Transcript Biomaterials Week 7

Biomaterials
Week 11
11/29/2010
Classes of Materials used in
Medicine
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2.7 Bioresorbable and
Bioerodible materials
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Introduction:
Bioresorbable and Bioerodible
Degradable implant, no need to be
removed
 Temporary presence
 Potential concern: toxicity
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Definition relating to the process or
erosion and/or degradation
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Used to indicate a given material
eventually disappear after having been
introduced into living organism
 Biodegradation
 Bioerosion
 Bioabsorption
 Bioresorption
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Degradation
Chemical process
 Cleavage of covalent bond
 Hydrolysis
 Oxidative and enzyme mechanism
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Erosion
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Physical change in size, shape, or mass of a
device
Consequence of degradation or simply
dissolution
Erosion can occur without degradation
Degradation can occur without erosion
Consensus Conference of the European Society
of Biomaterials: “biodegradation” biological
agents to cause the chemical degradation of
implanted device
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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
 Bioerosion: include both physical processes
(dissolution) and chemical processes (backbone
cleavage)
 Bioresorption and bioabsorption:
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Used interchanged
Polymer and its degradable product are removed by
cellular activities
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Overview of current available
degradable polymers
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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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Overview of current available
degradable polymers
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
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Requirements
Toxic component leached from the implant
(residual monomer, stabilizers,
polymerization initiator, emulsifiers,
sterilization by-product
 Potential toxicity of the degradation
products and subsequent metabolites
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FDA approved biodegradable polymers
Poly(lactic acid)
 Poly(glycolic acid)
 Polydioxanone
 Polycaprolactone
 Poly(PCPP-SA anhydride)
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Table 1 provide an overview of some representative
degradable polymers
Structural formula is shown in Fig 1
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Polydioxanone (PDS)
Poly (ether ester)
 Ring-opening
polymerization of pdioxanone monomer
 Low toxicity monomer
 Lower modulus than PLA
or PGA
 Used in
 Monofilament suture
 Suture clip
 Bone pin
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Poly(hydroxybutyrate) (PHB)聚羥基丁酯 ,
poly(hydroxyvalerate) (PHV) and copolymer
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Polyester from
microorganism
PHB: crystalline and
brittle
Copolymer PHB and PHV
acid: less crystalline more
flexible
Used: drug release,
suture, artificial skin and
vascular grafts
Slow degradation time
(500 days, 80 % stiffness)
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Polycaprolactone (PCL)聚己內酯多元醇
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Semicrystalline polymer
Degrade at lower pace
than PLA
Used in drug release:
active for over 1 year
Nontoxic and tissuecompatible materials
Used in wound
dressings, and
degradable staple
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Polyanhydrides
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Hydrolytic instability
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
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) )
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Polyanhydrides
React with drug containing amino group or
nucleophilic functional group
 Reaction with nucleophile: limit the type of
drug can be successfully incorporated
 Amine containing biomolecules could react
with anhydride bond on the surface
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Nucleophile: as an electron-donating reagent
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Polyanhydrides
Excellent biocompatibility
 Drug deliver
 Prepared by compression molding or
microencapsulation
 Insulin, bovine growth factors,
angiogenesis inhibitor (herparin, cortisone)
enzyme
 Nonviral vectors of delivering DNA in gene
therapy
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Poly(ortho ester)
Surface erosion
 Slab-like devices release
drug more constant rate
 Controlled-release drug
delivery
 Ortho ester link more
stable in base than in
acid
 Control degradation by
incorporated acidic and
basic excipients into
polymer matrix
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Poly(ortho ester)
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”
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Poly(ortho ester)-preparation
Trans-esterification of 2,2’-dimethoxyfuran
with a diol (a compound containing two hydroxyl groups )
 Acid-catalyzed addition reaction of diols
with diketeneacetal:
 3rd generation: soft and viscous liquids,
drug delivery, can be injectable form
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Poly(amino acid) and pseudo- Poly(amino acid)
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
 Low toxicity
 Early application: suture, artificial skin
substitutes, drug delivery system
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Poly(amino acid) and pseudo- Poly(amino acid)
Drugs attached to side chains, via a
spacer unit that distances the drug from
the backbone
 Poly(L-lysine) with methotrexate and
pepstatin
 Poly(glutamic acid) with adriamycin
 Appear attractive: few practical application
 Highly insoluble and nonprocessible
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Poly(amino acid) and pseudo- Poly(amino acid)
Pronounce tendency to swell in aqueous
 Difficult to predict drug release rate
 So far, no approved by FDA
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pseudo- Poly(amino acid)
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Backbone-modified “pseudo” poly(amino acid)
Polyester from N-protected trans-4-hydroxyl-Lproline and a polyiminocarbonate derived from
tyrosine dipeptide
Easy process by solvent or heat
High degree biocompatibility
Tyrosine-derived polycarbonates are highstrength materials: degradable orthopedic
implants
Poly (DTE carbonate): bone conductivity (bone
grow directly along the polymeric implant
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pseudo- Poly(amino acid)
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Reduce the number of interchain hydrogen bond
AA polymerized via repeated amide bonds
leading strong interchain hydrogen bonding
Hydrogen bonding leading to 2nd structure: αhelices 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)
Lower tendency to form hydrogen bonds
Better processibility and loss of crystallinity
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Polycyanocrylates
Bioadhesive
 Methyl Polycyanocrylates: commonly used
 Spontaneous polymerization at room
temperature in the presence of water
 Toxicity and erosion rate: depend on alkyl (having a
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monovalent organic group and especially one CnH2n+1 (as methyl) )
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Disadvantages:
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monomer very reactive component, toxic
Degradation release formaldehyde: intense
inflammation
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Polyphosphazenes:
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Backbone: nitrogen-phosphorus bonds
Interface between inorganic and organic
polymers
High thermal stability
Formation of controlled drug delivery
Claim to be biocompatible
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Chemical structure provide a readily accessible
“pendent” chain
Various drugs, peptide, biological compounds can be
attached and release via hydrogels
Used in skeletal tissue regeneration
Vaccine design
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Poly(glycolic acid) (PGA) and
poly(latic acid) (PLA) copolymers
Most used in bioerodible polymers
 PGA: simplest linear aliphatic polyester
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First synthetic absorbable suture (Dexon)
2-4 weeks: lose mechanical strength
Bone pin (Biofix)
Copolymer PGA +PLA (hydrophobic)
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Suture (Vicryl)
PGA- crystalline; lose crystallinity be copolymer
