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Biostability of medical elastomers: a review
Biostabilityof mediwl elastomers:a revievif P. Vondr&Eek Department
of Polymers,
Institute
of Chemical
Technology,
166 28 Prague 6, Czechoslovakia
B. Doleiel A. G. Akimov’s (Received
National
30 May
1983;
Research revised
Institute 7 July
for Protectron of Materials
and Corrosion, 250
97 Prague 9, Czechoslovakia
1983)
Biostability of synthetic elastomers used for manufacturing artificial replacements of human organs or their parts is a critical property of such materials as it determines the long-term function of a specific biomedical device This paper presents a critical review of the present knowledge of biostability of elastomeric biomedical materials used as artifacts functioning under the simultaneous
effects of dynamic flexing and contact with body fluids. The main
topics discussed are silicone rubber, elastomers for artificial blood pumps, and the methodology of model fatiguelife testing. Keywords: Polvmers, elastomers, rubber, flex-life tasting
implant
material,
biostabilitv,
The medical application of synthetic polymers has grown steadily over the past two decades and polymers are more and more used as permanent implants. This has been documented by the unique Implant Retrieval and Evaluation Programme performed at Case Western Reserve University in Cleveland’. This programme has provided the statistics of the implant presence in 4182 autopsies performed over the period 1972-80. These results have shown the exponential growth of polymer implant usage. In 1980 37% of the autopsies yielded implants, in contrast with only 9-l 6% yield in the period 1972-76. The most frequently used polymers found in the autopsies involved high density polyethylene, poly(methyl methacvlate), silicone rubber, polyester, polytetrafluoroethylene and poly(vinyl chloride). They represent the polymeric implantable materials used in the USA before 1980. Silicone rubber has been the most frequently used elastomer for biomedical purposes until now. Newer materials currently being evaluated for use in humans include the elastomeric segmented polyether urethanes and the polyolefinic elastomer Hexsyn. These elastomers are extensively studied as candidates for fabrication of various heart assist devices and total replacements. Obviously the elastomeric materials represent an important group of implantable polymers predominantly used in applications in which the elastic properties are required. Any polymeric material must meet many criteria in order to be able to fulfil successfully the permanent function of the elastomeric implant The criteria arise from real conditions of the specific implant application. One of *Paper presented at the conference ‘Polymers &no, Czechoslovakia. 20-22 October 1982. 0
1984
Butterworth
& Co (Publishers)
in Medicine’,
held in
silicone rubber, segmented
polyurethanes,
polyolefin
these criteria is the stability of implant properties during long-term contact with the biological environment, so called biostability. There is no doubt that the biostability is a critical property in many medical applications. Despite this, only a few, sometimes contradictory, data can be found in the literature. When testing the stability of any biomedical material one must start from the specific application conditions. Elastomers, being used for their elastic properties as replacements of elastic elements of the human body, are frequently subjected to dynamic deformation when simulating a physiological function of the original organ. Testing the biostabilityin vitro is a very complicated experimental task the most difficult part of which is the precise modelling of material exploitation under the conditions of the specific medical application. This is especially true with elastomeric implants subjected to flexing or other repeated deformations during their function in the human body, such as cardiac valves, heart assist devices, total artificial hearts, pacemaker lead insulations or finger joint endoprostheses. One must interpret and use literary data on elastomer biostability very carefully for assessment of their stability in other applications.
BIOSTABILITY Static
OF SILICONE
implantation
of silicone
RUBBER rubber
Measuring the effect of static implantation on the physical properties of silicone rubber has proved that this elastomer is very stable in contact with body fluids over a period of up to 2 yearsze5 (see Tab/e 7). This means that silicone rubber implants retain their physical properties for
Ltd. 0142-9612/84/050209-06$03.00 Biomaterials
1984,
Vol 5 July
209
Biostebility
of elastomers:
P. Vondr&ek
and 8. Dolefel
Table 7 Change in mechanical properties of silicone rubber during static subcutaneous or intramuscular implantation in dogs Implantation period (months)
Change in tensile strength
Change in elongation
1%)
W)
17
-
2.1
6 24
-
6.4 8.0
12
-
6.5
+ 11.3 -
Source
Leininger et aL2 Swanson,
-
8.4 15
LeBeau3
-
14
Roggendorf4
a long time (years) practically unchanged in static applications, in which the implant is not subjected to repeated mechanical flexing, such as soft tissue replacements for plastic surgery, implants for ophthalmology and oto laryngology, hydrocephalic shunts etc.
