Biomaterials, Medical Devices, and Artificial Organs

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The New Generation of Biomedical Polymers

J. M. Anderson & D. F. Gibbons

To cite this article: J. M. Anderson & D. F. Gibbons (1974) The New Generation of Biomedical
Polymers, Biomaterials, Medical Devices, and Artificial Organs, 2:3, 235-248, DOI:
10.3109/10731197409118593

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 BIOMAT., MED. DEV., ART. ORG., 2(3), 235-248 (1974)

The New Generation of

Biomedical Polymers

J. M. ANDERSON, Ph.D.
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Department of Macromol ecular Science

and

D. F. GIBBONS, Ph.D., D.Sc.

Department of Biomedical Engineering
Case Western Reserve University
Cleveland, Ohio 44106

ABSTRACT

Following a review of the compatibility of polymer with blood,

the use of polyurethanes, hydrogels, polylactic acid, poly-o-
cyanoacrylates, and polyarnino acids as biomedical polymers
is discussed.

I. INTRODUCTION

A great many polymers have been evaluated for use as implants

during the past two decadeq. This paper makes no attempt to present
a comprehensive review of all of the data on these polymers, most of
which have met with limited success. Rather we present first a brief
review of the current understanding of the thrombogenic behavior of
polymers and, second, the status of a number of polymers which
presently show promise for the future.

235
Copynght 0 1975 by Marcel Dekker. Inc All Rights Reserved Neither this work nor an) part
may be reproduced or transmitted m any form or h) any means electronic or mechanical includine
photocopying. rnicrofllming and recording. or by any information storage and retrieval system.
nthout pcrmwion in writinp from the publlrher
 236 ANDERSON AND GIBBONS
11. C O M P A T I B I L I T Y O F P O L Y M E R S WITH B L O O D

In spite of the large number of papers published on this subject

over the past decade, the factors which influence the thrombogenicity
of materials and polymers in particular are still not clear. Factors
which have been invoked include surface charge (zeta potential) [l],
surface energy [2], hydrophilicity [ 31, and the ease with which
surface bonding can occur 143. The major objection to ali of these
concepts, with the exception of the last, is that they a r e average
macroscopic properties of a surface, whereas the interaction of
the surface with proteins or the platelet-plasma membrane occurs
at the molecular level.
It has been well established that, after a polymer has been
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exposed to whole blood or plasma for times -10 to 100 sec, the
surface is coated with a protein layer [5, 61. More recently it
has been shown that the kinetics of this protein adsorption at
polymer surfaces is sensitive to both the protein specie (71 and,
more importantly, small changes in polymer structure and/or
morphology.
The understanding of clot formation at implant surfaces is
further complicated by the fact that it is not yet established
whether the primary mechanism for initiation is via the intrin-
sic pathway and initiated by the activation of Factor XI1 or the
extrinsic pathway via platelets, or both. The preponderance of
evidence at the present time on hydrophobic polymers, such as
the polyurethanes, suggests that the extrinsic pathway is pre-
dominant [9].

111. POLYURETHANES

The polyurethanes a r e a class of polymers whose mechanical

properties can vary from rigid, tough polymers to elastomers,
depending upon the individual monomer. The rigid, tough poly-
urethanes [ 101 have been used extensively for fittings and the
casing around artificial hearts [ 111. By far the most extensive
applications of this class of polymer for medical use have been
the elastomeric group of segmented polyurethanes.
The segmented polyurethanes derive their properties by
blending the flexible properties of an aliphatic block, either
polyether (such as polypropylene glycol) or polyester, reacted
with the diieocyanate rigid block, such as methyl bis(4-phenyl
isocyanate), and the blocks coupled with multifunctional
 THE NEW GENERATION OF BIOMEDICAL POLYMERS 237
mines [ 121. Recent literature contains many articles on the surface
properties, blood, and cell compatibility of these polymers [a, 13-15].
The segmented polyurethane, first developed as a commercial
elastomer by Dupont, has been widely exploited for the manufacture
of tubing, catheters, etc. [ 111, and has been shown to have excellent
fatigue reeietance in a blood pump [ 161.
The blood compatibility of the eegmented polyurethane varies,
depending upon the nature of the block monomers and the molecular
weight of the blocks [?I. A number of the segmented polyurethanes
are being used for the ventricle of left heart assist devices [17],
total hearts [la], and a copolymer of polyurethane with an organo-
siloxane has also been used for interaortic balloon devices [ 151
with reasonable success. Depending upon the design of the artificial
ventricle and, in particular, the maximum strain during cycling, the
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segmented polyurethanes can have reasonable life times. Their

fatigue resistance, however, decreases rapidly as the maximum
strain during cycling increases.

