incorporated Amine containing biomolecules could react with anhydride bond on the surface Amine containing biomolecules could react with anhydride bond on the surface Nucleophile: as an electron-donating reagent

23. 23 Polyanhydrides Excellent biocompatibility Excellent biocompatibility Drug deliver Drug deliver Prepared by compression molding or microencapsulation Prepared by compression molding or microencapsulation Insulin, bovine growth factors, angiogenesis inhibitor (herparin, cortisone) enzyme Insulin, bovine growth factors, angiogenesis inhibitor (herparin, cortisone) enzyme Nonviral vectors of delivering DNA in gene therapy Nonviral vectors of delivering DNA in gene therapy

24. 24 Poly(ortho ester) Surface erosion Surface erosion Slab-like devices release drug more constant rate Slab-like devices release drug more constant rate Controlled-release drug delivery Controlled-release drug delivery Ortho ester link more stable in base than in acid Ortho ester link more stable in base than in acid Control degradation by incorporated acidic and basic excipients into polymer matrix Control degradation by incorporated acidic and basic excipients into polymer matrix

25. 25 Poly(ortho ester) Surface erodability: incorporated with highly water-soluble drugs into polymeric matrix can result in swelling of polymer matrix Surface erodability: incorporated with highly water-soluble drugs into polymeric matrix can result in swelling of polymer matrix The increase amount of water imbedded into the matrix can cause “ bulk erosion ” instead of “ surface erosion ” The increase amount of water imbedded into the matrix can cause “ bulk erosion ” instead of “ surface erosion ”

26. 26 Poly(ortho ester)-preparation Trans-esterification of 2,2 ’ -dimethoxyfuran with a diol (a compound containing two hydroxyl groups ) Trans-esterification of 2,2 ’ -dimethoxyfuran with a diol (a compound containing two hydroxyl groups ) Acid-catalyzed addition reaction of diols with diketeneacetal: Acid-catalyzed addition reaction of diols with diketeneacetal: 3rd generation: soft and viscous liquids, drug delivery, can be injectable form 3rd generation: soft and viscous liquids, drug delivery, can be injectable form

27. 27 Poly(amino acid) and pseudo- Poly(amino acid) Protein composed of amino acids, obvious Protein composed of amino acids, obvious Amino acid side chains offer sites for the attachment for drugs, cross-linking agents, pendent (something suspended) groups (used to modify the physiomechanical properties of the polymer Amino acid side chains offer sites for the attachment for drugs, cross-linking agents, pendent (something suspended) groups (used to modify the physiomechanical properties of the polymer Low toxicity Low toxicity Early application: suture, artificial skin substitutes, drug delivery system Early application: suture, artificial skin substitutes, drug delivery system

28. 28 Poly(amino acid) and pseudo- Poly(amino acid) Drugs attached to side chains, via a spacer unit that distances the drug from the backbone Drugs attached to side chains, via a spacer unit that distances the drug from the backbone Poly(L-lysine) with methotrexate and pepstatin Poly(L-lysine) with methotrexate and pepstatin Poly(glutamic acid) with adriamycin Poly(glutamic acid) with adriamycin Appear attractive: few practical application Appear attractive: few practical application Highly insoluble and nonprocessible Highly insoluble and nonprocessible

29. 29 Poly(amino acid) and pseudo- Poly(amino acid) Pronounce tendency to swell in aqueous Pronounce tendency to swell in aqueous Difficult to predict drug release rate Difficult to predict drug release rate So far, no approved by FDA So far, no approved by FDA

30. 30 pseudo- Poly(amino acid) Backbone-modified “ pseudo ” poly(amino acid) Backbone-modified “ pseudo ” poly(amino acid) Polyester from N-protected trans-4-hydroxyl-L- proline and a polyiminocarbonate derived from tyrosine dipeptide Polyester from N-protected trans-4-hydroxyl-L- proline and a polyiminocarbonate derived from tyrosine dipeptide Easy process by solvent or heat Easy process by solvent or heat High degree biocompatibility High degree biocompatibility Tyrosine-derived polycarbonates are high- strength materials: degradable orthopedic implants Tyrosine-derived polycarbonates are high- strength materials: degradable orthopedic implants Poly (DTE carbonate): bone conductivity (bone grow directly along the polymeric implant Poly (DTE carbonate): bone conductivity (bone grow directly along the polymeric implant