Silicone
rubber heart valves
A quite different situation has been found in silicone rubber used as poppets in the Starr-Edwards (ball in cage) heart valve prosthesis. The heart valve poppet is subjected to a drastic cyclic long-term fatigue. It alternatively hits the valve cage and the orifice about 80 million times a year. A percentage of the implanted heartvalve poppets has been reported to fail. The failure is accompanied by the degradation of physical properties, and is generally believed to be induced by the absorption of blood lipids into the silicon impIan?-‘. Analysing the retrieved silicone rubber heart valve poppets, different authors reported experimental data showing a linear increase of lipid uptake with time of implantatior?, as shown in Figure 7. The weight gain, due to lipid absorption, of the retrieved poppets is as much as 17% of the original weight after 50 months of implantationg. Even higher lipid uptake has been reported”. All experimental data compiled from references6*8*g in Figure 1 were obtained by a Soxhlet extraction with chlorofor~methanol(2:l) solvent mixture and were corrected for the extracted uncured silicone rubber. Clinically used retrieved heart valve poppets implanted both in mitral and aortic position for time periods from 2-60 d were used, with the exception of data from reference 6 obtained with mitral positioned heart valve poppets only. Each
Figure I Weightgain or absorbed lipid content as a function of in viva implantation time. l weight gain in subcutaneous implantss, A lipidcontent in fingerjoint implants”, A lipid content in mitral’heart valve poppets6, 0 lipid content in heart valve poppets’, 0 lipid content in heart valve poppetsg.
210
Biomateriels
1984,
Vol5
July
experimental point is based on analysis of one heart valve ball. It is interesting that only a small percentage of the heart valves failed in their function due to dimensional changes or mechanical failure of the ball. This so called ‘ball variance’ is characterized by an increased level of absorbed blood lipids which, according to most authors, represents an important factor leading to silicone rubber degradation. This points to the specific influence of characteristic haemodynamic conditions and blood composition of each patient. A percentage of variant silicone rubber balls differs even according to the anatomical site of an application. Recently, approximately 1.5% of aortic’ball in cage’ heart valves have been reported to fail, whereas in the mitral valve replacement only 0.05% variant balls have been found”. This corresponds with experimental data of Carmen and Mutha7 who found higher lipid uptake in variant aortic valve poppets than in the mitral ones (see Figure 7 from reference7). Absorption of lipids seems to be an important prerequisite for structural changes in silicone rubber; however it cannot cause the failure by itself. The lipid absorption into silicone rubber implanted under static conditions, e.g. subcutaneously or intramuscularly, does not result in changes such as one can find in heart valve poppets3. It seems from the data of Carmen and Mutha7 that simple lipid absorption (cholesterol esters, cholesterol, triglycerides, free fatty acids) in the retrieved heart valve balls reaches an equilibrium lipid content of about 1.5% by wt. within the relatively short time of about 10 months. Beyond this level a complex, relatively polar, material is absorbed, probably originated from the oxidation of lipids absorbed into silicone rubber. This has been proved by in vitro experiments7f ‘. In the case of silicone rubber degradation no equilibrium total lipid content should be expected. The maximum total lipid content reported is not higher than 41% by wt in an unspecified poppet sample after 37 months of implantationg. The lipid absorption into principally static (subcutaneous) implants results in the equilibrium lipid content (based on weight gain data) not exceeding 1% by wt3, as shown in Figure 1. The data from reference 3 were obtained from subcutaneously implanted, medical grade, silicone rubber samples in beagle dogs. It has been suggested in this work that, in the case of subcutaneous implantation, no extractable silicone polymer leaches from the implant, and the rubber is not being degraded to extractable silicone polymers during implantation. This can be related to the fact that, in the subcutaneous environment, the implants are not in contact with circulating blood in which a much higherconcentration of oxygen is available for lipid oxidation. Therefore, predominantly simple lipid absorption in such implants can be expected. A similar situation was found, by a lipid content analysis, in the retrieved silicone rubber finger joint prostheses”, where the lipid content also did not exceed 1% by wt within 36 months of implantation. Finger joint prostheses are not in contact with circulating blood and undergo occasional flexing. These experimental findings correlate well with equilibrium simple lipid absorption data found in heart valve balls7. This points to the fact that, the lipid oxidation found in implants in contact with circulating blood for long periods of time cannot proceed in the subcutaneous or intraosteal environment where a much lower concentra-
Biostability
of elastomers:
P
Vond&ek
and B. Dole;el
tion of oxygen is available for such oxidation. The absorbed lipid oxidation seems to be responsible for a much higher total lipid content in implants in contact with the blood stream. Therefore, predominantly simple lipid absorption can be expected in subcutaneous or similar environments with relatively low oxygen concentrations. The long-term continual flexing of silicone rubber swollen with lipids in the oxidative environment of the specifically altered blood therefore seems to be an important aspect of biodegradation of silicone rubber implants in the blood stream. The alteration of mechanical properties of elastomeric implants in the cardiovascular system results probably from simultaneous action of many factors, the most important of which seem to be: absorption of blood lipids and their oxidation products; calcification”; haemodynamic conditions; dynamic fatigue; enzymatic attack; individual influence of the implant bearer.