IV. HYDROGELS

Water-polymer gels or hydrogels can be prepared from many

chemical substances, e.g., gelatin, polysaccharides, cross-linked
polyacrylamide polymers, polyelectrolyte complexes, and polymers
or copolymers derived from methacrylic esters containing at least
one hydroxyl group on the side chain. It is the later group of hydro-
gels, based primarily upon cross-linked polyglycol-methacrylates,
which a r e of major interest as a material suitable for medical
applications. They are of special interest also because they
represent the first polymers produced specifically to meet the
requirements for implantable prostheses [ 19, 201 rather than for
nonmedical technology. The reasoning behind their development
was to produce a polymeric network composed entirely of stable
C-C bonds, with side groups containing a high concentration of
hydroxyl groups which impart the strongly hydrophilic property
characteristic of the class.
Poly-2-hydroxyethyl methacrylate (PHEMA), cross-linked with
ethylene dimethacrylate or ethylene glycol dimethacrylate, is the
most widely explored example of this class and is widely known
by its trade name, Hydron. Some of the polymers and copolymers
which have been prepared from other methacrylate esters (21, 221
a r e listed in Table 1.
From the viewpoint of the properties of the final polymer for
medical applications, the important aspect of the methacrylate
 238 ANDERSON AND GIBBONS

TABLE 1
Ra

CHz CHzOH

CHzCHzOCHs

CHz CHzOCH z CHZCH3

CHz CH z OCH z CH SOH

CH z CH z CHI
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esters is the ease with which the combination of cross-linking and

solution polymerization occurs. Dependent upon the solvent con-
centration during polymerization, these hydrogels can take up to
35 to SO% by weight of water, thus producing a wide range of
mechanical properties. If, however, they are polymerized in
aqueous solutions, the polymer is precipitated during polymeri-
zation and forms a microporous sponge. The micropore size is
capable of being varied with ease over a very wide range (-0 to
1 mm). The effect of monomerb), cross-linking agent, degree of
cross-linking, and water concentration on the mechanical and
physical properties has been studied extensively [21, 23-26].
Mechanically the swelled hydrogels a r e weak and a number of
techniques have been developed to take advantage of their unique
hydrophilic properties by reinforcing with fibers and cloth or,
more importantly, by grafting as a surface layer onto a mechan-
ically stronger substrate. The methacrylic esters have been
successfully radiation grafted onto silastic [ 27, 281, polypropy-
lene [28], and polyurethane [29].
Initial cell culture studies 1301 and subcutaneous or intra-
peritoneal implants [31] have indicated that the neutral P H E W
 THE NEW GENERATION OF BIOMEDICAL POLYMERS 239

as a gel or sponge produced no pathologic reaction in rats. The

effect of introducing functional side groups which produce either
acidic or basic character to the gel has been investigated 1321. It
was demonstrated that side groups which imparted basic character
elicited chronic pathologic reactions. In the case of the neutral
sponge hydrogels, more recent data [33, 341 obtained from sub-
cutaneouc implants in pigs has shown that a pathogenic response
wae elicited and the implants became infiltrated with bone. In rats,
similar sponge implants were demonstrated to show ossification.
The evidence suggests, therefore, that caution should be used in
considering the microporous sponges as implants. Some indica-
tions that mammary augmentation on humans with PHEMA sponge
are starting to show radio-opaque shadows have been reported [34].
The thrombosis resistance of the methacrylic hydrogels has
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been studied by many groups [35, 361 and the evidence appears to
demonetrate that they a r e remarkably antithrombogenic and can
be considered as a suitable material for interfacing with the
cardiovascular system.
In spite of their relatively poor mechanical properties, a wide
variety of applications has been explored. Some of the earliest
applications were in reconstructive and plastic surgery [37, 381
where strength is not required but matching the resilience of
natural soft tissue is of primary importance. The methacrylic
hydrogels have attracted the greatest attention in opthalmology,
especially as a material for "soft" contact lenses suitable for
both the correction of ametropias and dispensing drug therapy
[38 J PHEMA has also been evaluated as a coating for sutures
[40] and for the fabrication of a wide variety of catheters and
medical tubing [41]. The ability to graft onto mechanically stronger
substrates has expanded their range of potential application to the
artificial kidney and heart.
Because of their high swelling and permeability characteristics,
the methacrylic ester polymer and copolymers a r e being extensively
evaluated as carriers for drug-release therapy [35, 421.