31. 31 pseudo- Poly(amino acid) Reduce the number of interchain hydrogen bond Reduce the number of interchain hydrogen bond AA polymerized via repeated amide bonds leading strong interchain hydrogen bonding AA polymerized via repeated amide bonds leading strong interchain hydrogen bonding Hydrogen bonding leading to 2nd structure: α- helices and β-pleated sheets Hydrogen bonding leading to 2nd structure: α- helices and β-pleated sheets In pseudo- Poly(amino acid): half on the amide bonds are replaced by other linkage (such as carbonate, ester, or iminocarbonate bonds) In pseudo- Poly(amino acid): half on the amide bonds are replaced by other linkage (such as carbonate, ester, or iminocarbonate bonds) Lower tendency to form hydrogen bonds Lower tendency to form hydrogen bonds Better processibility and loss of crystallinity Better processibility and loss of crystallinity

32. 32 Polycyanocrylates Bioadhesive Bioadhesive Methyl Polycyanocrylates: commonly used Methyl Polycyanocrylates: commonly used Spontaneous polymerization at room temperature in the presence of water Spontaneous polymerization at room temperature in the presence of water Toxicity and erosion rate: depend on alkyl (having a monovalent organic group and especially one CnH2n+1 (as methyl) ) Toxicity and erosion rate: depend on alkyl (having a monovalent organic group and especially one CnH2n+1 (as methyl) ) Disadvantages: Disadvantages: monomer very reactive component, toxic monomer very reactive component, toxic Degradation release formaldehyde: intense inflammation Degradation release formaldehyde: intense inflammation

33. 33 Polyphosphazenes: Backbone: nitrogen-phosphorus bonds Backbone: nitrogen-phosphorus bonds Interface between inorganic and organic polymers Interface between inorganic and organic polymers High thermal stability High thermal stability Formation of controlled drug delivery Formation of controlled drug delivery Claim to be biocompatible Claim to be biocompatible Chemical structure provide a readily accessible “ pendent ” chain Chemical structure provide a readily accessible “ pendent ” chain Various drugs, peptide, biological compounds can be attached and release via hydrogels Various drugs, peptide, biological compounds can be attached and release via hydrogels Used in skeletal tissue regeneration Used in skeletal tissue regeneration Vaccine design Vaccine design

34. 34 Poly(glycolic acid) (PGA) and poly(latic acid) (PLA) copolymers Most used in bioerodible polymers Most used in bioerodible polymers PGA: simplest linear aliphatic polyester PGA: 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 copolymer PGA- crystalline; lose crystallinity be copolymer PLA- Chiral ( 分子呈 ) 對掌性的 ; molecule not superimposable on its mirror site PLA- Chiral ( 分子呈 ) 對掌性的 ; molecule not superimposable on its mirror site

35. 35 Poly(glycolic acid) (PGA) and poly(latic acid) (PLA) copolymers Semi-crystalline L-PLA in high mechanical strength & toughness, suture or orthopedic Semi-crystalline L-PLA in high mechanical strength & toughness, suture or orthopedic Best advantage: safe, nontoxic, biocompatible (copolymer can be brought to market in less time, lower cost) Best advantage: safe, nontoxic, biocompatible (copolymer can be brought to market in less time, lower cost) Current products: Current products: suture suture GTR membrane for dentistry GTR membrane for dentistry Bone pins Bone pins Implantable drug delivery system Implantable drug delivery system

36. 36 Poly(glycolic acid) (PGA) and poly(latic acid) (PLA) copolymers Investigated in: Investigated in: vascular & urological stents vascular & urological stents Skin substitutes Skin substitutes Scaffold for tissue engineering Scaffold for tissue engineering Tissue reconstruction Tissue reconstruction Unsolved issues: Unsolved issues: Most cell do not attach to PGA & PLA surface, poor substrate for cell growth; for tissue engineering used is debatable Most cell do not attach to PGA & PLA surface, poor substrate for cell growth; for tissue engineering used is debatable Degradation product strong acid accumulate at implant site, delayed inflammatory response Degradation product strong acid accumulate at implant site, delayed inflammatory response