Silicone
rubber pacemaker
lead insulations
The other application, demanding a good flex-life and stability of silicone rubber working in the cardiovascular system, is the insulation of cardiac pacemaker leads. A systematic research of biostability of polyethylene and silicone rubber insulations is being carried out in Czechoslovakia with the co-operation of medical, engineering and polymer science institutions. The preliminary results of testing mechanical properties of the retrieved pacemaker lead insulations have shown that the tensile strength and elongation of polyethylene and silicone rubber tubing decrease with the exposition time13. A decrease to about 30% of the original value of the tensile strength of the silicone rubber tubing after 1 1 years of implantation has been reported. The modulus at 200% elongation of silicone rubber, which is a measure of the crosslink density, slowly increases in the initial period of implantation and drastically decreases after about 1 year of exposition (up to 50% of its original value after 11 years implantation). The change in crosslink density with implantation time, determined by the equilibrium swelling in toluene of the retrieved insulations, has provedI that the modulus (or stiffness) change of silicone rubber results from the decrease in the concentration of elastically effective crosslinks in rubber. It has also been found that the extractable fraction (sol) obtained by toluene swelling from the retrieved clinically used pacemaker lead insulation implanted for time periods from 7 to 4000 d increases linearly with implantation times’4. It is questionable whether the extractable sol consists of the absorbed lipids or predominantly of low-molecular weight polysiloxanes due to some degradation of the crosslinked silicone rubber matrix. This question seems to be indirectly answered by the experimental finding that the increase in sol fraction is accompanied by the decrease of crosslink density from equilibrium toluene swelling, as shown in Figure 2. Biolsi et al.“, however, did not find any linear polysiloxanes in heart valve poppets after an extended implantation period (58 months) by unspecified extraction/ spectroscopic techniques. These poppets were reported to have about 20% of solvent extractables and they
sl >Z
w
.20
J 0
5
15
IO
EXTRACTABLE
SOL
20
1%)
Figure 2 Volume fraction ofsilrcone rubberin the equihbnum swollen state (swollen in toluene) as a function of the sol fraction extracted by toluene ,n pacemaker lead Insulations retneved at various ,mplantation periods’4.
contained several per cent of unreacted linear polymer before body exposure. Therefore, one can assume that the low-molecular polysiloxanes originally present, and those which are generated from the silicone rubber network by some degradation processes, most probably based on hydrolytic decomposition (see the following paragraph), are washed out by blood lipids absorbing into the material. This situation is quite different from that found in implants positioned in body sites where they are not in contact with circulating blood. It can be stated that silicone rubber in applications where it is exposed to the permanent flexing while in contact with circulating blood will suffer a change of its structure and properties, like polyethylene~3. This change is especially significant in implantation periods longer than 1 year. However, the deterioration of mechanical properties of silicone rubber pacemaker lead insulations is not critical from the point of view of its functional reliability, since the implantation will not generally exceed a period of 15-20 years.
