1 s2.0 0079670083900059 Main

Prog. Polym. Sci., Vol. 9, pp. 1-58, 1 9 8 3 0079-6700183/010001-58529.
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Printed in Great Britain. All Rights Reserved. Copyright © 1983 Pergamon Press Ltd.
BIODEGRADATION OF B I O M E D I C A L POLYMERS
JIND~ICH KOPE~EK AND KAREL ULBRICH

Institute of Macromolecular Chemistry, CzechosiovakAcademy of Sciences, 16206 Prague 6,
Czechoslovakia
CONTENTS
1. Introduction 2
2. Synthetic polymers as biomaterials 3
2.1. The use of soluble polymers in medicine 3
2.2. The use of insoluble polymers in medicine 5
3. Interactions between polymers and enzymes in the living organism 6
3.1. The cell 6
3.1.1. The plasma membrane 7
3.1.2. Lysosomes 8
3.1.3. Endocytosis 9
3.2. Interactions of soluble polymers with enzymes 10
3.3. Interactions of insoluble polymers with enzymes 11
4. Biodegradation of synthetic polymers 12
4.1. Methods of testing of the biodegredation of biomedical polymers 13
4.2. Biodegradation of soluble polymers 14
4.2.1. Dextran 14
4.2.2. Hydroxyethylstarch 15
4.2.3. Gelatin and its derivatives 16
4.2.4. Polyvinylpyrrolidone 16
4.2.5. Polyvinylalcohol 17
4.2.6. Poly [N-(2-hydroxypropyl)methaerylamide ] 18
4.2.7. Poly-~,0-[N-(2-hydroxyethyl)-D,L-aspar tamide ] 18
4.2.8. Polyglycols 19
4.2.9. Poly(2-vinylpyridine- 1-oxide) 19
4.2.10. Poly(a-amino acids) 19
4.2.11. Polyelectrolytes 21
4.3. Biodegradation of insoluble polymers 21
4.3.1. Silicones 21
4.3.2. Polyurethanes 22
4.3.3. Natural rubber 23
4.3.4. Polyesters 26
4.3.4.1. Poly(~-hydroxy acids) 26
4.3.4.2. Poly(e-caprolactone) 29
4.3.4.3. Polyethyleneterephthalate 31
4.3.4.4. Other polymers containing ester groups 31
4.3.5. Polyethylene 33
4.3.6. Polypropylene 34
4.3.7. Polystyrene 34
2 J. KOPE(~EKand K. ULBR1CH
4.3.8. Polyamides 35
4.3.9. Poly(2-hydroxyethyl methacrylate) 37
4.3.10. Poly(methyl methacrylate) 37
4.3.11. Poly(alkyl-2-cyanoacrylates) 38
5. Tailor-made biodegradable polymers 39
5.1. Development of N-(2-hydroxypropyl)methacrylamide copolymers as carriers of
therapeutic agents 40
5.1.1. Relationship between the structure of oligopeptidic sequences bound on
N-(2-hydroxypropyl)methacrylamide copolymers and their
enzymaticaUy catalyzed hydrolysis 42
5.1.2. The fate ofN-(2-hydroxypropyl)methacrylamide copolymers at the
cellular level 45
5.1.3. The fate of N-(2-hydroxypropyl)methacrylamide copolymers in vivo 46
5.2. Development of drug delivery systems based on aliphatic polyesters 47
5.2.1. Long term delivery of contraceptives 47
5.2.2. Short term delivery of narcotic antagonists 47
6. Final comments 48
Acknowledgement 50
References 50
1. I N T R O D U C T I O N
The term biodegradation is applied mainly in two distinct fields, namely,

(a) in the interactions between polymer and mammals,
(b) in the interactions between polymers and micro-organisms.
The former case relates to changes occurring in biomedical polymers when they
are used in human and veterinary medicine; 1-5 the latter concerns processes which
take place when polymers come into contact with micro-organisms either after
application under natural conditons, or when they are added to wastes, including
dumps in the soil, or water borne contaminations are contained in the coastal
waters of the seas or lakes. 3' 6
The term biodegradation has been defined in various ways by different authors.
Sometimes biodegradation in context of the relationship between a polymer and a
living organism, has been used to include all the processes leading to the degrada-
tion of implants. Such a broad definition includes both enzymatically catalyzed
processes and a simple acid or base catalyzed hydrolysis or oxidation. In this review
the term biodegradation is applied to processes involving some specific vital activity
of the physiological environment.S' 7
Quite obviously, our knowledge o f the mechanism o f processes occurring in con-
tact within the physiological environment is too scarce yet, to enable us to discern
in all cases whether the process involved should be called biodegradation or not.
This is especially true in instances where changes in the polymer structre and
properties are small. If, however, one assumes that the development of experi-
mental methods suitable for the study o f the degradation mechanisms o f polymers
will continue, the consequent expansion of knowledge relating to degradative pro-
cesses means that the number of examples which are difficult to define will go on
decreasing.
BIODEGRADATION OF BIOMEDICAL POLYMERS 3
Even if degradation is caused by the attack of micro-organisms, the term bio-

degradation 3 or real microbial degradation 6 should only be applied to a process
involving at least some participation of enzyme activity. This again presumes that
the micro-organisms utilize the polymer as a source of carbon, and possible also of
nitrogen.
This paper deals with the biodegradation of polymers for medical purposes.
Papers devoted to microbial degradation are cited only in an attempt to facilitate
the understanding of the relationship between the structure of synthetic polymers
and their biodegradability. This area was recently reviewed.6' 8, 9 A complete biblio-
graphy of all the papers published in the field of biodegradation is not intended:
the aim is to demonstrate how knowledge of these processes is necessary to provide
solution to problems related to the development of novel types of biomedical
polymers.
The introduction is followed by a brief account of the uses of synthetic poly-
mers in medicine and by a discussion of the basic problems involved in the inter-
action between polymers and enzymes occurring in the physiological environment.
After that, the biodegradability of the most important groups of polymers is dis-
cussed. In subsequent sections, possibilities for the application of biodegradable
biomedical polymers are mentioned, and two cases are described which show how
the knowledge of the relationship between the structure and biodegradability of a
certain class of polymers can be used in the tailor-made synthesis of polymeric drug
carriers.
2. S Y N T H E T I C POLYMERS AS B I O M A T E R I A L S
The term biomaterials comprises not only synthetic polymers, but also natural
polymers, metals, ceramics, carbons, natural tissues and composites. 2 Discussion in
this article is mainly restricted to synthetic polymers. With respect to their uses,
soluble and insoluble (crosslinked) polymers should be considered separately. For a
chemist, soluble polymers are a simpler object: they are easier to characterize, and
the process of polymeranalogous reactions (e.g. drug binding) is easier to investi-
gate. On the other hand, insoluble polymers are more "advantageous" if we want to
investigate interactions with the physiological environment. The relative inertness
of the latter in connection with their interaction with living tissue is reflected in the
number of applications of these polymers in human medicine. In contrast, the use
of soluble synthetic polymers in medicine (e.g. as drug carriers) has not yet occur-
red although one might predict that it might emerge on a major scale in the next
decade.
2.1. The use o f soluble polymers in medicine

Recently, there has been a qualitative change in the development of novel types
of chemotherapeutic agents. 1° Initially this field was mainly restricted to the
4 J. KOPE(~EK and K. ULBRICH
synthesis of new chemical compounds and study of the relationship between their
structure and pharmacological activity, however, during the recent years, new con-
cepts in the development of drugs have been forwarded. These are based on the first
cases of success achieved in a long-term effort to prepare drugs which would con-
rain target-selective homing devices. The search for new concepts in this field of
research has brought about an increased interest in polymeric compounds and in
the investigation of their interactions with the physiological environment. Some
soluble polymers (in water and saline) are used clinicaly, many proposed applica-
tions have only reached the experimental stage and use in human medicine is hin-
dered by a great number of unsolved problems. It' ~2Polymer structure has an effect
on the immunological response of the organism, as on the elimination of the poly-
mer from the organism or the deposition of the polymer in different organs. With
proceeding elucidation of the factors just mentioned, one can expect the soluble
polymers to become more widely used in these following fields:
(a) Blood plasma expanders
Co) synthetic polymers active as drugs, i.e. polymers the pharmacological activity of
which can mainly be assigned to their molecular weight
(c) polymer bound drugs, i.e. drugs in which the active substance is bound to a
polymeric carrier molecule ~3 or drugs in which the active substance is incorpor-
ated into the main polymeric chain.
ad (a) Blood plasma expanders. A number of polymers have been investigated and
used for this purpose. We would like to mention both those polymers which enjoy
wide clinical use, and also those which have only been studied experimentaUy.
Using known biological properties, it may be possible to choose prospective drug
carriers from the latter.
Dextran, 14-16 hydroxyethyl starch, 17 gelatin and its derivatives (oxypoly-
gelatin,is modified fluid gelatin,19 urea-linked gelatin~) are used as blood plasma
expanders.~2, 2~.22 Continuing research is carried on of the biological properties of
polyvinylpyrrolidone2a'~ which was extensively used during the World War II.
Low-molecular weight (~ 15 000) polyvinylpyrrolidone and poly(vinyl alcohol) are
employed in the detoxication of the organism) s' 26
Of the experimentaUy tested polymers one should mention poly [No(2-hydroxy-
propyl)methacrylamide],27 poly-a,~-[N-(2-hydroxyethyl)-D,L-aspart-amide]2s and
condensation products of ethylene oxide and polypropylenegiycol.29
ad Co) Synthetic polymers active as drugs. Many polymers possess biological activity
connected with their high-molecular weight character. For instance, poly(2-
vinylpyridine-l-oxide) is an efficient drug against silicose. The low-molecular weight
analog is completely inactive; the optima activity is not reached below 30 000. ~a
A large group of polymers possessing biological activity la consists of polyelec-
trolytes, both anionic3°, 31 and cationic,a2 This group of polymers includes pyran
copolymers,aa polyacrylic acid,a4 polymethacrylic acid,a4 synthetic analogs of
nucleic acids,as' 36 polymers containing sulphate groups, a7 phosphorus, aT'as poly-a-
amino acids,a~' a9-42 polymers containing quaternary ammonium groups.4a' ~
ad (c) Polymer bound drugs. The binding of drugs to macromolecules offers a

potential mechanism to enhance the specificity of drug action, la'4s-sl The low-
molecular weight drug penetrates into the cell by free diffusion. If the drug is
attached to the carrier molecule, endocytosis becomes its only mode of entry s2 (cf.
Section 3.1.3). This can be a highly specific mechanism. The binding of the drug
onto the macromolecule is reflected in a number of specific effects299which influ-
ence the pharmacokinetics of the drug.
Antibodies,sa,~ proteins, ss hormones, s6 DNA, szs9 poly-a.amino acids, s9'6°
lectines,61 glycoproteins,62 liposomes,~, 49,6a,64 and synthetic poly-
mers s, 10-1a,26,4s, es, 66,299have been studied as drug carriers.
Synthetic polymers offer certain advantages over naturally occurring ones. They
can be tailor-made to possess properties appropriate to the biological system in
which they are to be used.
2.2. The use o f insoluble polymers in medicine

Problems connected with the use of insoluble synthetic polymers (water
insoluble, i.e. hydrophobic or crosslinked hydrophilic polymers) in medicine have
been systematically investigated for many years by many researchers, with a result
that not only the basic relations between the structure and biocompatibility of
these materials, but also various clinical applications are now known.
The main domains of biomedical applications of insoluble polymers are:
(a) Implants as substitutes (or parts) of the organs
(b) implants for contact with blood
(c) implants as drug carriers (drug delivery systems)
(d) diagnostic polymers (e ~. micro spheres).
Synthetic polymers represent a most varied group of biomaterials. 2' 4,6z na This
is mainly due to the fact that they may be prepared with an extreme variability of
composition and thus properties. Their structure may be easily modified (e.g. by
graftingng), and also they may be fabricated readily into complex shapes and struc-
tures .2
One very important factor with polymers is that with careful choice they can be
synthesized to be biologically inert. 9° Commercially produced polymers often
contain a number of extractible admixtures which may have toxic effects. As early
as the 1950's two independent groups had begun work aimed at the synthesis of
polymers specially intended for medicine. The Prague group 7° developed hydro-
philic polymers based on 2-hydroxyethyl methacrylate (Hydron~), while at Dew
Corning preparation of hydrophobic polymers, viz. medical grade silicones
(Silastic®), 17 was being developed. Both these types of polymers are still those most
widely used.:' 67,6s
It is very difficult to divide polymers into groups according to their structure, as
there are not distinct criteria which distinguish between them. Let us follow
Hoffman's classification,2 i.e. soft or rubbery polymers, semicrystalline polymers,
and acrylics and related polymers (Table 1).
J. KoPE~EK and K. ULBRICH
TABLE 1. Synthetic polymer biomaterials 2
(i) Rubbery polymeric biomaterlals Biomedical uses

silicones tissue substitutes, heart assist devices, drug
delivery devices
polyurethanes blood pumps, blood storage bags, pacemakers
poly (cis-isoprene) tubing
(ii) Semi-crystalline polymeric biomaterials
poly (a-hydroxy acids) sutures, drug delivery devices, bone fixation
poly (ethylene terephthalate) vascular grafts, heart valve sewing rings, implant
fixation and covering fabric, sutures
polyethylene artificial joints, drug delivery device, isolation of
cardiostimulating electrodes
polypropylene blood filters, joints, orthopaedic materials
polystyrene coatings
(iii) Derivatives of acrylic acida
poly(2-hydroxethyl methacrylate) soft contact lenses, implants in plastic surgery,
coatings, drug delivery matrices, column
packings, diagnostic microspheres
poly (methyl methacrylate) bone cement, contact lenses, dental fillings
poly (a-cyanoalkyl acrylates) tissue adhesives
poly (zinc acrylate) dental cement
aerylamide, methacrylic acid, comonomers for the preparation of modified
N-vinyl pyrrolidone hydrophilic polymers
aMonomers forming hydrophilic polymers must be copolymerized with crosslinking agents.
In a number of the applications mentioned above, it is important that the

properties of the polymer should not change in the physiological environment for a
long period of time (e.g. substitution of organs). In other cases, it is advantageous
to have the possibility to regulate their rate o f biodegradation (e.g. degradable
microspheres used to plug blood vessels reversibly~). This means that in order to
select a polymer for a given application, one must know, among other things, the
relationship between the polymer structure and its biodegradability.
3. I N T E R A C T I O N S BETWEEN P O L Y M E R S AND E N Z Y M E S IN THE