37. 37 Applications of synthetic, degradable polymers as biomaterials Classification of degradable medical implants

38. 38 Classification of degradable medical implants

39. 39 Classification of degradable medical implants 5 main type of degradable implants: A temporary support device A temporary support device A temporary barrier A temporary barrier An implantable drug delivery system An implantable drug delivery system The tissue engineering scaffold The tissue engineering scaffold The multifunctional implant The multifunctional implant

40. 40 A temporary support device Healing wound, broken bone, damaged blood vessel Healing wound, broken bone, damaged blood vessel Suture, bone fixation (bone nail, screws, plates), vessel grafts Suture, bone fixation (bone nail, screws, plates), vessel grafts Degradable implant would provide temporary, mechanical support until natural tissue heals and regains its strength Degradable implant would provide temporary, mechanical support until natural tissue heals and regains its strength Adjust the degradation rate of the temporary support device to the healing of the surrounding tissue represents one of the major challenges in the design of such devices Adjust the degradation rate of the temporary support device to the healing of the surrounding tissue represents one of the major challenges in the design of such devices

41. 41 A temporary support device Suture: most successful Suture: most successful PGA-Dexon PGA-Dexon First routine use of a degradable polymer in a major clinical application First routine use of a degradable polymer in a major clinical application 90:10 PGA/PLA (Vicryl) were developed 90:10 PGA/PLA (Vicryl) were developed Polydioxanone (PDS) Polydioxanone (PDS)

42. 42 Temporary barrier Medical adhesion prevention Medical adhesion prevention Adhesion formed between two tissue sections by clotting blood in extravascular tissue space followed by inflammation and fibrosis. Adhesion formed between two tissue sections by clotting blood in extravascular tissue space followed by inflammation and fibrosis. Cause pain, functional impairment, and problems during subsequent surgery Cause pain, functional impairment, and problems during subsequent surgery Surgical adhesions: caused of morbidity, and represent one of the most significant complications of a wide range of surgical procedures such as cardiac, spinal, and tendon surgery Surgical adhesions: caused of morbidity, and represent one of the most significant complications of a wide range of surgical procedures such as cardiac, spinal, and tendon surgery Investigated for sealing of breaches of the lung tissue that cause leakage Investigated for sealing of breaches of the lung tissue that cause leakage

43. 43 Temporary barrier Skin reconstruction: artificial skin Skin reconstruction: artificial skin Artificial, degradable collagen/glycosaminoglycan matrix that is placed on top of the skin lesion to stimulate the regrowth of a functional dermis Artificial, degradable collagen/glycosaminoglycan matrix that is placed on top of the skin lesion to stimulate the regrowth of a functional dermis Degradable collagen matrix with preseeded human fibroblasts Degradable collagen matrix with preseeded human fibroblasts Goal: stimulate the regrowth of the functional dermis Goal: stimulate the regrowth of the functional dermis Used in the treatment of burns and other deep skin lesions and represent an important application for temporary barrier type devices Used in the treatment of burns and other deep skin lesions and represent an important application for temporary barrier type devices

44. 44 An implantable drug delivery device By necessity a temporary device By necessity a temporary device The device will eventually run out of drug or the need for the delivery of a specific drug is eliminated once the diseased is treated The device will eventually run out of drug or the need for the delivery of a specific drug is eliminated once the diseased is treated Most widely investigated application of degradable polymers Most widely investigated application of degradable polymers