Hydrolytic
stability
of silicone
rubbers in model studies
Ward and Perry” have recently published results of their relatively short-term model study of silicone rubber stability in a simulated extracellular fluid. They conclude that some, not specified, structural changes occurred in silicone rubber manifesting themselves through the altered dynamic properties. Ward and Perry found the storage modulus G’ of silicone rubber to increase with immersion time in the pseudo-extracellular fluid within a relatively short time (approximately 15% increase in 6 weeks of immersion). This finding seems to have some relationship with the modulus increase found in pacemaker lead insulations in the initial period of impiantation13. The dynamic logarithmic decrement of silicone rubber immersed in the pseudo-extracellular fluid or distilled water at 37°C was found to decrease by approximately 25% after 4 months of immersion. Evidence has been put forward for slow hydrolytic
Biomaterials
1984,
Vol 5 July
211
Biostability
of elastomers:
I? Vond&ek
and B. Dolesel
decomposition of very lightly crosslinked polydimethyl siloxane16 under relatively mild conditions, When a previously extracted sample of lightly crosslinked unfilled silicone rubber was stored under laboratory conditions, a considerable amount of approximately 1% of soluble material was generated in 300 h. This process was accelerated somewhat at higher temperatures and strongly by the presence of ammonia vapours (4% of new soluble fraction after400 h in NH, vapours at 25°C). As it did not appear to take place under dry conditions, it was attributed to a hydrolytic decomposition catalysed by ammonia. It should be noted that this tendency was greatly reduced with the crosslinked vinyl-containing silicone polymer and with increasing crosslink density. Nearly all silicone rubber used in medicine and surgery contains a substantial portion of a silica filler and is highly crosslinked. Therefore, it is possible that the tendency to a hydrolytic decomposition is suppressed in commercial formulations of silicone rubber and can manifest itself only after a very long time of contact with the biological environment To prove or refuse this hypothesis, one would need to study a change in properties of a strictly defined material during implantation for more than 5 years.
siloxane rubber (Silastic 372 or Silastic MDX 4-4515) used originally for manufacturing finger joint implants with the additionally cured vinyl-terminated polydimethyl siloxane (Silastic MDX 4-4210) which possesses substantially improved tear resistance”. The latter silicone rubber is cured by reacting its vinyl-terminated groups with a silane-terminated polysiloxane using a chloroplatinic acid catalyst. The improved tear propagation characteristics are important in implants which are expected to flex and bear stress in contact with bones which may produce small defects in the implant surface. Clinical follow-up of a group of 496 patients with the improved finger joint implants has shown 13% with clinical complications but only 1.9% of implant fractures after 22 months”. Recently, a new type of finger joint prostheses has been introduced by Lord Corporation which consists of titanium alloy stems sized to fit the medullary cavity of the phalange or metacarpal and connected with the polyolefin elastomer flexible elemen?‘. The elastomeric member is made of Bion, a synthetic polyolefin elastomeP3 with an exceptional flex-life.
Silicone rubber inclusions in haemodialysis
Segmented
Evidence of the deteriorating effect of combining dynamic flexing and blood contact on properties of silicone rubber has been recently published by various authors, reporting a deposition of microscopic inclusions of silicone rubber in parenchymatic organs of long-term haemodialysis patients. For example, Leohapand et al.” have found particles of silicone rubber in 37% of the group of 78 longterm haemodialysis patients. The refractile particles of silicone rubber” have been most frequently found histologically in liver and spleen”,‘*. The probability of the occurrence of such particles, which apparently is not an important cause of chronic liver disease”, depends on the duration of maintenance haemodialysis. Their accumulation seem to be a stochastic process”. Apparently, the source of the silicone rubber inclusions is the inner wall of silicone rubber tubing exposed to flexing in contact with blood in peristaltic roller pumps used for dialysis. The inclusions were found to be identical with particles of silicone tubing exposed to roller pumps’*.
Attention has been recently focused on methodology of fatigue-life testing of elastomers working in a biological environment in connection with a selection of materials for constructing various cardiac assist systems and artificial blood pumps. The highest attention has been paid to segmented polyether urethanes (e.g. Biomer, Pellethane, Tecoflex, Avcothane), promising the best balance of performance characteristics such as blood compatibility, suitable manufacturing properties, and mechanical durability. Biostability of segmented polyether urethanes in vivo has been proved, e.g. by testing mechanical properties of Biomer used as blood sacks for the left ventricular assist device and total artificial heart after 2-3 months of functioning in calve.sz4. No statistically significant reduction in tensile strength or flexibility after this period of use in the biological environment has been found. There seems to be no obvious degradation due to exposure to blood, gas or vacuum during relatively shortterm experiments. Even though survival times of some artificial blood pumps have exceeded 10 months we may have reached the mechanical limit of the segmented polyether urethanes. Bucher125 recently reported that 70% of 10 consecutive totally artificial heart terminations with survival over two months were related to pump material failure. It seems that long-term (greater than 2 years) reliability of blood pumps will probably have to wait for another generation of biocompatible polymers26. There are also known cases of polyurethane pacemaker lead insulations failing in long-term service due to hydrolytic degradation2’.