PLA- Chiral (分子呈)對掌性的 ; molecule not
superimposable on its mirror site
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Poly(glycolic acid) (PGA) and
poly(latic acid) (PLA) copolymers
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)
 Current products:
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suture
 GTR membrane for dentistry
 Bone pins
 Implantable drug delivery system
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Poly(glycolic acid) (PGA) and
poly(latic acid) (PLA) copolymers
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Investigated in:
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vascular & urological stents
Skin substitutes
Scaffold for tissue engineering
Tissue reconstruction
Unsolved issues:
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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
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Applications of synthetic, degradable
polymers as biomaterials
Classification of degradable
medical implants
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Classification of degradable medical implants
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Classification of degradable medical implants
5 main type of degradable implants:
 A temporary support device
 A temporary barrier
 An implantable drug delivery system
 The tissue engineering scaffold
 The multifunctional implant
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A temporary support device
Healing wound, broken bone, damaged blood
vessel
 Suture, bone fixation (bone nail, screws, plates),
vessel grafts
 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
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A temporary support device
Suture: most successful
 PGA-Dexon
 First routine use of a degradable polymer
in a major clinical application
 90:10 PGA/PLA (Vicryl) were developed
 Polydioxanone (PDS)
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Temporary barrier
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Medical adhesion prevention
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
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
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Temporary barrier
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
 Degradable collagen matrix with preseeded
human fibroblasts
 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
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An implantable drug delivery 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
 Most widely investigated application of
degradable polymers
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An implantable drug delivery device
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Poly(latic acid) and poly(glycolic acid) have an extensive
safety profile based on their use as suture
Formulation of implantable controlled release devices
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
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 αchloro-nitrosourea compound used as an alkylating agent in chemotherapy
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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
 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
 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
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Tissue engineering scaffold
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
 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
 Open pore structure
 May be preseeded with cells in vitro prior, followed by
the safe resorption of scaffold material
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Tissue engineering scaffold
Guided tissue regeneration (GTR):
traditionally used in dentistry
 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
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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
 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
 Premature degradation of the scaffold material
can be as detrimental to the healing process as
remains intact for excessive period of time
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Tissue engineering scaffold
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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
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Multifunctional devices
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
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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;
 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
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Multifunctional devices
Biodegradable stents for implantation into
coronary arties
 Stents are designed to mechanically prevent to
collapse and restenosis (Recurrence of stenosis A constriction
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<
or narrowing of a duct or passage> 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
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Multifunctional devices
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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.
The release of BMP has been reported to stimulate bone
growth and therefore has potential to accelerate the
healing rate
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The process of bioerosion
Transformation from solid into water-soluble
materials
 Associated with
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Macroscopic change in appearance
Physiomechanical
Physical process
 Swelling
 Deformation
 Structural disintegration
 Weight loss
 Depletion of drug
 Loss of function
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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).
 We therefore limit the following discussion to
solid devices that bioerode because of the
hydrolytic cleavage of the polymer backbone.
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Factors that influence the rate of
bioerosion
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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 morphology of the polymer,
 the initial molecular weight an molecular weight
distribution of the polymer,
 the device fabrication process used to prepare the
device,
 the presence catalysts, additives, or plasticizers, and
 the geometry (specifically the surface area to volume
ratio) of the implanted device.
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Factors that influence the rate of
bioerosion
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.
 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.
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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.
 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.
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Factors that influence the rate of
bioerosion
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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.
sebacic acid a crystalline dicarboxylic acid C10H18O4 used
especially in the manufacture of synthetic resins
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Factors that influence the rate of
bioerosion
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The observed bioerosion rate is further influenced by the
morphology of the polymer.
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.
In this discussion it is therefore necessary to consider
three distinct morphological states:
semicrystalline,
 amorphous—glassy, and
 amorphous—rubbery.
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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.
 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%.
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Factors that influence the rate of
bioerosion
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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).
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, Llactic acid) is an amorphous polymer.
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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.
 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.
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Factors that influence the rate of
bioerosion
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.
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Factors that influence the rate of
bioerosion
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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 presence of plasticizers or additives,
 the manufacturing process,
 the initial molecular weight of the polymer, and
 the geometry of the device.
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To be continued
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