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Biomaterials

Week 11
11/29/2010
Classes of Materials used in
Medicine

2.7 Bioresorbable and


Bioerodible materials

Introduction: Bioresorbable and Bioerodible


Degradable

implant, no need to be

removed
Temporary presence
Potential concern: toxicity

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
Biodegradation
Bioerosion
Bioabsorption
Bioresorption

Degradation
Chemical

process
Cleavage of covalent bond
Hydrolysis
Oxidative and enzyme mechanism

Erosion
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:
Used

interchanged
Polymer and its degradable product are
removed by cellular activities
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Overview of current available


degradable polymers

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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10

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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)

Table 1 provide an overview of some


representative degradable polymers
Structural formula is shown in Fig 1
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15

16

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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) ,
poly(hydroxyvalerate) (PHV) and
copolymer
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)

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
Hydrolytic

instability

Aliphatic . (an organic compound having an openchain 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
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 2,2dimethoxyfuran 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)


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)


Reduce

the number of interchain hydrogen

bond
AA polymerized via repeated amide bonds
leading strong interchain hydrogen bonding
Hydrogen bonding leading to 2nd structure: helices and -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 monovalent organic group and especially one C nH2n+1 (as methyl) )

Disadvantages:
monomer

very reactive component, toxic


Degradation release formaldehyde: intense
inflammation
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Polyphosphazenes:
Backbone:

nitrogen-phosphorus bonds
Interface between inorganic and organic
polymers
High thermal stability
Formation of controlled drug delivery
Claim to be biocompatible
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
First

synthetic absorbable suture (Dexon)


2-4 weeks: lose mechanical strength
Bone pin (Biofix)
Copolymer

PGA +PLA (hydrophobic)

Suture

(Vicryl)
PGA- crystalline; lose crystallinity be copolymer
PLA- Chiral ( ) ; 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:
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
Investigated

in:

vascular

& urological stents


Skin substitutes
Scaffold for tissue engineering
Tissue reconstruction
Unsolved

issues:

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

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

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
, implantable device for administration of BCNU
to patients suffering from glioblastoma
amultiformae,
malignant rapidly
of the
a growing
usuallyastrocytoma
lethal form
of central
brain nervous
cancersystem

and usually of a cerebral hemisphere -- called also glioblastoma mul.ti.f

Carmustine or BCNU (= "bis-chloronitrosourea") is a45


mustard gasrelated -chloro-nitrosourea compound used as an alkylating agent in

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


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 or narrowing of a duct or passage> after

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
corrective surgery on a heart valve)

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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
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 watersoluble materials


Associated with
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

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 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
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)
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 10H18O4 used


especially in the manufacture of synthetic resins
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Factors that influence the rate of


bioerosion

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 (37C) amorphous polymers
with Tg above 37C will be in a glassy state, and
polymers with a Tg below 37C will in a rubbery
state.
In this discussion it is therefore necessary to
consider three distinct morphological states:
semicrystalline,
amorphousglassy,

and
amorphousrubbery.
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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

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 ( )
poly(D, L-lactic 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 (37C).
In this situation, water sorption into the
polymer could lower its Tg below 37C,
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

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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