Finger joint implants Despite the tendency to a hydrolytic decomposition and deterioration by flexing in contact with blood, silicone rubber is still one of the best polymeric materials for longterm implantations. One of its successful applications is to the replacement of finger joints where its durability and stability has been of great concern. In contrast to heart valve poppets the lipid absorption does not seem to affect significantly the flex-life of finger joint endoprostheses”. A reliable finger joint endoprosthesis should withhold 10 million flex cycles by approximately 90”‘. Results of model in vitro experiments on the Swanson-type of finger joint replacements have proved that silicone rubber endoprostheses fulfil this requirement’s-2’. For example, Czechoslovak finger joint implants produced by Rubena showed a flex-life of more than 50 million flex cycles by 83” in the simulated plasma at 37°C”. In 1975, Dow Corning replaced the peroxide cured polydimethyl
212
Biomaterials
1984,
Vol 5 July
BIOSTABILITY
Polyolefin
OF ELASTOMERS
FOR BLOOD PUMPS
polyurethanes
rubber
Lately, a new type of biomedical elastomer has been introduced, which seems to be a promising one for constructing heart blood pumps. The rubber, originally called Hexsyn by Goodyear, now renamed Bion by Lord
Biostabilitv
Corporation, is a synthetic polyolefin elastomeP3. The polymer backbone is a straight chain saturated hydrocarbon (like polyethylene) resistant to oxidation and ozonization, bearing olefinic pendants of 4-5 carbon atoms on every second carbon of the backbone. Some of the side substituents contain unsaturated double bonds through which sulphur cure can be accomplished. Hexsyn is produced by a copolymerization of 1 -hexene with a mixture of 4-methyl-1,4-hxadiene and 5-methyl-l, 4hexadiene23. When compounded and cured the rubber produces a low-modulus, soft-vulcanizate with exceptional fatigue properties. The flex-life of Hexsyn measured by ASTM D 430 De Mattia test is better than 300 million flex cycles2’* 28. In clinical applications, this material is prepared with a porous surface to which is attached a blood compatible gelatinous Iaye&*.
Model flex-life testing Various model testing experiments of fatigue or flex-life provide different results for different materials. For example, the De Mattia test method, commonly used in the rubber industry, will indicate Hexsyn as the most durable material in flexing (more than 300 million cycles). Segmented polyurethane Biomer will show its flex-life reduced by an order of magnitude (18 million cycles), while silicone rubber will have the flex-life reduced by two orders of magnitude (0.8 million cycles)22~28. On the contrary, silicone rubber shows a value for flexural fatigue-life comparable with polyurethanes when tested in cyclic tension (approximately 10 million cycles at 100% elongation)2s. The life-time of Hexsyn in uniaxial creep has been found to be considerably lower than that of segmented polyurethanes (Biomer, Avcothane)30. One must be very careful therefore in interpreting fatigue data for different polymeric materials obtained by different testing methods. The following example shows clearly how one can obtain misleading conclusions by testing the fatigue durability of elastomeric materials in an unsuitable way. Szycher et d3’ have chosen a bending flex method, working at -40°C for screening evaluation of flexure endurance of the candidate materials for use in blood pumps. The results obtained by the accelerated testing of flexural fatigue-life at cryogenic temperature cannot be universally extrapolated to the temperature of application (i.e. body temperature) for different materials with various Tg values. The repeated studys2, this time performed at 39°C in the diaphragm and bladder configuration testing modes in saline, have provided quite different conclusions as to the flex endurance of the considered candidate materials. The latter work has resuited in fiexural survival probability functions for 7 candidate materials tested. This seems to be currently the best published guidance for selection of elastomeric materials for manufacturing artificial heart pumps and assist devices from the point of view of their respective flexural durability. Segmented polyurethanes (Pellethane. Biometj and polyolefinic rubber (Hexsyn) have been indicated here as suitable materials for constructing the systems, the flexural endurance of which is a critical, lifesaving or life-threatening property.