V. P O L Y L A C T I C ACID

Of the many polymeric materials currently being investigated

for potential use in vascular prostheses, the polylactic acid type
of polymers occupies a unique category as determined by their
in vivo biodegradability. Also included in this category are the
polyamino acids which will be discussed later. This biodegradable
 240 ANDERSON AND GIBBONS

property allows these polymers to serve a supportive role, degrade

to nontoxic products which may be excreted or metabolized, and be
replaced by the body's own contiguous tissues.
The product of polylactic acid biodegradation is lactic acid, a
normal intermediate in carbohydrate metabolism and the end
product of the anaerobic metabolism of glucose or glycogen.
Lactic acid can be converted to glucose or oxidized through
pyruvic acid to carbon dioxide and water. This latter pathway
to carbon dioxide end products is suggested by radioactive implant
studies which show that the major fraction of radioactivity is lost
via respiration.
Polylactic acids are synthesized by the catalyzed ring-opening
condensation of the appropriate lactides. As the monomeric lactide
has an asymmetric carbon atom, two nonsuperimposable molecules
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or enantiomers are available for polymerization. Kulkarni and

co-workers [43] prepared two types of polylactic acids, the dl
form in which both enantiomers are present and the L(+)form in
which only one of the enantiomers is present, and examined in
detail their respective properties. In general, the L(+)polymer
displays a higher crystallinity, higher melting point, more brittle
mechanical behavior, and a lesser tendency to shrink when in fiber
form than does the dl polymer. This data correlates well with the
decreased susceptibility to in vitro degradation by the L(+)polymer
as compared to the dl polymer. The polymer properties listed
above enable these materials to be extruded into rods and melt
spun into fibers as well as cast into films.
Histopathological examination of implanted poly- L(+)-lactic
acid samples shows that these materials disappear from the
implant site at a rate of 5 to 10% per month with only the mildest
and most transient of inflammatory responses [44]. Detailed
studies of the in vivo degradation phenomena, using carbon- 14-
labeled poly-dl-lactic acid implant samples, show that the major
route of elimination of radioactivity was via respiration, and less
than 1.0% of the radioactivity was found in liver, lung, or kidney
[45]. In addition, resorption rates from this study indicate that
the in vivo degradation is not as rapid as previously suggested
as =-of the implant remained after 168 days. Scanning
electron microscopic examination of implanted poly-dl-lactic
acid samples suggests that the early loss of mechanical properties
prior to the loss of material via degradation is due to wetting and
plasticization of the implant [46].
Ruderman et al. [47] have developed and preliminarily examined
in dog studies a partially biodegradable vascular prosthesis using
poly-dl-lactic acid. The device was a woven cylinder 5 to 6 cm in
 THE NEW GENERATION OF BIOMEDICAL POLYMERS 24 1

length, 8 mm I.D., and 0.14 mm wall thickness, with a final composi-

tion of 24% poly-dl-lactic acid and 76% Dacron by weight. Canine
abdominal aorta was the site of implantation and, after 100 days, all
grafts were patent with no evidence of inflammation or calcification.
Small mural thrombi were noted as well as a very thin, well adherent
pseudoendothelium and extensive tissue ingrowth and adherence of
external tissue. In addition, the estimated loss of the polylactic
acid component was 60 to 100%.
While many studies have dealt with the various physical, chemical,
mechanical, and in vlvo degradation properties of the polylactic acids
and have pointed out the desirability of using these materials in cer-
tain instances, the work by Ruderman et al. marks a new step toward
the clinical use of these materials in the vascular system.
Polyglycolic acid varies only slightly from polylactic acid in its
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chemical composition and displays similar properties to those found