LIVING ORGANISM
The cell is the basic unit o f the living matter. If an understanding o f the inter-
actions between polymers and the living organism is to be achieved, they must be
considered at the cellular and subcellular levels. Hence in this section we describe
firstly some basic data on the structure and properties of the cell and secondly the
interaction of polymers with enzymes.
3.1. The cell

Cells are the basic building stone o f living matter. Cells are integrated into
tissues, tissues into organs, and organs into an organism. Cells themselves are highly
organized structures which contain a number o f organelles ~a (Fig. 1).
B I O D E G R A D A T I O N OF BIOMEDICAL POLYMERS 7
Golgi apparatus
D(~ , O = pinocytosis vesicle

mitochondrion
pores in nuclear
envelope
lysosome
endoplasmatic
reticulurn
polysomes
:?' ~ nucleolus
FIG. 1. Schematic diagram o f a cell and its organelles.
Eucaryotic cells are divided intracellularly into distinct compartments called

organdies. The membrane delimited organelles (cf. Fig. 1) include the nucleus,
mitochondria, chloroplasts, lysosomes, peroxisomes, the Golgi apparatus. Other
structures are also present inside the cell including nucleoli, chromosomes, ribo-
somes, centrioles and microtubules.
A detailed description of the structure and functions of the individual organdies
lies beyond the scope of this review. Mention is made only of the structure and
properties of the plasmatic membrane and lysosomes which are probably the most
important with respect to cellular interactions with polymers.
3.1.1. The p l a s m a m e m b r a n e - In a simplified manner, the structure of the plasma

membrane can be described in the following way: 7a It consists of proteins and
lipids, and as such is usually referred to as a lipoprotein membrane. Plasma mem-
branes of most cell types usually contain 1-4 times more protein (on weight basis)
than lipid. Since the molecular weight of lipids is lower by an order of magnitude
than that of proteins, there are usually far more lipid than protein molecules in the
membranes. Being rich in polar lipids, the membrane assumes a structure which is
composed of two layers of lipid molecules, mainly phospholipids and steroids49'73'74
(Fig. 2).
Each layer is one molecule thick and is arranged with hydrophobic ends of its
molecules in association with the hydrophobic ends of the molecules in the other
layer. The hydrophilic portions of the membrane lipids face outward towards the
surfaces of the "bimolecular layer" of lipid.
In animal cells, even in compact tissues such as liver, the plasma membranes of
adjacent cells are almost always separated by a space of 100-200A. Although
adjacent cells are tightly joined by "gap junctions".
rophobic portions
~I_ hydrophilic portion of

~'of lipid molecules
a lipid molecule
FIG. 2. Model o f a cellular m e m b r a n e . 49'~s'~*
On cell surfaces there can be specific polysaccharides, glycoproteins, proteins

and lipids. Thus, certain cells may have selective surface binding sites, including
some that can absorb extraceilular molecules.
3 . 1 . 2 . L y s o s o m e s - Lysosomes~' 7s,~s are membrane delimited structures (organelles)

containing a wide variety of characteristic hydrolytic enzymes, the optimal pH of
which lies in the acid region. With the exception of few cells, such as human red
blood cells, all animal cells possess lysosomes. Lysosomes may be divided~s'76 into
three categories:
(a) Primary lysosomes - lysosomes which have not yet undergone fusion withother
vesicles to bring them into contact with substrates.
(b) secondary lysosomes - the product of fusion of a primary lysosome with other
intracellular vesicles containing substrates.
(c) residual bodies - a type of secondary lysosome in which much of the content
is residual material not susceptible to, or only slowly susceptible to further
degradation.
There are many enzymes which play an active part in lysosomes. The basic
enzymes and substrates are shown in Fig. 3.
One should also mention the permeability of the lysosomal membrane. The
available data do indicate that only small molecules normally pass across the mem-
branes. Higher-molecular weight substrates may come into contact with lysosomal
enzymes in three ways:
BIODEGRADATIONOF BIOMEDICALPOLYMERS 9
ENZYMES SUBSTRATES
~ s Proleases ~ - Proteins
es and related enzymes - ~ - Nucleid acids
filycosidases ~\-- Polysaccharides
Aryl sullatases ~]~ Organic-linked sulphates
tipases, Phosphnlipeses _7_- Lipids
Phosphalases~ - ~ 7 - Organic - linked phosphates
\
Membraneimpermeable
Io enzymes and subsirates
FIG. 3. Major enzymatic activitiesof lysosomes.73'~s
(1) After the substrate has penetrated into the cell via endocytosis (cf. Section
3.1.3), the primary lysosome fuses with the newly formed vacuole (containing
the substrate).
(2) The lysosomal membrane is damaged, and the enzyme is released into both the
intracellular and extracellular space (in vivo, e.g. during inflammation, arthritis
and related phenomena).
(3) By the process of "autophagy". Membranes form around degenerate organelles
in the cytoplasm so that they become encured in a membrane bound vacuole
which can then fuse with lysosomes.
3.1.3. Endocytosis - Endocytosis is a general term 77 which describes processes by

which extracellular material enters a cell in vesicles formed from the plasma mem-
brane. In general endocytic phenomena fall into two broad categories, phagocytosis
and pinocytosis.~7Phagocytosis describes the ingestion of particulate matter such as
bacteria, latex beads and erythrocytes by specialized cells e~. macrophages,
whereas the more universal process of pinocytosis describes the engulfment of small
droplets of extracellular fluid.
During pinocytosis substances may be captured (Fig. 4) either (a) in solution or
Co) bound to the surface or (c) by a combination of both mechanisms.76 Process CO)
can allow entry of a much larger proportion of external molecules per unit than
process (a). In contrast, 76 all molecules entering a cell by process (a) enter at the
same proportional rate, i.e. nonselectively.
Not only extracellular substrates enter the cell interior by endocytosis. The
surface of cells is constantly renewed, ~s as the plasma membrane is internalized
during the endocytotic process and continuously recycled. Of course if polymer is
present, either adsorbed to the membrane surface or in the surrounding medium, it
will enter cells within endocytic vesicles.
The discovery that several cell types have receptors able to recognize and
10 J. KOPE~EK and K. ULBRICH
~. p!asma membrane cell exterior
a) b) c)
Fluid pinocytosis Mixed type Surface(adso.r0tive)
pinocytosJs plnocytosts
FIG. 4. Selectivity in pinocytosis. ~ ' 7~
consequently lead to efficient pinocytic capture of specific macromolecules bearing

particular determinants was an extremely important finding. 7a-ax Substrates con-
taining such determinants are delivered to lysosomes far more efficiently and
selectively than if they were simply captured in solution by the forming pinocytic
vesicle. A number of substances can be engulfed in this way, a~ e.g. hormones, glyco-
proteins, enzymes, cholesterol esters. Receptor-mediated pinocytosis may be used
to increase the selectivity of pinocytosis of modified natural s2, 9a or synthetic poly-
mers .84
3.2. Interactions of soluble polymers with enzymes

The injection route is the only effective route for the introduction of synthetic
soluble polymers into the organism, as Polymers do not usually penetrate the skin
and the uptake from the gastrointestinal tract is not essential (only some modified
polyethyleneglycols are an exceptional). Piths discussed very nicelyas the fate of
the polyvinyl analogs of nucleic acids after application in the organism. His conclu-
sions are of general validity. After application in the blood stream, polymers are
subsequently distributed and partly excreted from the organism. Depending on the
structure and molecular weight of the polymer, a fraction is excreted in the urine.
Simultaneously, polymers are cleared from the blood stream by endocytosis. Endo-
cytic cells are mainly found in liver, spleen, thymus and bone marrow. Polymers are
not able to cross the blood-brain barrier. Schematically, these conclusions are sum-
marized in Fig. 5.
There are differences in the ease of penetration of macromolecules from the
blood stream into tissues, a7 Capillaries of liver, spleen and bone marrow have
incomplete basal membranes and are lined with endothelial cells which are not con-
tinuously arranged. Thus, macromolecules can penetrate easily into these organs.
Capillaries in endocrine glands and in muscle have a somewhat tighter arrangement,
TOPICAL F POLYMER----.ORAL ROUTE-

APPLICATION f ~ GASTROINTESTINAL
J PARENTAt J TRACT
I ROUTE I
l INJECTIONI
BARRIER FOR~ ~ BARRIER FOR

LIPOPHOBIC COMR" ~ • LIPOPHOBICCOMPOUNDS
BRAIN= jt BLOODSTREAM.~________LIVER ~ BILE
BLOOD-BRAINBARRIER x~ ~ STORAGE
OTHER ORGANS
KIDNEY
URINE
FIG. 5. Scheme of distribution fate of synthetic polymers in living organism.
(From 3s J. Pitha, Polymeric Drugs: Effects of polyvinyl analogs of nucleic acids
on cells, animals and their viral infections, in C. G. Gebelein and F. F. Koblitz,
Eds., Biomedical and dental applications o f polymers, Plenum Press, New York
(1981), with permission).
and there is an almost perfect barrier formed which isolates the central nervous sys-
tem from the circulating blood. But even such barriers can be temporarily open for
macromolecules. Thus, the majority of cells in an organism can be reached by
macromolecules. The main mechanism responsible for the transfer of macromole-
cules into cells is that of endocytosis (cf. Section 3.1.3). Thus the majority of
macromolecules entering the cell do so in an enveloped form in the endocytic
vesicle. Secondary lysosomes can be extensively damaged by macromolecules, and
both the lysosomal enzymes and the foreign macromolecules are released into the
interior of the cell. It has been shown that the majority of macromolecules entering
the cell are degraded or encapsulated within one day.aS' a6
To sum up: soluble synthetic polymers may interact with enzymes in the blood
stream, in the cytoplasm or in lysosomes.
3.3. Interactions o f insoluble polymers with enzymes

Wide application of synthetic polymers in the medical practice (cf. Section 2)
requires a detailed knowledge of interactions on the polymer-tissue interface. This
area has been extensively reviewed. 1' 87-90
With respect to the content of this article, the most important results are those
relating to the investigation of cell function at the polymer-tissue interface. Salt-
house's group is very active in this field.91-93 They have studied a number of
enzyme systems of the cells associated with the tissue response to a variety of
implants.
During the subacute phase of a foreign body reaction 91 and in the chronic
inflammatory response, the macrophage is generally predominant in the cell popula-
tion and is usually accompanied by a varying population of lymphocytes, plasma
cells and flbroblasts. With inert nonirritating implants, the macrophage population
declines after one to two weeks and then fibroblasts form a collagenous capsule at
the surface of the implant. At an enhanced reaction of the organism, giant ceils
appear near the implant. Salthouse 91 regards macrophages as the principal donor of
hydrolase enzyme activity at implant sites. Macrophage lysosomes contain an array
of enzymes which are readily released into extracellular space.94 The major hydro-
lases, lipase, phospholipase, phosphomonoester hydrolases including acid phospha-
tase, sulphuric esterases, glycoside hydrolases, endopeptidases and exopeptidases,
including cathepsins B, C, D, E, elastase and collagenase.
The release of these enzymes into the extracellular space is common especially
with older macrophage populations3°° and the area of toxic or irritating material.91
The level of lysosomal enzyme activity can be a sensitive indicator of potentially
toxic additives present in implant materials. If they are non-toxic materials with
little or no biodegradability, macrophage enzyme activity is minimal. If, however,
the material is readily degradable, as for instance with catgut sutures, an intense
increase in hydrolase and peptidase activity is observed in macrophages adjacent to
the sutures. 93
If the response of the organism is low, predominantly polymorphonuclear leuco-
cytes (neutrophils) are found in the surroundings of the implant. These cells contri-
bute little to enzyme activity at the implant site in comparison to mononuclear
macrophage cells. Of the other types of cells present in the surroundings of the
implant, histiocytes, fibrocytes, fibroblasts, and lymphocytes should be mentioned.
These cell types have also been shown to contribute enzymatic activity correspond-
ing to various types of hydrolases.
In conclusion one should point out the similarity between the cellular and
enzyme responses at inflammatory sites (wound healing) and that at the polymer
tissue interface. In both cases the presence of macrophage is decisive for the
increase in hydrolase activity. Also there is a changing histological picture at the
implantation site (or inflammation site) during the healing-in, and the concentra-
tion and composition of enzymes in contact with the polymer surface vary during
the process.
4. BIODEGRADATION OF SYNTHETIC POLYMERS