45. 45 An implantable drug delivery device Poly(latic acid) and poly(glycolic acid) have an extensive safety profile based on their use as suture Poly(latic acid) and poly(glycolic acid) have an extensive safety profile based on their use as suture Formulation of implantable controlled release devices Formulation of implantable controlled release devices Implantable, controlled release formulation based on copolymers of lactic acid and glycolic acid have already become available. Implantable, controlled release formulation based on copolymers of lactic acid and glycolic acid have already become available. Polyanhydride in the formulation of an intracranial 頭蓋, implantable device for administration of BCNU to patients suffering from glioblastoma 神經膠母細胞瘤 multiformae, a usually lethal form of brain cancer Polyanhydride in the formulation of an intracranial 頭蓋, implantable device for administration of BCNU to patients suffering from glioblastoma 神經膠母細胞瘤 multiformae, 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 chemotherapymustard gasnitrosourea compoundalkylating agentchemotherapy

46. 46 Tissue engineering scaffold Degradable implant that is designed to act as an artificial extracellular matrix by providing space for cells to grow into and recognize into functional tissue Degradable implant that is designed to act as an artificial extracellular matrix by providing space for cells to grow into and recognize into functional tissue Man made implantable prostheses do not function as well as the native tissue Man made implantable prostheses do not function as well as the native tissue Or maintain the functionality of native tissue over long periods of time Or maintain the functionality of native tissue over long periods of time Interdisciplinary field that utilizes degradable polymers, among other substrates and biologics, to develop treatments that will allow the body to heal itself without the need for permanently implanted, artificial prosthetic devices Interdisciplinary field that utilizes degradable polymers, among other substrates and biologics, to develop treatments that will allow the body to heal itself without the need for permanently implanted, artificial prosthetic devices

47. 47 Tissue engineering scaffold Ideal case, a tissue engineering scaffold is implanted to restore lost tissue function, maintain tissue function, or enhance existing tissue function Ideal case, a tissue engineering scaffold is implanted to restore lost tissue function, maintain tissue function, or enhance existing tissue function Can take the form of feltlike material obtained from knitted or woven fibers or from fiber meshes Can take the form of feltlike material obtained from knitted or woven fibers or from fiber meshes Various procedures be used to obtain foams or sponges Various procedures be used to obtain foams or sponges Pore interconnectivity is a key properties: as cells need to be able to migrate and grow throughout the entire scaffold Pore interconnectivity is a key properties: as cells need to be able to migrate and grow throughout the entire scaffold Open pore structure Open pore structure May be preseeded with cells in vitro prior, followed by the safe resorption of scaffold material May be preseeded with cells in vitro prior, followed by the safe resorption of scaffold material

48. 48 Tissue engineering scaffold Guided tissue regeneration (GTR): traditionally used in dentistry Guided tissue regeneration (GTR): traditionally used in dentistry Scaffold encourage the growth of specific type of tissue Scaffold encourage the growth of specific type of tissue Treatment of periodontal disease, favor new bone growth in the periodontal pocket over soft tissue ingrowths Treatment of periodontal disease, favor new bone growth in the periodontal pocket over soft tissue ingrowths

49. 49 Tissue engineering scaffold Challenges in the design of tissue engineering scaffold is the need to adjust the rate of scaffold degradation to rate of tissue healing Challenges in the design of tissue engineering scaffold is the need to adjust the rate of scaffold degradation to rate of tissue healing Polymer may need to function on the order of days to months Polymer may need to function on the order of days to months For bone: scaffold must maintain some mechanical strength to support the bone structure while new bone is formed For bone: scaffold must maintain some mechanical strength to support the bone structure while new bone is formed Premature degradation of the scaffold material can be as detrimental to the healing process as remains intact for excessive period of time Premature degradation of the scaffold material can be as detrimental to the healing process as remains intact for excessive period of time

50. 50 Tissue engineering scaffold Future use of tissue engineering scaffolds has the potential to revolutionize the way aging, trauma, and disease-related loss of tissue function can be treated Future use of tissue engineering scaffolds has the potential to revolutionize the way aging, trauma, and disease-related loss of tissue function can be treated

51. 51 Multifunctional devices Combining several functions as one single device Combining several functions as one single device These applications envision the combination of several functions within the same device and require the design of custom-made materials with narrow range of predetermined materials properties These applications envision the combination of several functions within the same device and require the design of custom-made materials with narrow range of predetermined materials properties