for the polylactic acids. An excellent review article by Frazza and
Schmitt [48] deals with the physical and mechanical properties and
the implant behavior of polyglycolic acid as a biodegradable suture
material. Polyglycolic acid, in a single or bicomponent fabric, ha6
also been suggested for use as an arterial prosthesis [49].
In addition to vascular prostheses, polylactic acid and polyglycolic
acid materials have also been examined for use as artificial Bkln
[50], absorbable intermedullary rods, absorbable bone plate wlth
absorbable pins f49,511, and sustained drug-release systems [52].
Variability in the rate of biodegradation of the polylactic acid
polymers has been observed [44, 47, 511. This variation or lack
of control of the rate of biodegradation is probably due, in great
put, to the crystallinity and morphology of the implanted polymer.
Them properties, in turn, m a y be determined by the processing
conditions or methodology (fiber drawing and orientation, extrusion
and annealing conditions, etc.).
As discussed earlier, the chemical composition of the polymer
[dl or L(+)]may alm function to provide variability in the rate of
biodegradation. In addition, as evidence points toward a base-
catalyzed mechanism of biodegradation, the alkaline milieu at
the implant site must also be considered. Efforts are currently
underway to develop a class of polylactic-glycolic acid copolymers
with a broad range of physical and mechanical properties as well
as providing control over the rate of biodegradation.

VI. POLY-a- CYANOACRYLATES

The research and development of a-cyanoacrylates as bio-

medical polymers has been mainly directed toward their use as
 242 ANDERSON AND GIBBONS
a tissue adhesive to control hemostasis. In addition to the usual
characteristics commonly listed for biomedical polymers, the
a-cyanoacrylates offer additional advantages because they are
capable of 1) polymerizing rapidly in vivo, 2) wetting and spread-
ing on the tissue substrate, 3) forming a flexible firm which coats
the tissue substrate, and 4 ) biodegradation in vivo (531. The
a-cyanoacrylates a r e 2-cyanoacrylic acid esters with the ester
group on the side chain carboxyl groups providing variable in vivo
polymerization time, variable wetting and spreadability of the
tissue substrate, and variable rates of i n vivo degradation.
Using human blood, plasma, and serum, Leonard and co-worker8
I543 have shown that the 2-cyanoacrylate ester spreadability in-
crea8es and the in vitro polymerization time decreases as the
ester group is increased in size from methyl to n-octyl. The
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polymerization time on blood for the n-octyl ester is of the order

of 4 sec and has been described as being instantaneous, while under
the same conditions the methyl ester takes more than 300 sec to
polymerize. Bond strengths of tissue wounds closed with the
various 2-cyanoacrylate esters were found to increase as the
ester group increased in size.
Studies with carbon- 14-labeled 2-cyanoacrylate esters (54-561
indicate that in vitro and in vivo rates of degradation are analogous
and decrease as the size of the ester group increases. Labeling
studies further suggest that the mechanism of biodegradation is
via chain scission with formaldehyde being a degradation product.
Thus the observed histotoxicity of methyl 2-cyanoacrylate [ 571
can be explained by the rapid degradation of the methyl derivative
to formformaldehyde. Milder inflammatory responses with less
tissue necrosis are seen with the higher ester homologs, and this
correlates well with their slower rates of degradation. It would
appear that the slower degrading 2-cyanoacrylate esters, i.e.,
those with the longer ester groups, present lesser amounts of
toxic degradation products which can be more easily tolerated
and metabolized by the tissues over a given time interval. In an
effort to elucidate the in vivo biocompatibility of degrading n-butyl
2-cyanoacrylate polymer, liver function tests in dogs were moni-
tored for 6 months following implantation [ 581. The liver function
tests examined were S O T , SGPT, LDH, ICDH,BSP uptake, bilirubin,
prothrombin time, and partial thromboplastin time. Results from
these studies over the 6-month interval were within the reported
normal range values for these tests.
Matsumoto has published a review describing the various uses
and results of surgical applications of the cyanoacrylate monomers
[59]. Animal studies were carried out and involved the hemostasis
 THE NEW GENERATION OF BIOMEDICAL POLYMERS 243

and repair of hepatic and renal wounds, the sealing of resected lungs,
the reinforcement of vascular and intestinal anastomoses, m d the
closure of perforated intestine. Of much greater importance is the
report in this review of the successful use of the cyanoacrylate
tissue adhesive for hemostasis for otherwise fatal hemorrhage in
29 patients with mortal injuries to the liver, kidney, major arteries,
o r retroperitoneal space. A 5 to 19 month follow-up of seven
patients revealed no evidence of untoward sequela.
While a vast amount of work has gone into the research and
development of the a-cyanoacrylates as tissue adhesives, it
appears that these materials may never reach their full potential
in the clinical setting because the Federal Drug and Food Admin-
istration has suspended their use and, subsequently, their further
development. It would seem that the suspension is based on the
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poor qualities of the methyl a-cyanoacrylate and that little credance

is given the higher awl a-cyanoacrylates. Whatever the case,
further clinical evaluation of the a-cyanoacrylates is warranted,
based on the preliminary evidence presented earlier.