The biodegradation of polymers in a chosen environment (e.g. in the living
organism) depends predominantly on their chemical structure. In polymers with the
repeat monomer unit, the polymer may undergo degradation starting from the
chain end with release of a monomer unit or another low-molecular weight com-
pound. If the polymer contains bonds susceptible to enzymatically catalyzed
hydrolysis, only these bonds are degraded, and polymer fragments or high-molecular
weight fragments are also formed. However, the enzymatic degradation of a certain
susceptible bond is not affected merely by the structure in the close vicinity of the
site undergoing degradation. The formation of the enzyme-substrate complex is
accompanied by interactions with the longer part of the polymer chain. For
instance, the active site of papain occupies such a large space that seven amino-acid
residues9s are involved in the interaction with the substrate (protein). The structure
of each of these seven amino-acid residues affects in a certain way the rate of degra-
dation of the single bond situated in the catalytic site of the enzyme.
The ease with which the enzyme-substrate (polymer) complex is formed
depends also on the supermolecular structure of the polymer. In the case of soluble
polymers, the shape of the polymer chain in solution will be of importance. It is
known, for instance, that denatured proteins are enzymatically degraded more
quickly than the native ones. This is due to the fact that denatured proteins in solu-
tion assume the shape of a statistical coil which can form an enzyme-substrate
complex much more readily.
If one considers crosslinked or water-insoluble polymers, the situation becomes
much more complex. By comparing the rate of enzymatic degradation of two co-
polymers of the same composition (copolymers of N-(2-hydroxypropyl)methacryl-
amide) containing oligopeptidic sequences in their side chains,s' ~' 9~ one of which is
soluble~ and the other of which is crosslinked (above the point of gelation;97) so
that it only swells in water, one can see that the latter undergoes biodegradation
much more slowly and that the rate of this process strongly depends on the degree
of crosslinking (and thus on the degree of swelling). Starting from a certain degree
of swelling, the polymer allows the enzyme to penetrate into the coil, so that
degradation may proceed in the bulk of the polymer (and not only on the surface).
The effect of hydrophilicity on the rate of degradation is quite general, e.g. it has
been observed in the microbial degradation of polyamides.9s
The most complicated situation is observed with insoluble hydrophobic poly-
mers containing crystalline domains. In this case it is necessary that an abiotic (e.g.
mechanical) degradation of the polymer should occur first.3 The disintegrated poly-
mer (sometimes modified by nonenzymatic processes, e.g. by oxidation) then
undergoes degradation more readily.
4.1. Methods of testing of the biodegradation of biomedical polymers

Two approaches for the study of biodegradable polymers can be distinguished:
(a) Investigation of the properties of commercially produced polymers (including
medical grade) with the aim to extend, using the known time changes of their struc-
ture and properties in contact with the physiological environment, the possibilities
of their application.
(b) Synthesis of tailor-made polymers the structure of which satisfies conditions of

a certain application, e.g. development of soluble drug carriers specifically targeted
to certain cells, i.e. polymers containing bonds stable in the blood circulation and in
the extracellular space, but degradable by intracellular (lysosomal) enzymes.
In the former of these two cases an in vivo test is the most usual one. The poly-
mer is implanted in a certain localization, explanted after a chosen time interval,
changes (if any) are analyzed. Using labelled (e.g. with 14C) polymers, it is possible
to examine the occurrence of degradation products released from the implant and
excreted by the organism.
Those engaged in the synthesis of tailor-made polymers prefer to study degrada-
tion in model environments (even though in this case too in vivo experiment must
also be chosen as the final test). The following systems may be used:
(i) Degradation with model enzymes (chymotrypsin, trypsin, papaln, subtilisin,
elastase)
(ii) degradation with intraceUular enzymes (either with a mixture of lysosomal
enzymes or with the individual isolated enzymes, such as individual cathepsins)
(iii) degradation in blood serum
(iv) degradation with isolated tissues, e.g. with the yolk-sac 1°° chick embryo liver
culture .99
The methods just mentioned must be adjusted according to the polymer used
(soluble or insoluble). In the former case the change in the molecular weight distri-
bution can be examined. In the latter, investigation of the first stage of degradation
should contain mechanical, macroscopic, microscopic and physicochemical evalu-
ation. Theoretically, it would be possible to also determine the molecular weight
distribution of the sol, but in practice this procedure is subject to an extensive
experimental error.
During in vivo experiments with soluble polymers, the main processes under
investigation are elimination from the blood stream, rate of release from the organ-
ism, deposition of the polymer in the organs, and if possible, changes in the molecu-
lar weight distribution of the polymer in the individual compartments.
When working with insoluble polymers, changes in the mechanical, physical and
physico-chemical properties are usually studied, with detection of polymer frag-
ments in the urine and faeces. A detailed investigation of the fate of soluble degra-
dation products - arising from insoluble polymers would be possible only if the
rate of degradation were sufficiently high, so that reliable results could be obtained
within the limits of the sensitivity of the methods used.
4.2. Biodegradation o f soluble polymers

4.2.1. Dextran - Dextrans are high-molecular weight polysaccharides consisting
of a-D-glucose units joined predominantly by 1 -~ 6 glucosidic linkages. They are
formed by the action of the enzyme dextransaccharase during the growth of various
bacteria in environments containing saccharose. The use of a particular strain,
B I O D E G R A D A T I O N OF BIOMEDICAL POLYMERS 15
B-512, of Leuconostoc mesenteroides produces a dextran with a minimum number

of side chains (i.e. 1 ~ 3 linkages). Before clinical use the molecular weight must be
adjusted in advance by partial acid hydrolysis followed by fractionationJ °1 The
most widely used are Macrodex® (3~tw= 70000) and Rheomacrodex® (~tw =
40 000). (Distribution curves cf. refs. 12, 14.)
As with the majority of soluble polymers, molecules administered with a low
molecular weight (less than 50 000) are eliminated from the organism through the
kidneys. 22 With normally functioning kidneys, at 3~w = 70 000 approx. 30% and
40% of the total administered amount is eliminated within 6 hr and 24 hr respec-
tively. Polymer deposited in cells of the reticuloendothelial system is degraded,
firstly by the enzyme dextranase (dextran 1,6-glucosidase) to glucose, ~°2 which is
then totally hydrolysed to yield CO2 and H20.
A detailed study of the enzymatic hydrolysis of dextran has been reported by
BasedowJ °a Some preceding papers ~°4-~°7 had already made it clear that the degra-
dation of dextran with endo-dextranases was not random, since the t~-(1 ~6)-D-
glucosidic linkages in the vicinity of branch linkages and at the ends of the chain
were more stable than the other linkages. In addition to glucose, the incubation
mixture contains branched oligosaccharides - isomaltotriose and isomaltoseJ °4' los
Basedow ~°3 studied the hydrolysis of two dextran fractions (from Leuconostoc
mesenteroides, strain NRRL B-512) with a narrow molecular weight distribution
(/l~w - 88 000; 9 000). He compared the results of acid hydrolysis of these fractions
with hydrolysis catalyzed by endodextranase from P e n i c i l l i u m f u n i c u l o s u m .
The results showed that the rates of enzymatic hydrolyses were proportional to
the molecular weight. The individual rate constants of bond cleavage increased from
the midpoint of the chain towards both ends. In enzymatic hydrolysis smaller
molecular weight fragments are formed than during acid hydrolysis.
A detailed study of the structure of native dextrans (determination of the con-
tent of 1 -->2; 1-->3; 1-+4 bonds) is assisted by an analysis of the degradation
products after incubation of the dextran with isolated enzymes, e.g. with bacterial
exodextranases - glucodextranase/exo-(1 -~ 6)-a-D-glucosidase, or isomaltodextran-
ase (exo-isomaltohydrolase).1°8 The possibility of using selective enzymatic (and
nonenzymatic) degradations of carbohydrate polymers in the study of their
detailed structure has been dealt with in ref. 109. A theoretical analysis of the
degradation of polysaccharides with ~t-amylases can be found in ref. 110. The
accumulated data show that following an initial random attack on a long polymer
substrate, the enzyme frequently releases only one of the substrate fragments. The
retained fragment may be repetitively hydrolyzed near one end to release a series
of oligosaccharides before the enzyme-substrate fragment complex finally disso-
ciates.
4.2.2. H y d r o x y e t h y l s t a r c h - Hydroxyethylstarch fliES) was suggested as a blood

plasma expander by WidersheimJ 7 It is prepared by the reaction of starch with
ethylene oxide. Such substitution (hydroxyethylation) of starch is carried out in
order to reduce the rate of biodegradation of the polymer with a-amylases present
in the serum. Commercial hydroxyethylstarch is prepared from waxy maize starch.
This particular genetic variant of maize has only one component in the starch
granule, namely amylopectin,m The most commonly accepted model for HES is
one in which the substituent hydroxyethyl groups are found on carbon 6 of the
glucose ring. m The actual structure is however much more complicated. In
addition to substitution on atoms 2 and 3, polyethylene oxide side chains are also
formed.
The detailed structure of HES also determines the process of enzymatic degrada-
tion. With increasing degree of substitution ~2 the susceptibility to a-amylase
catalyzed hydrolysis decreases. Similar results have also been obtained in a study of
the linear starch component, amylose. It was shown m that the exo-enzymes,
/3-amylase, phosphorylase, and amyloglucosidase, have a negligible effect on
hydroxyethylamylose even at very low degrees of substitution. The endo-enzymes,
~,-amylases, degrade substituted amyloses. Their only requirement is that several
unsubstituted glucose residues be bound in sequence.
4.2.3. G e l a t i n a n d its d e r i v a t i v e s - As already mentioned (cf. Section 2.1) there are

three different types of gelatin used as blood plasma expanders. Peptide chains are
crosslinked with glyoxal, succinic acid anhydride or di-isocyanates.~2 Peptide
chains of modified gelatins are biodegradable,21'ha they are hydrolyzed by a
number of enzymes, including serum proteases. The intravascular half-life of these
polymers21 is only 2-3 hr.
4.2.4. P o l y v i n y l p y r r o l i d o n e - Poly(1-vinyl-2-pyrrolidone) (PVP is a polymer

having a C-C backbone. It is nondegradable and its behaviour in the living organism
is strongly dependent on the molecular weight distribution. 12' ll4, 1Is
(i) PVP molecules with molecular weight up to 25 000 are eliminated by glomeru-
lar f'dtration, which is a rapid process (a matter of days)
(ii) PVP molecules having Mw between 25 000 and 110000 are eliminated by post-
glomerular filtration (a matter of weeks)
(iii) PVP molecules with molecular weight above 110 000 are taken up preferen-
tially by the cells of the reticuloendothelial system which can lead to pro-
longed storage, but elimination via urinary secretion still seems to be possible,
presumably through postglomerular endothelial gaps.
(iv) Another route by which PVP molecules may be eliminated from the organism
is through the liver and its biliary system into the intestine (either passing
through the intestinal mucosa or with gall).
Not only for the polymer just mentioned, but generally for all synthetic poly-
mers with the C-C backbone the molecular weight distribution is a suitable tool for
complete elimination of the polymer from the living organism. Some authors even
use the term biodegradable in such a way that it includes nonbiodegradable poly-
mers small enough to pass the renal threshold, u6
4.2.5. P o l y v i n y l a l c o h o l - Polyvinylalcohol (PVOH) is able to form complexes with

a number of compounds and is therefore used in the detoxication of the organ-
ism. 2~,sl Owing to its low molecular weight (10000-15000)after application in
v i v o , the polymer is eliminated from the organism by glomerular filtration.
Enzymatic degradation of PVOH was studied by using an enzyme isolated from
soil bacteria of the Pseudomonas strain, nT' us The enzyme (Mw 30000, isoelectric
point 10.3) was characterized as s. alcohol peroxidase, u9 Based on an analysis of the
degradation products, Suzuki ns deduced that PVOH is oxidized to 1,3-diketone
with release of H2Oz. In the further step the polymer is hydrolyzed to acid and
methylketone:
~eXj~ CH 2 CH CH 2 CH CH 2 CH ~ ' L r ~
I
OH OH
I I
OH
Ienzyme
~1 + 202
CH 2 C CH 2 C CH 2 CH~'XJ"
II
0
II
0
)
Oil + 2H202
IH20
CH2 C OH + CH 3 C CH2 CH~X./"~
O
II II
O
I
OH
Watanabe 12° proposed another mechanism where the product of enzymolysis is

acid and secondary alcohol.
CH2 CH CH2 CH CH2,J'k~

I
OH
I
OH
I enzyme
02, H20
CH 2 C OH + CH3 CH CH 2
II
0
I
OH
PVOH is degraded by the enzyme mentioned above to small fragments, n7 Bio-

degradation of PVOH is mediated not only by the enzyme isolated from the strain
Pseudomonas or by bacteria of this strain, but may also be accomplished by using
other bacterial strains, such as F l a v o b a c t e r i u m 3°~ or A c i n e t o b a c t e r . 302
4.2.6. P o l y [ N - ( 2 - h y d r o x y p r o p y l ) m e t h a c r y l a m i d e ] - This polymer 121'122 has been

systematically studied with respect to its biological properties. 27' 123-12s Copolymers
based on N-(2-hydroxypropyl)methacrylamide (HPMA) are being developed as drug
carriers.S, 4s, 84,126,127 As with other polymers with the C-C backbone, no changes
in the molecular weight of the polymer can be perceived in time intervals in which
the soluble polymer is in contact with the living organism. The relation between the
molecular weight and rate of elimination of the polymer from animal organism is
described in ref. 128. Duration of action of low molecular weight nonbiodegradable
macromolecules can be increased by connecting them to each other with bio-
degradable bonds to form a higher molecular weight polymer. Poly(HPMA) chains
were connected by oligopeptide sequences degradable by chymotrypsin,129'13o
trypsin 131 and papainJ a2 The relationship between the molecular weight of these
modified copolymers and their rate of pinocytic capture by rat visceral yolk sacs in
vitro is being studied at the University of KeeleJ 33
4.2.7. P o l y - a , ~ - [ N - ( 2 - h y d r o x y e t h y l ) - D , L - a s p a r t a m i d e ] - This polymer was pro-

posed as a blood plasma expander by Neri e t al. 2a' la4 Work is also going on to
develop this type of polymer as a drug carrierJ 3s-139 The enzymatic degradation of
the main chain was tested with chymotrypsin, trypsin, pronase, papain and ficin, and
in no case was degradation observed. Also microbial degradation was measured
when the polymer was the only nitrogen source. It was found 13s that about 5% of
the nitrogen of the aspartic acid was utilized. It was assumed that the degradation
proceeded from the ends until the D-unit was reached.
4.2.8. Polyglycols - Polyethyleneglycols (PEG) or copolymers of ethylene glycol