52. 52 Multifunctional devices Ultrahigh-strength poly(lactic acid) biodegradable bone screws and bone nails opens the possibility of combining the “ mechanical support ” function of the device with a “ site-specific drug delivery ” function; Ultrahigh-strength poly(lactic acid) biodegradable bone screws and bone nails opens the possibility of combining the “ mechanical support ” function of the device with a “ site-specific drug delivery ” function; A biodegradable bone nail that holds the fractured bone in place can simultaneously stimulate the growth of new bone tissue at the fracture site by slowly release bone growth factors throughout its degradation process A biodegradable bone nail that holds the fractured bone in place can simultaneously stimulate the growth of new bone tissue at the fracture site by slowly release bone growth factors throughout its degradation process

53. 53 Multifunctional devices Biodegradable stents for implantation into coronary arties Biodegradable stents for implantation into coronary arties Stents are designed to mechanically prevent to collapse and restenosis (Recurrence of stenosis after corrective surgery on a heart valve) of arteries that have been opened by balloon angioplasty Stents are designed to mechanically prevent to collapse and restenosis (Recurrence of stenosis after corrective surgery on a heart valve) of arteries that have been opened by balloon angioplasty Ultimately, the stents could deliver an antiinflammatory or antithrombogenic agent directly to the site of vascular injury Ultimately, the stents could deliver an antiinflammatory or antithrombogenic agent directly to the site of vascular injury

54. 54 Multifunctional devices Most important multifunctional device for future applications is a tissue engineering scaffold that also serve as a drug delivery system for cytokines, growth hormones, or other agents that directly affect cells and tissue within the vicinity of the implanted scaffold Most important multifunctional device for future applications is a tissue engineering scaffold that also serve as a drug delivery system for cytokines, growth hormones, or other agents that directly affect cells and tissue within the vicinity of the implanted scaffold E.g. bone regeneration scaffold that is placed within a bone defect to allow the regeneration of bone while releasing bone morphogenic protein (BMP) at implant site. E.g. bone regeneration scaffold that is placed within a bone defect to allow the regeneration of bone while releasing bone morphogenic protein (BMP) at implant site. The release of BMP has been reported to stimulate bone growth and therefore has potential to accelerate the healing rate The release of BMP has been reported to stimulate bone growth and therefore has potential to accelerate the healing rate

55. 55 The process of bioerosion Transformation from solid into water-soluble materials Transformation from solid into water-soluble materials Associated with Associated with Macroscopic change in appearance Macroscopic change in appearance Physiomechanical Physiomechanical Physical process Physical process Swelling Swelling Deformation Deformation Structural disintegration Structural disintegration Weight loss Weight loss Depletion of drug Depletion of drug Loss of function Loss of function

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57. 57 Factors that influence the rate of bioerosion Although the solubilization of intact polymer as well as several distinct mechanisms of chemical degradation have been recognized as possible causes for the observed bioerosion of a solid, polymeric implant, virtually all currently available implant materials erode because of the hydrolytic cleavage of the polymer backbone (mechanism III in Fig. 2). Although the solubilization of intact polymer as well as several distinct mechanisms of chemical degradation have been recognized as possible causes for the observed bioerosion of a solid, polymeric implant, virtually all currently available implant materials erode because of the hydrolytic cleavage of the polymer backbone (mechanism III in Fig. 2). We therefore limit the following discussion to solid devices that bioerode because of the hydrolytic cleavage of the polymer backbone. We therefore limit the following discussion to solid devices that bioerode because of the hydrolytic cleavage of the polymer backbone.

58. 58 Factors that influence the rate of bioerosion In this case, the main factors that determine the overall rate of the erosion process are In this case, the main factors that determine the overall rate of the erosion process are the chemical stability of the hydrolytically susceptible groups in the polymer backbone the hydrophilic/hydrophobic character of the repeat units, the chemical stability of the hydrolytically susceptible groups in the polymer backbone the hydrophilic/hydrophobic character of the repeat units, the morphology of the polymer, the morphology of the polymer, the initial molecular weight an molecular weight distribution of the polymer, the initial molecular weight an molecular weight distribution of the polymer, the device fabrication process used to prepare the device, the device fabrication process used to prepare the device, the presence catalysts, additives, or plasticizers, and the presence catalysts, additives, or plasticizers, and the geometry (specifically the surface area to volume ratio) of the implanted device. the geometry (specifically the surface area to volume ratio) of the implanted device.