f? Vond&ek
and B. Dolesel
chemical structure of the elastomer used, but also on the application conditions. The same material can show different biostability characteristics and life-time in different applications. The evaluation of silicone rubber behaviour in dynamic applications (heart valve poppets, pacemaker lead insulation, haemodialysis roller pump tubing) in contact with circulating blood shows much higher variance in properties than in subcutaneous, intramuscular or intraosteal silicone rubber implants. This is probably related to the different oxygen concentration at various body sites, and to different modes of mechanical stressing. There is no universal in virra testing procedure for the assessment of elastomer in viva fatigue properties. There are various experimental data in the literature, obtained by different in vitro model testing procedures, which should be interpreted very carefully, expecially in relation to in viva conditions. The same probably applies for interpreting in viva data obtained in animals, This seems to be especially true in the case of blood pumps elements. When selecting the suitable polymeric material for a specific application and testing its life-time by simulated in vitro experiments, one must bear in mind the application conditions to obtain relevant results and conclusions. Biostability of an elastomeric implant may depend not only on stability of the basic elastomer, but also on secondary factors, such as filler content or crosslink density. The review shows that silicone rubber, segmented polyurethanes and polyolefinic rubber are suitable for many medical implant applications, but that they can suffer from some property changes during their service life. Therefore, one cannot expect unlimited reliable lifetime of such implants. This is the reason why the authors regard biostability research as very important. Biostability research is still in its infancy and it is necessary to focus attention, in this field of biomaterial science, not only to obtain the empirical knowledge of biostability of specific materials at specific applications but also on the mechanisms contributing to the deterioration of the implanted polymers. This would provide the possibility of an active improvement in biostability of polymeric biomaterials. As biostability testing of elastomeric implants retrieved from human patients provides the most valuable data, we recommend that more implant retrieval and evaluation programmes should be organized to get a higher quantity of relevant experimental data. In an ideal case, all clinically used polymeric implants should be retrieved and evaluated from the point of view of biostability. Such an ideal situation should be the aim of all who are interested in this interdisciplinary field of polymer science, technology and medicine.
ACKNOWLEDGEMENT The authors wish to thank Dr. J. Kopecek of the Institute of Macromolecular Chemistry, Czechoslovak Academy of Sciences, for reviewing the manuscript and for valuable comments.
REFERENCES
CDNCLUSIONS The biostability and life-time term implantation depends
of elastomers:
of elastomers in the longnot only on the type of
1 2
Anderson, J.M., Polymeric implants in the human, in /UPACZ&h Macromol. Symp. Papers, Amherst, 1982, p 338 Leininger, R.I., Markovit~h, V., Peters, A. and Hawks, W.A..
Biomaterials
t984.
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Biostabiiity
of elastomers:
P. Vond&ek
and 8. Doke.?el
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of Polymers,
Institute
of Chemical
Technology,
166 28 Prague 6, Czechoslovakia
B. Doleiel A. G. Akimov’s (Received
National
30 May
1983;
Research revised
Institute 7 July
for Protectron of Materials
and Corrosion, 250
97 Prague 9, Czechoslovakia
1983)
Biostability of synthetic elastomers used for manufacturing artificial replacements of human organs or their parts is a critical property of such materials as it determines the long-term function of a specific biomedical device This paper presents a critical review of the present knowledge of biostability of elastomeric biomedical materials used as artifacts functioning under the simultaneous
effects of dynamic flexing and contact with body fluids. The main
topics discussed are silicone rubber, elastomers for artificial blood pumps, and the methodology of model fatiguelife testing. Keywords: Polvmers, elastomers, rubber, flex-life tasting
implant
material,
biostabilitv,