have been suggested as blood plasma expanders 29 or carriers of biologically active
agents. 14°
The biodegradability of polyethyleneglycols was mainly investigated by activa-
tion of micro-organisms. 141 Polyethyleneglycols up to M w ~ 1500 serve as a source
of carbon for various bacteria and are degraded by the latter. Active strains are, e.g.
Acinetobacter, Pseudomonas and Flavobacterium. 142 Biodegradation of PEG with
higher M w requires the use of adapted strains of bacteria cultivated on PEG with an
M w similar to that of PEG to be degraded. 141 Thus, e.g. a strain cultivated in the
presence of PEG 4000 metabolizes PEG in the range Mw 300-4000.14a With
increasing molecular weight the rate of biodegradation decreases. ~4'~4s By using
this procedure, biodegradation of PEG up to M w 5 000 was accomplished in several
laboratories. ~41'~4a'146 One group reported ~47 the biodegradation of PEG with
Mw 20 000.
Polyglycols were also utilized in the synthesis of block copolymers in which
sequences of natural polymers were one of the components. Terpolymers have been
described 148 prepared from the hydroxy-terminated amylose triacetate oligomer
which was reacted with di-isocyanates and afterwards with polypropyleneglycol.
After deacetylation these polymers were readily degraded by c~-amylase.
Similar terpolymers were prepared from depolymerized cellulose triacetate, di-
isocyanate and polypropyleneglycol with subsequent deacetylation. ~49'iso
It was apparent that the incorporation of cellulose oligomer blocks resulted in
biodegradability. There was a substantial decrease in the intrinsic viscosity when
incubating polymer solutions with cellulysin at 50°C.
4.2.9. Poly(2-vinylpyridine-l-oxide) - This polymer possesses a protective effect

against silicose, lsl Poly(2-vinylpyridine-l.oxide) (PVPNO), if present in lyso-
somes, 1s2 prevents particles of silica dust from damaging the lysosomal membrane.
The polymer is not biodegradable. Depending on molecular weight, the polymer is
eliminated from the organism, undergoes pinocytosis and is deposited in lysosomes.
The accumulation of 14C.PVPNO in lysosomes of mouse fibroblasts in culture has
been studied by Fetzer. 1s2 PVPNO is able to inhibit silicate-induced hemolysis of
erythrocytes in vitro, lsa
4.2.10. Poly(a-amino acids) - Synthetic poly(a-amino acids) may be employed as

drug carriers 6s' ls4 or as degradable sequences joining nondegradable chains of vinyl
polymers.S, 66 In addition to practical aims, an important fact is also that poly(a-
amino acids) are high-molecular weight models of proteins. A number of polymers
of a-amino acids have been synthesized, 66 viz. homopolymers, random copolymers,
sequential copolymers and block copolymers. The enzymatic degradability of
water-soluble poly(a-amino acids) has been studied extensively. Their rate of degra-
dation depends on the chemical and physical structures of the polymer. For a given
polymer and enzyme these structures may be varied within broad limits by varying
pH or ionic strength, or by adding water-miscible solvents etc. The enzymatically
catalyzed hydrolysis of polyglutarnic acid and polylysine can be given as an
example. Iss-lsa The unusually large pH-dependence of action of chymotrypsin,
elastase, ficin, papain and subtilisin on both poly(glutamic acid) and polylysine was
accounted for in terms of a single mechanism, lss-~ss It has been assumed that pep-
tide bonds in helical regions of the synthetic polypeptide were not hydrolyzed and
that in random coil regions only those peptide bonds were hydrolyzed in which the
adjacent amino acid side chains were uncharged.
A detailed study of the trypsin catalyzed hydrolysis of polylysine (a potential
drug carrier, cf. ref. 154) was made by Waley and Watson. Is9 This hydrolysis (at
pH = 7.6) produces initially mostly di-, tri-, and tetralysine. The terminal bonds are
not split but those near the end are split preferentially
susceptible bonds
Lys-Lys-Lys-Lys-Lys-Lys-Lys-Lys-Lys.Lys
9 8 7 6 5 4 3 2 1
Using a lower concentration of trypsin, Katchalski et al. 16owere able to detect in

the digest, oligopeptides containing 2-9 lysine residues in the initial stages of
reaction. The larger oligopeptides and the original polymer disappeared from the
reaction mixture when the incubation period was prolonged. The f'mal products of
hydrolysis (Lys2, Lys3, Lys4) were in accord with the finding of ?ef. 159.
Some typical results of the biodegradation of poly(o~.amino acids) are presented
in Tables 2 and 3.
TABLE 2. Digestibility of poly(~-amino acids) by chymotrypsin ~61
Polymer of Digested (+) or pH Ref.

not (--) digested
DL-Alanine slow + 7.7;8.0 162
Aspattic acid -- 7.7 ;8.0 162
Glutamic acid -- 7.7 ;8.0 162, 193
Glutamic acid + 4.5-7.0 156
D-Glutamic acid -- 7.7 ;8.0 162
Histidine -- 7.7 ;8.0 162
DL-Homoserine slow + 7.7 ;8.0 162
Lysine + 7.4;7.7;8.0 157, 162,
163, 164
Tyrosine + 7.7 ;8.0 162
Tyrosine -- 7.3-7.5 ;8.3 165
TADLE 3. Digestibility of polylysine by proteolytic enzymes~6~
Enzyme pH Digested (+) Majorproducts Ref.

or not (--) of hydrolysis
digested
Arthrobacter proteinase 8.0 + oligopeptides 166
Alcalase
(subtilisin Carlsberg) 8.0 + Lys, Lys4, Ly% 165
Bromelain 7.0 + Lys, Lys3, Ly% 165
Carboxypeptidase-B 7.9-9.3 + Lys 157,168
Cathepsin D2 4.7 + 164
Chymotrypsin 7.4 ;7.7 ;8.0 + 157,162,
163, 164
Fibrirolysin (bovine) 7.4 + Lys2, Lys3, Lys4 167
Papain 7.0-12.0 + oligopeptides 157, 160
Pepsin 2.0-5.4 -- 157,162,
164
Staphylococcus aureusa 3.2-6.1 ;7.1-9.5 164
Trypsin 6.0-10.0 + Lys2, Lys3, Lys4 157,159,
160
aCulture medium from Staphylococcus aureus.
4.2.11. P o l y e l e c t r o l y t e s - Synthetic polyelectrolytes2e which contain the - C - C -
or other (e.g. - C - O - C - ) bonds do not undergo biodestruction in the organism.
Both the toxicity and the rate of elimination of polyelectrolytes from the organism
markedly depend on molecular weight or its distribution. For instance, the unfrac-
tionated copolymer of maleic anhydride with divinyl ether (pyran copolymer) con-
tains high-molecular weight fractions (3~rwup to 500 O 0 0 ; M w / M n = 9), which cause
a number of side effects when injectured. 169 Much of the t4C-labelled polymer is
eliminated rapidly (70% lost after six weeks), whereas the rest is eliminated very
slowly, so that the pyran copolymer is detectable even nine months after the appli-
cation. 17° For a sufficiently long retention in circulation with subsequent elimina-
tion of the polymer from the organism, the optimum molecular weight range is
30 000-50,000. Pyran copolymers with a narrow molecular weight distribution can
be prepared by a low.temperature radical polymerization using tetrahydrofuran as
the chain transfer agent. 17°' 171 As in other cases, optimization of the molecular
weight distribution of the nondegradable pyran copolymer offers a potential route
for extending its clinical uses. 26' 33
Also in the case of other polyelectrolytes molecular we;ght markedly affects bio-
logical activity. Isotactic polyacrylic acid possesses its highest antiviral
activity17t, l~ in the molecular weight range 6 000-15,000, i.e. in a range which can
readily be eliminated from the organism.
4.3. B i o d e g r a d a t i o n o f i n s o l u b l e p o l y m e r s
4.3.1. S i l i c o n e s - Silicone rubber is biocompatible. Its contact with the living tissue
does not induce side reactions, it becomes encapsulated with fibrous tissue, 71' t~
and also because of its semi-inorganic structure does not degrade or readily change
its propertiesJ 74' 175 In long-term application there are some insignificant changes in
the mechanical properties. 174-177 These changes become more pronounced if the
polymer is in contact with blood and concurrently subject to mechanical stress, as
is the case in the replacement of the heart valve. 71,178,1"/9Implants made of silicone
rubber, show a rise in the implant weight ("~ 1%). This is caused by sorption of
lipids onto the polymer and it has been proved that sorbed lipids and their oxida-
tion products la°' 181 are responsible for the observed changes in the mechanical
properties. The presence of proteins and phospholipids in the implants has not been
demonstratedJ 74 It can be said that silicone rubbers are very suitable materials for
medical uses. They are stable in the organism, the low-molecular weight fraction is
not washed out of them, and the polymer is not degraded to any significant
extentJ 74
4.3.2. Polyurethanes - In the living organism polyurethanes undergo rapid degra-

dation. 182 For example eight months after intramuscular implantation in dogs the
tensile strength was found to drop by 77% and after 16 months the implanted sam-
ples (0.2 mm thick) were completely destroyed. This probably occurs by simple
hydrolysis in parallel with hydrolysis involving the participation of enzymes. Simi-
lar results were obtained by Lipatova et al. laa They studied the biodegradability in
vivo of three types of polyurethanes based on 1,6.di-isocyanatohexane, ethylene
glycol and poly(diethylene glycol succinate) M w 750, or poly(diethylene glycol
adipates) M w 800 and 1500. The highest rate of degradation was observed in the
last mentioned sample. The role of cellular enzymes was assumed.
Polyurethanes are also used as tissue adhesives. 1~-186 The time taken for their
biodegradation in the living organism is less than one year. Enzymes participate in
this processJ 87 Z. Mal3~ from the hospital in 10sti nad Labem, Czechoslovakia, suc-
cessfully applied the polyurethane adhesive 18s in approx. 100 operationsJ 88
Roby 8 prepared a series of polymers including polyurethanes from a variety of
phenylated monomers. He assumed that a polymer structure containing a phenyl
substituent would increase its susceptibility to hydrolysis by enzymes which display
specifity particular towards aromatic substituents, such as chymotrypsin, pepsin
and subtilisin. It was also assumed that the introduction of the aromatic group
would decrease the crystaUinity of the resulting polymers. After incubation of these
polymers with chymotrypsin, pepsin and subtilisin, only minimal weight losses were
observed. It was noteworthy that enzymatic degradation of unsubstituted polymers
proceeded more quickly. This may be due to the fact that either no optically active
isomer was prepared (the enzymes just mentioned degrade preferentially
L-isomers), or alternatively that there was a too high concentration of aromatic
groups. It has been reported 189 that a high concentration of aromatic groups in a
polyester derived from phenyl-lactic acid inhibited the action of chymotrypsin.
Maximum hydrolysis was observed with a 5% aromatic incorporation.
In order to increase the rate of enzymatic degradation, Vasilchenko et al. 19o, 191
incorporated amino acid residues and dipeptides into the structure of polyurethanes
based on polyoxytetramethylene and 1,6-di-isocyanatohexane. They have shown
that the incorporation of the dipeptide Phe-Ser increased the susceptibility of
modified polyurethanes to chymotrypsin,~91 whereas the polyurethane containing
the dipeptide Gly-Gly was not cleaved. On the other hand,19° both polymers were
degraded after subcutaneous implantation in rabbits. The relationship between the
structure and biodegradability of polyurethanes was investigated in detail, also from
the microbiological point of view. Darby and Kaplan 192 studied the susceptibility of
approx. 100 laboratory synthesized polyurethanes to fungal attack. Poly(ether
urethanes) were moderately to highly resistant to attack by Aspergillus niger,
Penicillium funiculosum and others whereas all poly(ester urethanes) were highly
susceptible. The susceptibility of the latter depends not only on the structure of the
diol but also the di-isocyanate used. The presence of at least two preferably three
(unbranched) linked methylene groups seems to be necessary.
Knowledge of the relationship between the structure and biodegradability of
polyurethanes can be used as a basis for their tailor-made synthesis for certain uses.
A very suitable structure with respect to both biocompatibility and mechanical
properties is that of segmental polyurethanes. They are prepared by a two-stage
synthesis, such as:
HO-[-(CH2)~-O~CH2)~]wOH + 20CN-R~-NCO ,
polyether diol di-isocyanate
O O
. OCN-R '-NH-~-O-[-(CH,)~-O-[CH2)~/vO-~-NH-RI-NCO .
H2N-R2-NH2 /
diamine (chain"- "'"~(CH~-Off'CHL~Y
extender)
O O O O
U 1 U 2 U U '
O=-C-NH-R -NH-C-NH-R -NH-C-NH-C-O--[-(CH,x)-x--O-(-CH,y)~-~'--.,'~
segmentedpolyether-urethane/urea
4.3.3. Natural rubber - Poly(cis-l,4-isoprene) is the main component of natural

rubber. If natural rubber is to be used as an implant, it must be thoroughly freed
from all soluble admixtures, such as proteins, polysaccharides and the like;
however, biocompatibility of unmodified natural rubber is low. 19'1'19s Natural
rubber, variously modified, is most frequently used in the preparation of tubing,
catheters, ~94 artificial hearts, ~gs-~ga tracheal tubes, ~99 etc. This material possesses
excellent mechanical properties, but in long-term applications in the living organism
it undergoes degradation,19a accompanied by changes in mechanical properties (ten-
sile strength, elongation at break)) 9s The biodegradability of natural rubber
depends on the purification procedure of the initial latex, choice of the vulcanizing
TABLE 4. The chemical structures and relevant physical properties of some polyesters ~=
Polymer Formula Physical properties
Poly(glycolic acid) Crystalline, tough, inelastic, T m = 230 °, T e = 36 °
I- O Me 7
Poly(D-lactic acid) O --- O Crystalline, tough, inelastic, T m = 180 °, T g = 67 °

O
g
Poly(D,L-lactic acid) Amorphous, tough, inelastic, T g = 57 °
Et
Poly(D, L-ethylglycolic acid) Amorphous, rubbery, Te-~ 16 °
[_E~t O _/.
Poly(dimethylglycolic acid) Crystalline. tough, inelastic, T m = 240 °