59. 59 Factors that influence the rate of bioerosion The susceptibility of the polymer backbone toward hydrolytic cleavage is probably the most fundamental parameter. The susceptibility of the polymer backbone toward hydrolytic cleavage is probably the most fundamental parameter. Generally speaking, anhydrides 失水酸 tend to hydrolyzed faster than ester bonds that in turn hydrolyze faster than amide bonds. Generally speaking, anhydrides 失水酸 tend to hydrolyzed faster than ester bonds that in turn hydrolyze faster than amide bonds. Thus, polyanhydrides will tend to degrade faster than polyesters that in turn will have a higher tendency to bioerode than polyamides. Thus, polyanhydrides will tend to degrade faster than polyesters that in turn will have a higher tendency to bioerode than polyamides. Based on the known susceptibility of the polymer backbone structure toward hydrolysis, it is possible to make predictions about the bioerosion of a given polymer. Based on the known susceptibility of the polymer backbone structure toward hydrolysis, it is possible to make predictions about the bioerosion of a given polymer.

60. 60 Factors that influence the rate of bioerosion However, the actual erosion rate of a solid polymer cannot be predicted on the basis of the polymer backbone structure alone. However, the actual erosion rate of a solid polymer cannot be predicted on the basis of the polymer backbone structure alone. The observed erosion rate is strongly dependent on the ability of water molecules to penetrate into the polymeric matrix. The observed erosion rate is strongly dependent on the ability of water molecules to penetrate into the polymeric matrix. The hydrophilic versus hydrophobic character of the polymer, which is a function of the structure of the monomeric starting materials, can therefore have an overwhelming influence on the observed bioerosion rate. The hydrophilic versus hydrophobic character of the polymer, which is a function of the structure of the monomeric starting materials, can therefore have an overwhelming influence on the observed bioerosion rate.

61. 61 Factors that influence the rate of bioerosion For instance, the erosion rate of polyanhydrides can be slowed by about three orders of magnitude when the less hydrophobic sebacic acid is replaced by the more hydrophobic bis(carboxy phenoxy)propane as the monomeric starting material. For instance, the erosion rate of polyanhydrides can be slowed by about three orders of magnitude when the less hydrophobic sebacic acid is replaced by the more hydrophobic bis(carboxy phenoxy)propane as the monomeric starting material. Likewise, devices made of poly(glycolic acid) 羥基乙 酸 erode faster than identical devices made of the more hydrophobic poly(lactic acid), although the ester bonds have about the same chemical reactivity toward water in both polymers. Likewise, devices made of poly(glycolic acid) 羥基乙 酸 erode faster than identical devices made of the more hydrophobic poly(lactic acid), although the ester bonds have about the same chemical reactivity toward water in both polymers. sebacic acid a crystalline dicarboxylic acid C 10 H 18 O 4 used especially in the manufacture of synthetic resins sebacic acid a crystalline dicarboxylic acid C 10 H 18 O 4 used especially in the manufacture of synthetic resins

62. 62 Factors that influence the rate of bioerosion The observed bioerosion rate is further influenced by the morphology of the polymer. The observed bioerosion rate is further influenced by the morphology of the polymer. Polymers can be classified as either semicrystalline or amorphous. Polymers can be classified as either semicrystalline or amorphous. At body temperature (37°C) amorphous polymers with Tg above 37°C will be in a glassy state, and polymers with a Tg below 37°C will in a rubbery state. At body temperature (37°C) amorphous polymers with Tg above 37°C will be in a glassy state, and polymers with a Tg below 37°C will in a rubbery state. In this discussion it is therefore necessary to consider three distinct morphological states: In this discussion it is therefore necessary to consider three distinct morphological states: semicrystalline, semicrystalline, amorphous — glassy, and amorphous — glassy, and amorphous — rubbery. amorphous — rubbery.