The medical application of synthetic polymers has grown steadily over the past two decades and polymers are more and more used as permanent implants. This has been documented by the unique Implant Retrieval and Evaluation Programme performed at Case Western Reserve University in Cleveland’. This programme has provided the statistics of the implant presence in 4182 autopsies performed over the period 1972-80. These results have shown the exponential growth of polymer implant usage. In 1980 37% of the autopsies yielded implants, in contrast with only 9-l 6% yield in the period 1972-76. The most frequently used polymers found in the autopsies involved high density polyethylene, poly(methyl methacvlate), silicone rubber, polyester, polytetrafluoroethylene and poly(vinyl chloride). They represent the polymeric implantable materials used in the USA before 1980. Silicone rubber has been the most frequently used elastomer for biomedical purposes until now. Newer materials currently being evaluated for use in humans include the elastomeric segmented polyether urethanes and the polyolefinic elastomer Hexsyn. These elastomers are extensively studied as candidates for fabrication of various heart assist devices and total replacements. Obviously the elastomeric materials represent an important group of implantable polymers predominantly used in applications in which the elastic properties are required. Any polymeric material must meet many criteria in order to be able to fulfil successfully the permanent function of the elastomeric implant The criteria arise from real conditions of the specific implant application. One of *Paper presented at the conference ‘Polymers &no, Czechoslovakia. 20-22 October 1982. 0
1984
Butterworth
& Co (Publishers)
in Medicine’,
held in
silicone rubber, segmented
polyurethanes,
polyolefin
these criteria is the stability of implant properties during long-term contact with the biological environment, so called biostability. There is no doubt that the biostability is a critical property in many medical applications. Despite this, only a few, sometimes contradictory, data can be found in the literature. When testing the stability of any biomedical material one must start from the specific application conditions. Elastomers, being used for their elastic properties as replacements of elastic elements of the human body, are frequently subjected to dynamic deformation when simulating a physiological function of the original organ. Testing the biostabilityin vitro is a very complicated experimental task the most difficult part of which is the precise modelling of material exploitation under the conditions of the specific medical application. This is especially true with elastomeric implants subjected to flexing or other repeated deformations during their function in the human body, such as cardiac valves, heart assist devices, total artificial hearts, pacemaker lead insulations or finger joint endoprostheses. One must interpret and use literary data on elastomer biostability very carefully for assessment of their stability in other applications.
BIOSTABILITY Static
OF SILICONE
implantation
of silicone
RUBBER rubber
Measuring the effect of static implantation on the physical properties of silicone rubber has proved that this elastomer is very stable in contact with body fluids over a period of up to 2 yearsze5 (see Tab/e 7). This means that silicone rubber implants retain their physical properties for
Ltd. 0142-9612/84/050209-06$03.00 Biomaterials
1984,
Vol 5 July
209
Biostebility
of elastomers:
P. Vondr&ek
and 8. Dolefel
Table 7 Change in mechanical properties of silicone rubber during static subcutaneous or intramuscular implantation in dogs Implantation period (months)
Change in tensile strength
Change in elongation
1%)
W)
17
-
2.1
6 24
-
6.4 8.0
12
-
6.5
+ 11.3 -
Source
Leininger et aL2 Swanson,
-
8.4 15
LeBeau3
-
14
Roggendorf4
a long time (years) practically unchanged in static applications, in which the implant is not subjected to repeated mechanical flexing, such as soft tissue replacements for plastic surgery, implants for ophthalmology and oto laryngology, hydrocephalic shunts etc.
Silicone
rubber heart valves
A quite different situation has been found in silicone rubber used as poppets in the Starr-Edwards (ball in cage) heart valve prosthesis. The heart valve poppet is subjected to a drastic cyclic long-term fatigue. It alternatively hits the valve cage and the orifice about 80 million times a year. A percentage of the implanted heartvalve poppets has been reported to fail. The failure is accompanied by the degradation of physical properties, and is generally believed to be induced by the absorption of blood lipids into the silicon impIan?-‘. Analysing the retrieved silicone rubber heart valve poppets, different authors reported experimental data showing a linear increase of lipid uptake with time of implantatior?, as shown in Figure 7. The weight gain, due to lipid absorption, of the retrieved poppets is as much as 17% of the original weight after 50 months of implantationg. Even higher lipid uptake has been reported”. All experimental data compiled from references6*8*g in Figure 1 were obtained by a Soxhlet extraction with chlorofor~methanol(2:l) solvent mixture and were corrected for the extracted uncured silicone rubber. Clinically used retrieved heart valve poppets implanted both in mitral and aortic position for time periods from 2-60 d were used, with the exception of data from reference 6 obtained with mitral positioned heart valve poppets only. Each
Figure I Weightgain or absorbed lipid content as a function of in viva implantation time. l weight gain in subcutaneous implantss, A lipidcontent in fingerjoint implants”, A lipid content in mitral’heart valve poppets6, 0 lipid content in heart valve poppets’, 0 lipid content in heart valve poppetsg.