T A B L E 4. Continued
Polymer Formula Physical properties
Poly(e-caprolactone) 0
Crystalline, tough, flexible, Tm = 63 °, Tg = - - 6 5 °
x T
2
Poly(alkylene adipate) 3 45 ° - - 59 °
10 77 ° --56 °
Z
O
=.
O
O ~ o
Poly(ethylene terephthalate) v
Crystalline, tough, inelastic, Tm = 256 °, T w = 67 ° ¢3
q~
OJ. O
.<
f/3
tO
Oh
26 J. KOPEI~EK and K. ULBRICH
system, polymer modification and post-cure purification. 194 Thus, e.g. ~,-ray cured
natural rubber after 1 year of subcutaneous implantation in dogs is degraded much
more quickly than sulphur cured natural rubber or biolized materials. 19s Treatment
of natural rubber by biolysis, i.e. by the introduction of heparin with gelatin or dog
and bovine albumin, and treatment with aldehydes (formaldehyde, glutaraldehyde)
considerably improves durability in the organism, mainly biocompatibility and anti-
thrombogenicityj96,197 Tissue compatibility may also be improved by coating with
Hydron®. 19s Modified natural rubber, if applied in the organism, is then compara-
tively stable, and its mechanical properties are better than those of e.g. Silastic®;
however, in a long-term application in the organism it is too reactive, ~gs and its uses
are therefore limited.
4.3.4. P o l y e s t e r s - Polyesters are one type of polymer that undergoes changes in

the organism which may be attributed both to simple hydrolysis and to the partici-
pation of enzymatically catalyzed reactions. They are also a good example to use in
order to demonstrate how changes in the chemical and physical structure of poly-
mers can affect their degradability. Thus, e.g. on the basis of theoretical considera-
tions2°° it can be assumed that the rate of non-enzymatic hydrolysis of polymers of
a-hydroxy acids will be greater than of polymers of/3, 3', 8, and e-hydroxy analogs;
aromatic esters will be least readily hydrolysed. Bulky substituents adjacent to the
ester group can retard hydrolysis by steric hindrances. The polymer morphology
and permeability is also very important. Here the Tg (glass transition temperature)
and Tm (melting point) provide a good indication of structure-morphology relation-
ships (Table 4).
By changing the structure of polyesters, it is possible to affect those properties
(Tg, and degree of crystallinity) which are related to biodegradability. For instance
by increasing the length of the methylene repeat unit it is possible substantially to
reduce the Tg without changing the crystallinity. On the other hand, introduction
of two different alkyl groups (as in poly(D,L-methylethylglycolicacid)) eliminates
both the crystallinity and reduces the T~.
There is a good correlation between the Tg and the permeability of poly-
esters. 2°° This is important with respect to their application in drug release systems.
Below we examine the biodegradability of some chosen polyester types in
greater detail.
4.3.4.1. Poly(ot-hydroxy acids) - Poly(a-hydroxy acids) are a class of polyesters

which includes2°1 polyglycolic acid (PGA), polylactic acid (PLA) (L- or, L- and D-
stereocopolymers), copolymers of lactic and glycolic acids as well as higher homo-
logues, e.g. poly(a-hydroxy butyric acid), poly(L~-hydroxyisovaleric acid).2tu
poly(L-phenyllactic acid) 189 and polymers or copolymers of mandelic and tartaric
acids. To date, biodegradable sutures based on polyglycolic acid Dexon®,2°3 and
copolymers of lactic and glycolic acid (Vicryl~2°4) are used commercially. Poly(a-
hydroxy acids) are also used as biodegradable matrices for drug release. 2°° Of the
many other applications of these polymers which are at present in the experimental
stage, experiments aimed at the development of bone fixation parts should be men-
tioned. 2°1,2°s,~°~ The biodegradability of these polymers has been extensively
studied both fn vitro and in vivo, and the basic relationships between the chemical
and physical structure, on the one hand, and biodegradability on the other are now
known.
4.3.4.1.1. Polymers and copolymers of lactic and glycolic acids. Experiments with
model enzymes (e.g. ficin and carboxypeptidase A) in vitro 2°7 and experiments
in vivo 2°z 20a have both shown that in addition to simple hydrolysis, polymers of
this type also undergo biodegradation by enzymes. It was shown 2°7 that poly-
glycolic acid degraded faster under acute inflammation conditions involving neutro-
phils than in the presence of the chronic cellular response containing macrophages.
This result makes it possible to postulate which intracellular enzymes91 may be
responsible for the biodegradation in vivo.
The rate of biodegradation of poly(a-hydroxy acids) depends on many factors,
such as the chemical composition of (co)polymers, stereoregularity, the degree of
crystallinity (which may be considerably affected by the thermal history of the
sample), the presence of low molecular weight admixtures and the like. Especially
when studying earlier papers one should be cautious in accepting the conclusions, as
sometimes the samples in question are not sufficiently well defined.
An investigation of the effect of the structure of lactic and glycolic acids poly-
mers allows us to conclude that the biodegradation of polyglycolic acid in a living
organism proceeds more quickly than the biodegradation of polylactic acid.2°9' 21o
Copolymers of both acids are degraded more quickly than homopolymersY °'2u
Copolymers containing 25-70% GA are amorphous and therefore capable of the
fastest degradation. Figure 6 shows the relationship between the composition of co-
polymers of LA and GA and their rate of biodegradation in vivo.
The history of a sample is also very important. Vert et al. 2°1 summarized factors
affecting the biodegradation of poly(L-lactic acid) (PLA 100) in the following
points:,
(1) Mw must be as high as possible but it is not a crucial factor.
(2) Residual monomer and low Mw compounds initially present, or produced dur-
ing the processing, cause degradation and must be eliminated.
(3) Heating needed for the processing gives rise to degradation.
(4) Sterilization by ~- and 7-rays causes degradation; in contrast ethylene oxide
sterilizes PLA 100 without degradation.
(5) Annealing increases the crystallinity of PLA 100 and decreases the degradation
rate if it is performed at proper temperature. If it is performed at too high a
temperature it causes degradation.
In a polymer of the same chemical composition there is also a pronounced effect
of stereoregularity. The decrease in tensile strength of different lactic acid stereo-
copolymers depending on time of implantation is shown in Fig. 7.
28 J. KOPE(~EK a n d K. U L B R I C H
6
e-
c-
O
E
~4
0 LA ~-100
100 ~-- GA 0
copolymer composition
FIG. 6. Half-life (in months) of various copolymets of lactic and glycolicacids
implanted in rats. (From211 R. A. Miller, et al., J. Biorned. Mater. Res. 11,711
(1977); with permission).
4.3.4.1.2. Polymers and copolymers of other whydroxyacids. These (co)polymers

have limited practical value. The study of biodegradation of many polymers of
a-hydroxyacids has given a better idea of the relationship between their structure
and biodegradability.
Copolymers of D-tartaric acid with diols containing 2, 6, 8, l0 and 12 CH2
groups are degradable by Aspergillus niger.212 The rate of microbial degradation
depends on the number of CH~ groups. The highest values being reached with 6 and
eight CH2 groups.
A series of polymers were prepared from 1,6-di-isocyanatohexane and various
concentrations of glycolic or D,L-mandelic acid.2n Only the copolymer which con-
tained 50% D,L.mandelic acid residues and 1,6-di-isocyanatohexane was degraded
by Aspergillus niger and elastas¢.
Polylactic acid with a low (< 5%) content of ~-phenyl-lactic acid can be degraded
during the incubation with chymotrypsin.2~3 A high-strength biodegradable fibre
can be prepared from the block terpolymer composed of P(LA-GA) chains joined
70
PLA 100
PLA 98
z~6o
{'~50 - PLA 92
40 \\
30
- "~~,~ PLA 75
20
10 I •,
0 1 2
Implantation time ( month )
FIG. 7. Variations o f the tensile strength with time for various stereocopolymers
of L- and D- lactic acids. The numbers denote the content of the L-isomer, e.g.
PLA 100 is poly L-lactic acid. (From 201 M. Vert, et ai., 26th Int. IUPACSymp. on
Macromolecules, Florence, Italy (1980). With permission.
by N,N'-isophthaloyl-bis(phthalimide). 214 This polymer is resorbed in vivo within

six weeks. A copolymer consisting of 76% dacron and 24% PLA was suggested as an
aorta implant, and its biodegradability was proved. 215
4.3.4.2. Poly(e-caprolactone) - This compound is one of the polymers frequently

used in drug release systems. 216'218,297 Its rate of degradation in physiological
environment is lower than that of poly(D,L-lactic acid). 2°° Simple hydrolysis plays
a decisive role in the degradation of this polymer. 219 A detailed study of hydrolysis
in vitro 219 has demonstrated that the rate of degradation depends on a number of
factors:
(i) On molecular weight of the polymer and its distribution. 22°,221 Polymers with
low molecular weight are hydrolyzed much more rapidly than those with higher
molecular weight
(ii) on the degree of crystallinity of the polymer. Hydrolysis proceeds in amorphous
regions of the polymer
~1.0
~"0.8
O
U 0.6
>0.5
z_
~ 0.4
Z
<0.3
T
U
_.1
<
Z
O 0.2
F--
L~
0.1
40 80 120
TIME,WEEKS
FIG. 8. Relative rates of biodegradation (change in the intrinsic viscosity with
time) of different aliphatic polyesters implanted in rabbit. (From 2°° C. G. Pitt et
al. ) Biodegradable Drug Delivery Systems Based on Aliphatic Polyesters: Applica-
tion to Contraceptives and Narcotic Antagonists, in R. Baker, Ed. Controlled
Release o f Bioactive Material, Academic Press (1980), with permission).
(iii) the hydrolytic process is an autocatalytic one; it obeys the relation Mn/M°n =
e -kt up to A n ~ 5 000
(iv) within pH 4-7 the rate of hydrolysis is almost unchanged
(v) the rate of hydrolysis may be increased by copolymerization with ~-valero-
lactone, 2°° e-decalactone, or by the incorporation of residues of glycolic and lactic
acids.2Oo, 297 The higher rate of hydrolysis of copolymers compared with the homo-
polymer must be attributed to morphological changes leading to a decrease in the
crystallinity of copolymers.
A comparison between the relative rates of biodegradation of different aliphatic
polyesters in vivo is shown in Fig. 8. It illustrates the dependence of degradation
rate on chemical structure and morphology.
Recently 222 it was shown, that the in vivo degradation of polyesters in the
rubbery state is dominated by an enzymatic degradation taking place on ,the poly-
mer surface, provided the segmental mobility of the polymer chains is sufficiently
high to permit the required chain conformation for enzymatic attack.
4.3.4.3. Polyethyleneterephthalate - When subjected to a long-term contact with

physiological environment, aromatic polyesters only undergo small changes. During
a long-term implantation (years) in the living organism the polymer is gradually des-
troyed and its mechanical properties change. In polyethyleneterephthalate fibres
the properties of the polymer changed after eight years. 22a'224 By measuring the
rate of degradation in vivo, the average time of resorption in man was estimated to
be ~ 30 years. 22s'226 Due to its stability, polyethyleneterephthalate is used in the
prostheses of aorta, large arteries and other internal organs and tissues. 22s
4.3.4.4. Other polymers containing ester groups - Huang et al. 227 prepared oligo-
meric poly(ester urea), poly(L-phenylalanine)ethyleneglycol (1,6-di-isocyanato-
hexane). They showed that after incubation with chymotrypsin for 10 days about
20% of the polymer had passed into solution. A similar model with glycine instead
of phenylalanine was not degraded.
-- (NH-- CH - - COO- CH 2 - C H2 - OOC- CH - - NH - - CO - - NH- ( C H ; ~ ) 6 - - NH - - CO) 4 -
I I
By introducing ester groups, it is possible to increase the biodegradability of

polymers. Tokiwa et al. 22a showed that by incorporating polyester blocks into poly-
amide, it was possible to prepare polymers degradable by several commercial lipases.
An important group of polymers are polyorthoesters and similar polymers. This
group includes compounds with hydrolytically degradable bonds having the follow-
ing structures:
+\/o
°
CH 3 0 CH 2 CH2~O CH 3
\c / \c / \c /
--[-oj \ o
polyorthoesters
st+
-'[-°\c/°
o/ \o
I I
polycarbonates
! J
condensates of diols with 2,2'-diethoxypyrrolidone
R1
poly(amide acetals)
The polymers mentioned above are used in the preparation of sustained drug release
systems,229-2as are hydrolyticaUy degradable, the rate of drug release from the poly.
meric matrix is of zero order and is proportional to the rate of erosion of the
polymer. In the in vitro hydrolysis, lactones and cychc carbonates were detected,
along with diols, as the products of hydrolysis. The low molecular weight products
of the in vivo hydrolysis were co.hydroxyacids, diols, CO2 and co-amino acids.
Polymers made of these materials were used in the preparation of matrices suited
for the release of drugs used in ophthalmology,~ in the release of norethin-
drone, 2as-2ss hydrocortisone,2al and the like.
A whole number of other biodegradable polymers2a7'2as are used in the prepara-
tion of drug release systems. Of these polymers, let us mention at least linear or
crosslinked polymers of dihydropyrans2ss with the structure
i i H3
-{-o c--o c.2 o--c.~ c c.~ ,-o
I
CH3
and also poly(1,4-butylene diglycolate),
HO%C~CH 2 , O~CH2~C O CH2 CH2 CH2~CH2~O~n