VII. POLYAMINO ACIDS

Poly-a-amino acids, polymers composed of a-amino acids which

a r e common to the body, a r e being investigated for their potential
as biomedical polymers. Uses that have already been suggested
for these polymers include hemodialysis membranes, biodegradable
sutures, artificial skin substitutes, and sustained-release devices.
This list of potential applications is increasing as studies continue
to show new and varied properties for this broad class of polymers.
The majority of materials investigaged to date are random copoly-
mers composed of two components, one of which usually provides
the desired property for the given application. In addition, variation
in composition in any given two-component system appears to alter
considerably the property under consideration.
As in the case of the lactic acid polymers, the respective a-amino
acids contain an asymmetric carbon which gives rise to two e m t i o -
meric forms, L and D, for each amino acid. The a-amino acids
found in the body a r e of the L form and one might expect the D forms
to be resistant to the enzymic hydrolyses commonly associated with
the Lpolypeptides and proteins. Whatever the case, this offers
another means by which to control behavior, particularly the
host responses to these polymers [60].
Unusual membrane characteristics have been reported for
DLmethionine- Gleucine copolymers and suggest their potential
 244 ANDERSON AND GIBBONS

use in blood oxygenators and artificial kidneys [61]. By controlled

oxidation of the methionine side chain, variable hydrophilicities
and water vapor transmission rates can be developed. Also,
increasing the percent composition of D G methionine increases
the carbon dioxide-oxygen separation factor. Using a similar
class of polymers, DGmethionine-DGleucine copolymers, the
extent of methionine oxidation appeared to control the transport
of sodium chloride, urea, creatinine, uric acid, and bacitracin
[ S Z ] . Thus transport properties in this copolymer system could
be varied by 1) variation in the extent of side chain polarity (the
percent composition of methionine), and 2) variation in the
copolymer hydrophilicity (extent of methionine side chain
oxidation).
Polypeptide nylon-velour laminates have been examined as
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artificial akin grafts and were reported to serve well as a frame-

work for fibroblastic proliferation with adherence [MI. The
polypeptide laminates allowed escape of infectious exudate and
delayed separation from the wound bed. Three clinical cases
have been presented showing the successful temporary use of
polypeptide laminates as wound coverings prior to autogenous
grafting [64]. The polypeptide laminate "take" rates were com-
parable with those observed for autografts, and the laminates
appeared to retard fluid, electrolyte, and protein loss.
Sutures of poly-L-glutamic acid, in which the surfaces were
partially esterified, have been examined [65]. Increasing the
percent esterification decreases the rate of biodegradation of
these materials. The absorption time, durability, and tensile
properties of these sutures can be controlled by varying the
degree of esterification and predrawing the fibers prior to the
eeterification treatment.
Dohiman and co-workers have investigated the use of hydro-
cortisone-impregnated polypeptide as a sustained-release system
for the suppression of corneal xenograft inflammatory reactions
.
in rabbits [SS] These devices a r e being developed and produced
by the ALZA Corp., Pa10 Alto, California.
A series of y-benzyl-Lglutamate- Gleucine copolymers have
been investigated by Anderson and co-workers [SO, 671 for poten-
tial biomedical applications. Extensive treatment by paeudo-
extracellular fluids and enzymes, pronase and papain, showed
that theee polymers undergo very little in vitro degradation over
prolonged periods. Theae results were substantiated by tensile
experiments on implanted samples [00]. Histological examination
of tissue following implantation of these polymers in rats showed
very mild reactions with a thin, translucent fibrous capsule
 THE NEW GENERATION OF BIOMEDICAL POLYMERS 245

surrounding the implant. Thromboresistance studies of the r-benzyl-

L-glutamate- Gleucine copolymers were most encouraging. In
general, as the percent composition of benzyl glutamate is increased,
the thromboresistance increases [68]. Biodegradable a-amino acid
copolymers have been developed in which the rate of biodegradation
can be controlled by varying the percent composition of glutamic
acid residues in the copolymer [60]. Efforts directed tolrrsrd the
development of degradable and nondegradable a-amino copolymers
is currently underway, and these materials appear to be quite
promising in view of their wide range of physical, mechanical,
and histological properties [go].

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Received by editor M a y 4, 1974