63. 63 Factors that influence the rate of bioerosion In the crystalline state, the polymer chains are densely packed and organized into crystalline domains that resist the penetration of water. In the crystalline state, the polymer chains are densely packed and organized into crystalline domains that resist the penetration of water. Consequently, backbone hydrolysis tends to occur in the amorphous regions of a semicrystalline polymer and at the surface of the crystalline regions. Consequently, backbone hydrolysis tends to occur in the amorphous regions of a semicrystalline polymer and at the surface of the crystalline regions. This phenomenon is of particular importance to the erosion of devices made of poly(L-lactic acid) and poly(glycolic acid) which tend to have high degrees of crystallinity around 50%. This phenomenon is of particular importance to the erosion of devices made of poly(L-lactic acid) and poly(glycolic acid) which tend to have high degrees of crystallinity around 50%.

64. 64 Factors that influence the rate of bioerosion Another good illustration of the influence of the polymer morphology on the rate of bioerosion is provided by a comparison of poly(L-lactic acid) and poly(D, L-lactic acid): Another good illustration of the influence of the polymer morphology on the rate of bioerosion is provided by a comparison of poly(L-lactic acid) and poly(D, L-lactic acid): Although these two polymers have chemically identical backbone structures and an identical degree of hydrophobicity, devices made of poly(L-lactic acid) tend to degrade much more slowly than identical devices made of poly(D, L-lactic acid). Although these two polymers have chemically identical backbone structures and an identical degree of hydrophobicity, devices made of poly(L-lactic acid) tend to degrade much more slowly than identical devices made of poly(D, L-lactic acid). The slower rate of bioerosion of poly poly(L-lactic acid) is due to the fact that this stereoregular polymer is semicrystalline, while the racemic 外消旋 ( 體 ) 的 poly(D, L- lactic acid) is an amorphous polymer. The slower rate of bioerosion of poly poly(L-lactic acid) is due to the fact that this stereoregular polymer is semicrystalline, while the racemic 外消旋 ( 體 ) 的 poly(D, L- lactic acid) is an amorphous polymer.

65. 65 Factors that influence the rate of bioerosion Likewise, a polymer in its glassy state is less permeable to water than the same polymer when it is in its rubbery state. Likewise, a polymer in its glassy state is less permeable to water than the same polymer when it is in its rubbery state. This observation could be of importance in cases where an amorphous polymer has a glass transition temperature that is not for above body temperature (37°C). This observation could be of importance in cases where an amorphous polymer has a glass transition temperature that is not for above body temperature (37°C). In this situation, water sorption into the polymer could lower its Tg below 37°C, resulting in abrupt changes in the bioerosion rate. In this situation, water sorption into the polymer could lower its Tg below 37°C, resulting in abrupt changes in the bioerosion rate.

66. 66 Factors that influence the rate of bioerosion The manufacturing process may also have a significant effect on the erosion profile. The manufacturing process may also have a significant effect on the erosion profile. For example, Mathiowitz and co-workers (Mathiowitz et al., 1990) showed that polyanhydride microspheres produced by melt encaspulation were very dense and eroded slowly, whereas when the same polymers were formed into microspheres by solvent evaporation, the microspheres were very porous (and therefore more water permeable) and eroded more rapidly. For example, Mathiowitz and co-workers (Mathiowitz et al., 1990) showed that polyanhydride microspheres produced by melt encaspulation were very dense and eroded slowly, whereas when the same polymers were formed into microspheres by solvent evaporation, the microspheres were very porous (and therefore more water permeable) and eroded more rapidly.

67. 67 Factors that influence the rate of bioerosion The preceding examples illustrate an important technological principle in the design of bioeroding devices: The preceding examples illustrate an important technological principle in the design of bioeroding devices: The bioerosion rate of a given polymer is not an unchangeable property, but depends to a very large degree on readily controllable factors such as The bioerosion rate of a given polymer is not an unchangeable property, but depends to a very large degree 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.

68. 68 To be continued