II
o
I
o
polymers containing an orthoformic ester group in their backbone
--[- CH H O\
i
CH2 0/
CH
and polymers containing a glycolic ester unit in combination with -O-CH2CH2-

unit.
--[CO-CH2-O-CH2-CH2-O]~n
4.3.5. Polyethylene - Polyethylene ranks among the hydrophobic polymers with

good biocompatibility. It is used in the preparation of artificial joints and of wire
insulation for cardiostimulating electrodes (pace-makers). Polyethylene and other
polyolefms are often quoted as materials possessing considerable stability against
biodegradation. In spite of this, however, during long-term contact of polyethylene
with a physiological environment very slow degradation takes place which is reflec-
ted in chemical changes and changes in mechanical properties. 23s When poly-
ethylene was labelled with 14C and implanted subcutaneously in test animals, first
traces of 14C were detected in the urine after six months, indicating degradation to
low molecular weight components. 239 Intramuscular application of polyethylene~°
films results, after 17 months, in a decrease of tensile strength of 29% and the
elongation at break decreases by 47%. A particularly pronounced decrease in tensile
strength and especially in elongation at break indicating embrittlement of the poly-
mer was observed in polyethylene samples three years after intravascular implanta-
tion in human body. 226 DoleZe123s'~1 investigated in greater detail the behaviour of
polyethylene insulations of cardiostimulating electrodes (pace-makers) implanted in
the human body. He demonstrated that degradation takes place both in the human
organism and in test animals, this is accompanied by the formation of carbonyl
groups (I 745 cm -1) and by a change in the content of double bonds. The process of
deterioration of mechanical properties was in agreement with changes observed in
the chemical structure. The biodegradation of polyethylene in the human organism
is faster than thermo-oxidative degradation at 50 and 60°C. Even if the mechanism
of degradation of polyethylene in the organism has not yet been elucidated, the
results obtained ~1 suggest that the degradation proceeds with the participation of
enzymes (probably dehydrogenases and oxidases). It may be assumed that the

mechanism may resemble the microbial degradation of alkanes, and thus be an oxi-
dation-reduction reaction proceeding by a radical mechanism. A radical mechanism
of biodegradation is also assumed by Kulkarni 243 and Levine.244 With respect to the
hydrophobic character and crystalline structure of the polymer, it may be assumed
that in the first stage only endgroups of the chain can be oxidized by the enzymes.
More extensive biodegradation must obviously be preceded by abiogenic degrada-
tion.3
The microbial degradation of polyethylene was studied in detail by Albertsson
e t a / . 2'*s-~7 It was shown that the biodegradation of PE is affected by its morph-
ology,2~, 24s by the presence of antioxidants, 2'~ by preliminary irradiation with a
UV source, by the presence of photodegradation enhancers, and by molecular
weight.
4.3.6. Polypropylene - A detailed study of the behaviour of polypropylene in the

subcutaneous implantation in hamsters 2s° has revealed that the content of carboxyl
and carbonyl groups increases in polypropylene during the time of implantation
(1740 cm-~). The rigidity and brittleness of the polymer increases simultaneously.
The rate of biodegradation of polypropylene implanted in the organism is higher
than the rate of degradation of polypropylene in thermo-oxidation at 37°C. In
another study 2~ it was found that after the intramuscular implantation of poly-
propylene fibres for seven months the tensile strength remained unchanged, while
the elongation at "break" decreased by 27%. The results just reported are in
qualitative agreement with those described earlier for the biodegradation of poly-
ethylene.
4.3.7. Polystyrene - Polystyrene (PS) is very resistant towards biodegradation. If

a 14C-labelled polymer is applied in the living organism, the first traces of the iso-
tope 14C are not detected in the urine five months after the application. 239
Microbial degradation of PS proceeds at a slow rate. 2sl Several ways for increas-
ing the rate of degradation have been described in the literature. Preceding photo-
degradation can increase the rate of biodegradation of PS but it still remains very
low and rather difficult to determine. 2s2 Other authors prepare polymer blends by
mixing PS with biodegradable components such as cellulose 2sl or starch. 2s~
Studies describing an increase in the biodegradability of polystyrene by intro-
ducing lignin related functional groups at the benzene rings of polystyrene seem
very interesting. 2~-2s7 Lignin-like polystyrene derivatives can be degraded with
comparative ease 2s4 with bacteria Moraxella and Actinomycete micromonaspora.
Poly(p-hydroxystyrene), poly(3-methoxy-4-hydroxystyrene), poly(3,5-dimethoxy-
4-hydroxystyrene), poly(4-acetoxystyrene) and poly(4-acetoxy-3-methoxystyrene)
were degraded in this manner. 2s7 Degradation products of substituted polystyrenes
released by microorganisms are low molecular weight compounds, 2ss e.g. poly(3-
methoxy-4-hydroxystyrene) is degraded to yield vanillic acid, and the latter
undergoes degradation through ~-carboxymucoic acid to maleic and oxalic acidsY 6

The step reactions responsible for the conversion of poly(3-methoxy-4-hydroxy-
styrene) to maleic and oaxalic acids are somewhat similar to the step reactions res-
ponsible for the degradation of lignin by micro-organisms.:s6
4.3.8. P o l y a m i d e s - The biodegradation of nylon 6 and nylon 6,6 (in the form of
fibres intravascularly in dogs) was investigated in vivo. A rapid decrease in the ten-
sile strength and elongation was observed. At the same time, the surface layers of
fibres were split off. After 210 days the fibre surface was strongly etched. 224 Simi-
lar results were obtained by Harrison 2ss and by Rogova e t al. 2s9 The tensile strength
of nylon 6,6 decreased after intravascular implantation by 25% after 89 days and
by 83% after 726 days. 2ss Polyamide appears to be degraded in vivo both by simple
hydrolysis and also by hydrolysis catalyzed by proteolytic enzymes.26° This view is
also supported by the fact that the degradation of fibres in vivo proceeds from the
surface. 261
Huang e t aL ~62 have tried to modify the structure of polyamides (and other
polymers) to increase enzymatic hydrolysis. They synthesized c~-benzylated nylons,
anticipating that the introduction of the ct-benzyl group would make the nylons
more susceptible to enzyme (chymotrypsin or pepsin) cleavage. The fact that
benzylated nylon 6,3 was biodegradable, whereas benzylated nylons n,6 were not
reflects over-simplification in the initial assumptions. Even though e.g. chymotryp-
sin splits bonds adjacent to hydrophobic aromatic substituents, a much larger part
of the polymer chain takes part in the formation of the enzyme-substrate complex
(20-25 ~.).
(CH2)6 NH CO CH CO NH ] x
I
CH2
benzylated nylon 6,3
Pavlisko 263 prepared a series of polyamides containing hydroxyl and methyl

substituents. These polymers were synthesized from sebacoyl chloride and 1,3-
diamino-2-propanol (or 1,2-diamino-l-methylethane) and contained pendant
methyl and hydroxyl groups which were intended to resemble alanine and serine
residues
O O O O
36 J. K O P E ~ E K a n d K. U L B R I C H
Also copolymers were synthesized from sebacoylchloride and both the hydroxy-
and methyl substituted diamines. All these polymers were incubated (approx. 1
week) with chymotrypsin, papain, subtilisin, elastase, thermolysin and the extents
of degradation measured. The most effective enzymes were elastase, thermolysin
and chymotrypsin, the max. observed % hydrolysis was ~ 30%. It was shown that
the relative number of hydrophilic-hydrophobic residues alter the polymers bio-
degradability.
Another group of polyamides was prepared263-polyfumaramides with different
spacing between the olefinic fumaramide units.
O O
-(~-CH=CH-~-NH-(CH2)-(NH)~-x
0 0 0 0
~-(CH2)~-~-NH-(CH2),-NH-~-CH=CH-~-NH-(CH2)6-NFI-)-
Biodegradation of these substrates (by enzymes or bacteria) showed that conforma-
tional flexibility associated with the individual monomer was an important design
consideration for biodegradability. It was also shown that rigidity along the copoly-
fumaramide chains inhibited biodegradation.
Huang and coworkers prepared 262 a poly(amide-urethane) (/lCn = 7 500) from
mandelic acid and 1,6-di-isocyanatohexane. This polymer was readily degraded by
elastase.
0 0 0 0
d d
Roby a has shown that copoly(amide-esters) of the type
O
II
O
II
O
II
O
II
are degradable by subtilisin.

Bailey e t al. 9s prepared regularly alternating copolyamides from glycine and
e-aminocaproic acid. They showed that these are readily degradable by a number of
bacteria and fungi. If glycine was substituted by the more hydrophilic serin, bio-
degradation occurred more rapidly.
In conclusion, one should also mention crosslinked poly(a-amino acids). Hiltner
e t al. 264-~s6 synthesized crosslinked poly(2-hydroxyethyl-L-glutamine) and studied
its degradation both in vitro and in vivo. In model experiments trypsin and collagen-
ase had no effect, but pronase and papain dissolved the hydrogel366 In viPo 26s
degradation of the water swollen polymer was only observed during the first 2
weeks of subcutaneous implantation in rats and was attributed to hydrolysis by
proteolytic enzymes released during the acute and chronic stages of the normal
inflammatory response.
4.3.9. P o l y ( 2 - h y d r o x y e t h y l methacrylate) - This was the first hydrophilic gel to be

developed for medical uses.70 Poly(2-hydroxethyl methacrylate) crosslinked with a
small amount of ethylene dimethacrylate interacts with aqueous solutions by swell-
ing to some equilibrium degree. All hydrogels including this polymer resemble in
their physical properties living tissue more so than any other class of synthetic bio-
materials.6a, 70,267-269 This is also reflected in its good biocompatibility. The effect
of porosity of the polymer on the process of its healing-in has been investiga-
ted.270, 271 The homogeneous macroporous gel is healed-in by encapsulation with a
fibrous capsule. 2~ With increasing porosity the newly formed fibrous tissue grows
through the implant, and in some cases (depending on the degree of porosity)cal-
cium is deposited. 270'271 This may sometimes have unfavourable effects on the func-
tionality of the implant .272
This polymer is extremely stable. The hydrolytic stability was tested in
vitro.268' 27a,274 In in rive experiments changes at the surface of the implant were
observed using an electron microscope six months 2~ after implantation, but these
changes were minimal. This observation is also corroborated by the finding that
poly(2-hydroxyethyl mathacrylate) applied in the plastic surgery of the nose 27s
is functional and without any macroscopically perceptible changes in patients
operated on 15 years ago.276
4.3.10. P o l y ( m e t h y l methacrylate) - Poly(methyl methacrylate) is well tolerated

by living tissue,277 its rate of degradation in living organism is very slow, and after
subcutaneous implantation of 14C-labelled poly(methyl methacrylate) in rats 2a9
radioactive transformation degradation products of the polymer were detected in
the urine 6.5 months after the implantation.
This polymer is mainly used as bone cement and sometimes problems arise in
this type of application because of the toxicity of the monomeric methyl meth-
acrylate (MMA). The latter, however, is not formed by degradation: its presence
ensues from the mode of the application. In this case liquid monomeric MMA is
mixed with prepolymerized polyMMA (or with the copolymer of MMA and
styrene) containing inhibitor. The paste obtained is polymerized in situ. It depends
on the polymerization conditions how much residual monomer remains in the poly-
merized system. It is known that the maximal conversion depends on Tg of the sys-
tem. 27a To increase the maximal conversion (= to decrease the content of residual
monomer) it si necessary to increase the temperature, or to add plasticizers into the
polymerizing system. The rise in temperature is limited, because the surrounding
tissue may be damaged by heat. Results are also dependent on the precision with
which the polymerization is conducted in each individual patient. Monomeric MMA
in the organism brings about respiratory and cardiovascular complications. At the

cellular level most side effects seem to be due to the penetration of MMA as a
lipolytic solute into the cell membrane. Toxicology of MMA and polyMMA has
been recently reviewed in detail. 277
4.3.11. Poly(alkyl-2-cyanoacrylates) - The capacity of rapidly polymerizing mono.

meric alkyl-2-cyanoacrylates to adhere firmly to moist surfaces has evoked
considerable medical interest in their potentialities as tissue adhesives. ~a4,279
The biodegradation of these polymers has been investigated both in
vitro 99'279"2a° and in vivo. 2s~'282 Hegyeli99 developed a quantitative in vitro tech-
nique, and the results obtained have been in basic agreement with long-term implan-
tation studies. The technique is based on the degradation of radio-labelled polymers
in chick embryo organ homogenates. The results obtained for the biodegradation of
poly(alkyl-2-cyanoacrylates) using this method are summarized in Table 5.99 These
in vitro data are in agreement with results from rat and dog long-term in vivo im-
plantation studies 283 which showed that poly(methyl-2-cyanoacrylate) is degraded
more rapidly than the butyl derivative. The lower rate of degradation of 2.cyano-
acrylates with a higher alkyl also affects their biocompatibility. Tissues are more
relevant to polymers with a higher alkyl content and this is obviously due to the
fact that tissue can more readily metabolize, the lower the concentration of degra-
dation products present at any given time. 279
TABLE 5. Percent degradation by 14-day old chick embryo

liver culture99in 24 hr at 37°C
Poly(alkyl-2-cyanoacrylate) % degradation
Methyl 52.2
Ethyl 3.1
Propyl 1.99
lso-butyl 1.52
Butyl 0.73
Using model studies, Leonard et al. 279 suggested the mechanism of hydrolytic
degradation of poly(alkyl-2-cyanoacrylates). They assume that the degradation is
started by the initial attack of the hydroxyl ion, leading to the reverse Knoevenagel
reaction.
Wade and Leonard 28! studied the biodegradability of polymers of 2-cyano-
acrylate-2.14C, -3-14C and -14CN in order to find out if the scheme below also holds
in the living organism. By analyzing urine in order to detect radiolabelled degrada-
tion products they found that the data obtained in vivo are consistent with the
hypothesis that random chain scission and ester hydrolysis may be involved in the
degradation of 2-cyanoacrylates assuming that the released formaldehyde is
metabolized to CO2. However, it is apparent that, in addition, other modes of
degradation are operative.
CN CN CN CN
I I~ I +
I
Oc~.r,
CH2--C--CH2--C + OH~ --- ~ . p k . f ~ C H 2 _ _ C - - C H 2 - - O H
I I I I
C=O
C-~--O C -'~--~O C=O
I
O
O O O
I I I I
R
R R R
CN CN
I
C=O + tt20 ~
I
C~O
I
O
I
O
I
R
I
R
CIt CN
~ c"~-i -~"2-°" + °"° ~ -I + CH2~O + 1120
C=O C~O
I
O O
I
I
R
I
R
Physiological environment has great influence on the rate of biodegradation of

these polymers. For instance, the same sample of poly(methyl-2-cyanoacrylate) is
degraded within 107 days in guinea pigs whilst in rats the same process takes 154
days. 2s2
5. TAILOR-MADE BIODEGRADABLE POLYMERS

In this section we want to illustrate how information relating to the mechanism
of degradation can be employed in the synthesis of polymers tailor-made for a
specific application. Two examples have been chosen in order to demonstrate how
synthetic polymers (soluble and insoluble) may contribute to the synthesis of new
therapeutic agents. We would also like to emphasize the necessity of basic research
in the field of degradation. As Pitt e t al. 2oo rightly pointed out, many reports of
polymer biodegradation are confined to evaluation of a single property, and in

many cases the specifications of the polymer are not reported. This can lead to
severe misunderstanding as the residence times of polymer in the body may vary by
an order of magnitude depending on its molecular weight, morphology, physical
form etc. In order to utilize synthetic polymers in sophisticated applications in
human medicine, it is absolutely necessary, among other things, to understand the
relationship between the structure and biodegradability of each individual class of
polymers, both in vitro and in vivo.
The first example we have chosen is the development of N-(2-hydroxypropyl)-
methacrylamide (soluble) copolymers as carriers of therapeutic agents, which is a
joint project between our laboratory and of the Department of Biological Sciences,
University of Keele (U.K.) The second example chosen by us is the development of
biodegradable drug delivery systems based on aliphatic polyesters, i.e. the use of an
initially insoluble polymer used in the administration of contraceptives and narcotic
antagonists - a project of Research Triangle Institute, North Carolina.
5.1. Development of N-(2-hydroxypropyl)methacrylamide copolymers as carriers of

therapeutic agents
Low molecular weight drugs penetrate all cell types by free diffusion or active
transport across the cell membrane. An unavoidable consequence of low molecular
weight drugs with low specificity is the production of unwanted side effects as well
as therapeutic benefit. Attachment of a drug to a macromolecular carrier changes
its mode of entry into the cell to that of pinocytosis and thus provides the oppor-
tunity to:~27
(i) Target the drug specifically to the cell type where action is required
(ii) deliver the drug intracellularly over a prolonged period of time at concentra-
tion chosen to maximize therapeutic efficacy.
For this purpose only durgs acting intracellularly and not requiring a preliminary
metabolic transformation step should be considered.~S6 Release and thus activation
of the drug would occur by endocytic uptake of the drug-carrier complex by the
cell followed by intralysosomal release of the drug from its carrier. The selectivity
of the drug-carrier complex would be a funciton of the affinity of the carrier for
the surface of the target cells, and of its endocytosis by these cells. It will also
depend upon the accessibility of the carrier complex to these cells. 2~
Schematically the drug-carrier system may be represented as follows:
J
where ~ is a soluble polymeric carrier, ( ~ ) . . drug, ( ~ . . targeting moiety,

.. spacer.
To synthesize an "ideal" drug-carrier system it is necessary to optimize all parts
of this model. At the beginning of any such project there is always insufficient
knowledge for doing so. Hence, it is necessary to choose a variable model system
which will allow a gradual development of the drug-carrier system during the
research towards the optimal goal.
(a) Carrier. Although some natural polymers have been used as carriers, '~ syn-
thetic polymers possess certain advantages compared with natural ones. Their struc-
ture can be altered more easily and they can be tailored so as to have properties
required by a certain biological system. Poly [N-(2-hydroxypropyl)methacrylamide]
was chosen as the basic polymeric chain. 27' 121,123, 12s,187 This polymer is non-
biodegradable but low molecular weight chains may be connected by biodegradable
sequences. 129, 130, 132
(b) Drug. For model studies p-nitroaniline was used as a drug model, s As thera-
peutic agents mitoclasic drugs colcemid and deacetylcolchicine were used. Experi-
ments witi~ these drugs bound to HPMA carriers gave data consistent with internal-
ization of the drug-carrier complex by pinocytosis with subsequent liberation of
active drug. 127
(c) Targeting moiety. It was shown that it is possible to modulate the rate of
pinocytic capture of polymers by altering their molecular weight 2as or by addition
of certain residues, e.g. tyramine. 136 This possibility is also operative with HPMA
copolymers. 217 Another possibility which has been investigated is the use of amino-
sugars to target the carrier molecule. This procedure is based on the known fact
that small changes in the structure of glycoproteins lead to dramatic changes in the
fate of modified glycoproteins in the organism, sl At the University of Keele it was
shown84,127, 217 using in vivo studies that HPMA copolymers can be directed very
efficiently to liver cells by inclusion of a small number of side-chains terminating
in galactose.
(d) Spacer. The choice of the spacer must also relate to mechanism of drug
liberation from the carrier and the mode of drug binding onto the polymer carrier.
If a drug delivery system is to be effective, i.e. if the drug is to be gradually released
only after internalization into cells by pinocytosis, the drug-carrier linkage must be
stable in the blood stream but allow the release of the drug by lysosomal enzymes.
To make the chosen system suitable for binding a number of drugs, one must select
a spacer which with manipulation of its structure will allow the control of the rate
of drug release. In our studies an oligopeptidic side chain was chosen as a suitable
spacer. Using this type of side chain both length and structure can be altered by
changing the sequences of amino acid residues. To be able to choose the optimal
sequence mode for binding between the polymer carrier and drug, one must know
the relationship which exists between the structure of oligopeptidic sequences
bound on HPMA copolymers and their biodegradability. The procedure employed
in the study of this problem is described in the following paragraph.
42 J. KOPEt~EK and K. ULBRICH
5.1.1. Relationship between the structure o f oligopeptidic sequences bound on

N-(2-hydroxypropyljmethacrylamide copolymers and their enzymatically catalyzed
hydrolysis - We chose p-nitroaniline as a drug model for model experiments. A
series of copolymers of the type,
were prepared in which AAi is the amino acid residue; NAp is p-nitroaniline.
With respect to drug release, the most important process is the cleavage of the
bond between the amino acid residue AA1 and NAp (denoted with an arrow). The
procedure employed in the optimization of the polymer-drug bond required
gradual answers to a number of questions. Question 1 : How is the amino acid com.
position of the oligopeptidic sequence attached to the polymer carrier related to
the degradability of the bond at its end'?.
~-Chymotrypisn was chosen as the model enzyme. It is an enzyme that has been
extensively investigated. The relationship between the structure of oligopeptidic
sequences (not bound to the polymer carrier) and the rate of their chymotrypsin-
catalyzed hydrolysis is known. 2s9'2~ The structure of its active site is also
known.291 Its active site is rather large and capable of combining with a number of
amino acid residues. It is convenient to subdivide the binding site of an enzyme to
subunits 9s and to describe the interaction of subsites (Si) with amino acid residues
(Pi) as S - P interactions, 9s cf. Fig. 9. The results of degradation of a number of
model polymers are shown in Fig. 10. The results show that the clevage of the
AAI-NAp bond (AAI being residues of phenylalanine or tyrosine, i.e. of amino
acids specific of chymotrypsin) depends on these factors:
(i) The rate of degradation increases with the length of the oligopeptidic sequence
(2-4 amino acid residues)
/
f///,//////////]
I s,t, I, s,J, Fy
( - N H CH CO-NH CH CO-NH CH CO- NH CH CO-NH CH CO- NH CH CO-
l
R4
P~
I
I
I
I
R3
P3
|
I
'
I
n
!
R2
"2
I
I
I
i
P'I
~
~
I I
Cleavage
I
RI
,
...,
'i
I
I
t
I
'
R2
,
i,~I
'2
I
I
,
FIG. 9. Schematic representation of the possible enzyme substrate complex.9s

I ~-P2--Pw--NAp
• -~
II
I
il ~ P 3 - - P2--Pl --NAp
I
me
10 m
11 mu
J
12
13
14
15 I
I I I I
2 4 6 lq kcal/K M lO-3(imol-ls-1 )
FIG. 10. Results of the cleavage of bonds in oligopeptidic side chains in N-(2-
hydroxypropyl)methacrylamide copolymers by chymotrypsin. The cleavage of
the chromogenic group (NAp, p-nitroanailine) was monitored. The degradability
is characterized by keat/KM; the higher this ratio, the more readily the substrate
is degraded. 9~
1 : P2=Gly; Pl=Phe
2-9: P3=GIy; P2=Gly,Ala,g-Ala,lle,Leu,Phe,D-Phe,Val; Pl=Phe
10-11: P.a=Ala,D-Ala; P2=Val; Pl=Phe
12-13 : P4-P3-P2=Gly-Gly-Phe; Pl=Phe,Tyr
14: P4-P3-P2-Pt =Gly-Gly-Val-Phe
15: P4-P3-P2-P1=AIa-Gly-Val-Phe
(ii) with a sequence of certain length, the rate of degradation can be affected by
modifying the structure of the sequence
(iii) the results can be correlated with degradation of low molecular weight sub-
strates.
The results allow us to infer that the steric hindrance by the polymer coil in the
formation of the enzyme-substrate complex is diminished with increased spacing
from the polymeric backbone.
Question 2: How the effect of two polymer coils is reflected in the degradability o f
the oligopeptidic sequence?
If two coils of HPMA copolymers are considered, there are at least two cases:
(i) Two independently moving coils - the system polymer bound substrate and
polymer bound chymotrypsin (P-S + P-CT)
(ii) two dependently moving coils - chymotrypsin and polymer containing an
oligopeptide sequence in the bridge joining two synthetic polymer chains
(P-S-P + CT).
In the first case it was shown 96 that the formation of the enzyme-substrate com-
plex is more difficult compared to the case P - S + CT. The rates of cleavage of
polymeric substrates by bound chymotrypsin were slower than when using free
chymotrypsin.
The second case may be of use in the optimization of the carrier structure (in
particular molecular weight). The joining of short synthetic polymer chains by bio-
degradable bonds makes possible regulation of the rate of elimination of polymer
carriers from the organism. Degradation of substrates of the type
by chymotrypsin was shown to proceed at a rate which depends on both steric and
structural factors. 13° There is a pronounced effect of structure on the leaving group
side of the oligopeptide chain. Tetrapeptidic sequences are sufficient to achieve
cleavage of 100% of sequences.
Question 3: Do these conclusions hold only for chymotrypsin or also for other
proteolytic enzymes?
An investigation of polymeric substrates degradable with trypsin 131 and
papain 132 demonstrated that the conclusions thus obtained are more widely applic-
able.
Question 4: What is the relationship between the structure of oligopeptide side-
chains and their degradability by lysosomal enzymes?
As has been discussed above, after its penetration into the intracellular space the
polymer "ends up" in secondary lysosomes, where it is in contact with lysosomal
enzymes. In this compartment the drug must be gradually released in its active
form. The suitability of the model system discussed for controlled release of drugs
within the lysosomal compartment was verified by incubation of a series of copoly-
mers of HPMA containing oligopeptide side-chains terminated in p-nitroaniline
with a mixture of lysosomal enzymes isolated from rat liver.4s' 292 The results have
shown that lysosomal enzymes are able to degrade oligopeptide side-chains attached
to HPMA copolymers. Analysis of the degradation products has shown 292 that
degradation of the bond at the end of the side-chain completely predominated
over that of other bonds along the oligopeptide sequence. From the results, the
importance of thiol proteases in the degradation of polymer substrates was obvious.
Question 5: Is it possible to prepare substrates tailor-made for a certain intracellular
enzyme?
Data are lacking for a real tailor-made synthesis. One can only start from the
degradation process of compounds reported in the literature. For instance, using
the known fact that cathepsin L prefers hydrophobic residues in P2 and P3
positions, we succeeded in synthesizing oligopeptide side chains with an increased
rate of degradation in the incubation with lysosomal enzymes.66' 292
For a real tailor-made synthesis of polymeric substrates whose structure corre-
sponds exactly with the specificity of the individual lysosomal enzymes one must
know the relationship between the structure of oligopeptide sequences in the co-
polymers under study and the rate of their degradation by the individual lysosomal
enzymes. The first steps in this direction have already been taken. The relationship
between the structure of polymeric substrates and the their degradability by lyso-
somal sulph-hydryl protease cathepsin B is shown in Fig. 11.293
An important finding is that unlike the model enzymes mentioned above, the steric
effect is not so pronounced in this case.
After more such data have been accumulated, it will be possible to regulate very
precisely the rate of release of the drug in the lysosomal compartment.
5.1.2. The fate o f N-(2-hydroxypropyl)methacrylamide copolymers at the cellular

level - Duncan et al.~26 measured the rate of pinocytic uptake of copolymers of
HPMA containing oligopeptide side chains terminated in p-nitroaniline. Copolymers
containing 4 different side chains - G l y - I l e - T y r - N A p ; - G l y - G l y - T y r - N A p ;
- G l y - P h e - T y r - N A p ; - G l y - / 3 - A l a - T y r - N A p , were radio-iodinated and incuba-
ted with rat visceral yolk sacs cultured in vitro. All copolymers were captured by
~-Gly Phe Tyr Ala -NAp

~-Gly Phe Leu Gly-NAp
Bz - Arg - NAp
<O..
Z ~-Gly Phe Ala-NAp
~-GlyLeu Ala- NAp
~-Ala Vai Ala-NAp
~-Gly Val Ala-NAp

~-Gly Val Leu-NAp
~ ~ Ala Gly Val Phe- NAp
J ~-Ala Val Phe-NAp

~Gly Phe Leu Gly Phe-NAp
~-Gly Phe Gly Phe-NAp
10 20 30 time (min)
FIG. 11. Results of the cleavage of bonds in oligopeptidie side chains in N-(2-
hydroxypropyl)methacrylamide copolymers by cathepsin B. (P. Rejmanov~et al.,
u n p u b l i s h e d results.293) C o n c e n t r a t i o n o f side chains 1.2 X 10 -4 m o l e . 1 - i; concen-
tration of cathepsin B 5.1 X 10-~mole.l-L 0.1 M phosphate buffer;pH = 6.0.
46 .I. KOPE(~EKand K. ULBRICH
fluid-phase pinocytosis and three o f the side chains (with the exception of - G l y - ~
- A l a - T y r - N A p ) were susceptible to lysosomal hydrolysis (Fig. 12). The rate o f
lysosomal hydrolysis following pinocytic uptake by rat visceral yolk sac varied with
side chain composition. Similar experiments have shown 217 that physiologically
active drugs (instead o f NAp) are liberated after internalization of the carrier-drug
complex. Thus by manipulating the side chain composition, the rate of intracellular
drug release could be modulated to meet the needs of the system in which it is
required to operate. 126
5.1.3. The fate of N-(2-hydroxypropylJmethacrylamide copolymers in vivo - It was

shown that copolymers of HPMA, containing oligopeptide sequences terminated in
p-nitroaniline, (drug model) are hydrolyzed in vivo294after intravenous injection in
rats, resulting in the appearance ofp-nitroaniline in urine.
The results with HPMA copolymers with some side-chains terminating in a recog-
nition marker (galactosamine, mannosamine or glucosamine) have shown 29s that it
is possible to direct soluble polymers to specified cells or organs within the body.
30
t-
O
o_
E 20
D
10
1 2 3 4
FIG. 12. Uptake and degradation of ~2SI-labelled N-(2-hydroxypropyDmethacryl-
amide copolymers by rat visceral yolk sac.~26The amount of copolymer accumu-
lated by the yolk sacs (Q) or degraded and released back into the culture medium
(a) is shown. P-GIy-X-Tyr-NAp; X: 1 - Ile; 2 - Gly; 3 - Pho; 4 - ~-Ala.
This conclusion is based on the finding that incorporation of 2-4 galactose residues
per macromolecule raised the rate of capture by the liver some 10-20 fold and
greatly altered the pattern of blood clearance.29s
Currently, at the University of Keele, properties of HPMA copolymers conjuga-
ted with antirnicrotubule drugs, colcemid and deacetylcolchicine are being
examined.127, 29s Preliminary results have shown that polymer complexes containing
these drugs are pinocytosed and subsequently degraded to release pharmacologic-
ally active product intracellularly.
5.2. Development o f drug delivery systems based on aliphatic polyesters

It is well known that the actions of many drugs are related to their concentra-
tion in the body. Controlling the rate of drug delivery is a way to obtain ideal drug
action. Rate control makes both safe and effective use of therapeutical agents
whose concentrations in blood must be maintained within a narrow range. 296 New
drug delivery systems have been developed which are based on the principles of
zero-order pharmacology. In such systems the drug is released at a constant rate.
One such system has been developed at the Research Triangle Institute in North
Carolina.2o0, 216, 218, 219, 220, 222 Schindler et al. studied the biodegradability of poly(e-
caprolactone), poly(D,L-lactic acid) and various copolymers and have shown that it
is possible with exact knowledge of the structure.properties relationships, to
prepare drug-delivery systems for long term (1 year) delivery and for short term
(1-2 months) delivery of therapeutic agents.
5.2.1. Long term delivery o f contraceptives - The possibility of using aliphatic

polyesters in the preparation of drug delivery systems is based on the extensive
studies of degradation of these polymers, namely poly(e-caprolactone).297 An
important property from the point of view of practical applications is that the bio-
degradation of poly(e-caprolactone) is characterized by an induction period prior to
weight loss. During the degradation there is a continuous decrease in molecular
weight accompanied by a slow increase in crystallinity, elastic modulus, and
decrease in the elongation at break and ultimate tensile strength. Weight loss starts
when the molecular weight is less than about 30 000.
Pitt et aL 2o0' 216,21a,219 took advantage of the above mentioned properties and of
the high permea~bilft3? o f poly(e-caprolactone) and developed a device capable of
subdermal delivery of contraceptive levels, i.e. ~ 50/ag/day of levonorgestrel for a
period of at least one year. As can be seen from Fig. 13, poly(e-caprolactone) is a
suitable polymer for this purpose, it is permeable to levonorgestrel and an induction
period of 1 year prior to the start of bioerosion is easily achieved.
5.2.2. Short term delivery o f narcotic antagonists - For this application it is neces-
sary to have a polymer which should be biostable for a period of anything between
4 and 12 weeks and which then undergoes rapid bioerosion. Pitt et al. 2o0decided to
-5 40
o')
E
30
20
~ PSULE IMPLANTED IN RAT ON
33 DAY
Id
_~NV I T R O ) ~
I I
% 50 100 150
LU DAY
I
15
200 250 300

DAY
FIG. 13. Daily rate of release of levonorgestrel from a poly(e-caprolaetone) capsule
implanted in rat after 32 day in vitro. Release rate determined by measurement of
radioactivity in urine and faeces. Difference in the in vitro and in vivo rates is the
result of metabolic loss of radiolabel by routes other than urine and faeces (From 2°°
C. G. Pitt et aL, Biodegradable Drug Delivery Systems Based on Aliphatic Polyesters:
Application to Contraceptives and Narcotic Antagonists, in R. Baker, E., Controlled
Release o f Bioactive Material, Academic Press (1980), with permission).
modify the properties of poly(e-caprolactone) by incorporating units of D,L.lactic

acid. The rate of degradation of copolymers is higher than that of homopoly-
mers.20o, 211 The increased rate of biodegradation can be attributed to morpho-
logical changes. Figure 14 shows the relationship between the composition of
copolymers of e-caprolactone/D,L-lactic acid and thief biodegradation in vivo. The
transport properties of the polymers were also studied. While poly(D,L-lactic acid)
is 10 4 times less permeable to progesterone than poly(e-caprolactone), copolymers
of D,L.lactic acid and e-caprolactone have the same permeability as poly(e-capro-
lactone). This is understandable, for copolymerization affords a polymer with
Tg between the Tg's of the two homopolymers and with less crystallinity than
poly(e-caprolactone). By employing such a complex approach, the research per-
formed in RTI leads towards the choice of suitable polymers for certain applica-
tions.222. 298
6. F I N A L COMMENTS
In this review we have tried to summarize the known facts relating to biodegra-
dation of medical polymers. It seems to us that our present knowledge in this area
ILl
,:(
,._I
~~~ =7,o- ......."-• 20 mole~'ooDL-Lacti
39mole~' Acid
c
DL-LacticAcid
2"0 -. o-----o 60moleO~DL_LacticAcid
o, '"-e.. o-.....-e 75mole~DL-LacticAcid
>.- 1.0 2"-0 '.e.4*-.0
F--
0 0.2
U 0-4
>
I 33.-I n " ""'"-..... T
0.2 - 'x.6t2"'"~S--~'u 16t12~"

Z
\ 2 0 ~ ' - & ~ 47"-7
i
e~
F-
04
Z
0.05 - 76"-¢~)~)
I I I
8 16 24 32
TIME,WEEKS
FIG. 14. Rates of biodegradation of poly(e-caprolactone-co-D,L-lactic acid) cap-
sules after implantation in rabbits. Numbers at individual data points show
averaged magnitude of weight loss. (From 2°° C. G. Pitt et aL, Biodegradable Drug
Delivery systems Based on Aliphatic Polyesters: Application to Contraceptives
and Narcotic Antagonists, in R. Baker, E., Controlled Release o f Bioactive
Material, Academic Press (1980), with permission).
is insufficient to permit the full exploitation of the challenge it provides. The know-
ledge of the mechanism of biodegradation would allow us to synthesize polymers
which are not only suitable for long-term application, but also suitable for
applications in which the desired life-time could be adjusted according to known
rates of biodegradation. Such polymers would be of use in many areas with
medical, agricultural and ecological applications. Of medical applications, one ought
to mention the synthesis of polymeric drugs, drug delivery systems and the develop-
ment of new types of porous implants that could undergo biodegradation at the
same rate as the new tissue is laid down. 9a
In order to be able to predict the biodegradability from the polymer structure,
or on the contrary, to be able to choose for a certain degradation rate the proper
structure, it is necessary to obtain, by systematic investigation, a number of results
concerning all factors influencing this process, e.g. configurational effect, conforma-
tional effect, molecular weight and branching effect, crystallinity, network density.
For model studies, it is best to start with optimal conditions, when the polymeric
substrate and enzyme are both in solution, and to investigate insoluble crosslinked
polymers using results obtained in solution. In the case of insoluble polymers,
even for crosslinked hydrophilic polymers swollen in water the rate of biodegra-
dation is strongly dependent on the network density, 97 and suitable structures
have to be chosen to obtain sufficient rates of biodegradation.
Nevertheless, as we have shown in the fifth part of this review, in individual cases
it is possible to reach the optimal structure of tailor-made biodegradable polymers
on the basis of present knowledge. This finding is encouraging in that the medical
role of polymers, still rather minor, may eventually reach its enormous potential
value.
ACKNOWLEDGEMENT
We are indebted to Dr. Ruth Duncan ~ r v a l u ~ l e discussions.
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Prog. Polym. Sci., Vol. 9, pp. 1-58, 1 9 8 3 0079-6700183/010001-58529.

JIND~ICH KOPE~EK AND KAREL ULBRICH

The term biodegradation is applied mainly in two distinct fields, namely,

Even if degradation is caused by the attack of micro-organisms, the term bio-

2.1. The use o f soluble polymers in medicine

ad (c) Polymer bound drugs. The binding of drugs to macromolecules offers a

2.2. The use o f insoluble polymers in medicine

TABLE 1. Synthetic polymer biomaterials 2

(i) Rubbery polymeric biomaterlals Biomedical uses

In a number of the applications mentioned above, it is important that the

3. I N T E R A C T I O N S BETWEEN P O L Y M E R S AND E N Z Y M E S IN THE

3.1. The cell

D(~ , O = pinocytosis vesicle

Eucaryotic cells are divided intracellularly into distinct compartments called

3.1.1. The p l a s m a m e m b r a n e - In a simplified manner, the structure of the plasma

~I_ hydrophilic portion of

On cell surfaces there can be specific polysaccharides, glycoproteins, proteins

3 . 1 . 2 . L y s o s o m e s - Lysosomes~' 7s,~s are membrane delimited structures (organelles)

3.1.3. Endocytosis - Endocytosis is a general term 77 which describes processes by

~. p!asma membrane cell exterior

consequently lead to efficient pinocytic capture of specific macromolecules bearing

3.2. Interactions of soluble polymers with enzymes

TOPICAL F POLYMER----.ORAL ROUTE-

BARRIER FOR~ ~ BARRIER FOR

3.3. Interactions o f insoluble polymers with enzymes

4. BIODEGRADATION OF SYNTHETIC POLYMERS

4.1. Methods of testing of the biodegradation of biomedical polymers

(b) Synthesis of tailor-made polymers the structure of which satisfies conditions of

4.2. Biodegradation o f soluble polymers

B-512, of Leuconostoc mesenteroides produces a dextran with a minimum number

4.2.2. H y d r o x y e t h y l s t a r c h - Hydroxyethylstarch fliES) was suggested as a blood

4.2.3. G e l a t i n a n d its d e r i v a t i v e s - As already mentioned (cf. Section 2.1) there are

4.2.4. P o l y v i n y l p y r r o l i d o n e - Poly(1-vinyl-2-pyrrolidone) (PVP is a polymer

4.2.5. P o l y v i n y l a l c o h o l - Polyvinylalcohol (PVOH) is able to form complexes with

CH2 C OH + CH 3 C CH2 CH~X./"~

Watanabe 12° proposed another mechanism where the product of enzymolysis is

CH2 CH CH2 CH CH2,J'k~

PVOH is degraded by the enzyme mentioned above to small fragments, n7 Bio-

4.2.6. P o l y [ N - ( 2 - h y d r o x y p r o p y l ) m e t h a c r y l a m i d e ] - This polymer 121'122 has been

4.2.7. P o l y - a , ~ - [ N - ( 2 - h y d r o x y e t h y l ) - D , L - a s p a r t a m i d e ] - This polymer was pro-

4.2.8. Polyglycols - Polyethyleneglycols (PEG) or copolymers of ethylene glycol

4.2.9. Poly(2-vinylpyridine-l-oxide) - This polymer possesses a protective effect

4.2.10. Poly(a-amino acids) - Synthetic poly(a-amino acids) may be employed as

Using a lower concentration of trypsin, Katchalski et al. 16owere able to detect in

TABLE 2. Digestibility of poly(~-amino acids) by chymotrypsin ~61

Polymer of Digested (+) or pH Ref.

TADLE 3. Digestibility of polylysine by proteolytic enzymes~6~

Enzyme pH Digested (+) Majorproducts Ref.

4.3.2. Polyurethanes - In the living organism polyurethanes undergo rapid degra-

4.3.3. Natural rubber - Poly(cis-l,4-isoprene) is the main component of natural

Polymer Formula Physical properties

Poly(glycolic acid) Crystalline, tough, inelastic, T m = 230 °, T e = 36 °

Poly(D-lactic acid) O --- O Crystalline, tough, inelastic, T m = 180 °, T g = 67 °

Poly(D, L-ethylglycolic acid) Amorphous, rubbery, Te-~ 16 °

Poly(dimethylglycolic acid) Crystalline. tough, inelastic, T m = 240 °

Polymer Formula Physical properties

4.3.4. P o l y e s t e r s - Polyesters are one type of polymer that undergoes changes in

4.3.4.1. Poly(ot-hydroxy acids) - Poly(a-hydroxy acids) are a class of polyesters

4.3.4.1.2. Polymers and copolymers of other whydroxyacids. These (co)polymers

by N,N'-isophthaloyl-bis(phthalimide). 214 This polymer is resorbed in vivo within

4.3.4.2. Poly(e-caprolactone) - This compound is one of the polymers frequently

4.3.4.3. Polyethyleneterephthalate - When subjected to a long-term contact with

-- (NH-- CH - - COO- CH 2 - C H2 - OOC- CH - - NH - - CO - - NH- ( C H ; ~ ) 6 - - NH - - CO) 4 -