210
Biomateriels
1984,
Vol5
July
experimental point is based on analysis of one heart valve ball. It is interesting that only a small percentage of the heart valves failed in their function due to dimensional changes or mechanical failure of the ball. This so called ‘ball variance’ is characterized by an increased level of absorbed blood lipids which, according to most authors, represents an important factor leading to silicone rubber degradation. This points to the specific influence of characteristic haemodynamic conditions and blood composition of each patient. A percentage of variant silicone rubber balls differs even according to the anatomical site of an application. Recently, approximately 1.5% of aortic’ball in cage’ heart valves have been reported to fail, whereas in the mitral valve replacement only 0.05% variant balls have been found”. This corresponds with experimental data of Carmen and Mutha7 who found higher lipid uptake in variant aortic valve poppets than in the mitral ones (see Figure 7 from reference7). Absorption of lipids seems to be an important prerequisite for structural changes in silicone rubber; however it cannot cause the failure by itself. The lipid absorption into silicone rubber implanted under static conditions, e.g. subcutaneously or intramuscularly, does not result in changes such as one can find in heart valve poppets3. It seems from the data of Carmen and Mutha7 that simple lipid absorption (cholesterol esters, cholesterol, triglycerides, free fatty acids) in the retrieved heart valve balls reaches an equilibrium lipid content of about 1.5% by wt. within the relatively short time of about 10 months. Beyond this level a complex, relatively polar, material is absorbed, probably originated from the oxidation of lipids absorbed into silicone rubber. This has been proved by in vitro experiments7f ‘. In the case of silicone rubber degradation no equilibrium total lipid content should be expected. The maximum total lipid content reported is not higher than 41% by wt in an unspecified poppet sample after 37 months of implantationg. The lipid absorption into principally static (subcutaneous) implants results in the equilibrium lipid content (based on weight gain data) not exceeding 1% by wt3, as shown in Figure 1. The data from reference 3 were obtained from subcutaneously implanted, medical grade, silicone rubber samples in beagle dogs. It has been suggested in this work that, in the case of subcutaneous implantation, no extractable silicone polymer leaches from the implant, and the rubber is not being degraded to extractable silicone polymers during implantation. This can be related to the fact that, in the subcutaneous environment, the implants are not in contact with circulating blood in which a much higherconcentration of oxygen is available for lipid oxidation. Therefore, predominantly simple lipid absorption in such implants can be expected. A similar situation was found, by a lipid content analysis, in the retrieved silicone rubber finger joint prostheses”, where the lipid content also did not exceed 1% by wt within 36 months of implantation. Finger joint prostheses are not in contact with circulating blood and undergo occasional flexing. These experimental findings correlate well with equilibrium simple lipid absorption data found in heart valve balls7. This points to the fact that, the lipid oxidation found in implants in contact with circulating blood for long periods of time cannot proceed in the subcutaneous or intraosteal environment where a much lower concentra-
Biostability
of elastomers:
P
Vond&ek
and B. Dole;el
tion of oxygen is available for such oxidation. The absorbed lipid oxidation seems to be responsible for a much higher total lipid content in implants in contact with the blood stream. Therefore, predominantly simple lipid absorption can be expected in subcutaneous or similar environments with relatively low oxygen concentrations. The long-term continual flexing of silicone rubber swollen with lipids in the oxidative environment of the specifically altered blood therefore seems to be an important aspect of biodegradation of silicone rubber implants in the blood stream. The alteration of mechanical properties of elastomeric implants in the cardiovascular system results probably from simultaneous action of many factors, the most important of which seem to be: absorption of blood lipids and their oxidation products; calcification”; haemodynamic conditions; dynamic fatigue; enzymatic attack; individual influence of the implant bearer.
Silicone
rubber pacemaker
lead insulations
The other application, demanding a good flex-life and stability of silicone rubber working in the cardiovascular system, is the insulation of cardiac pacemaker leads. A systematic research of biostability of polyethylene and silicone rubber insulations is being carried out in Czechoslovakia with the co-operation of medical, engineering and polymer science institutions. The preliminary results of testing mechanical properties of the retrieved pacemaker lead insulations have shown that the tensile strength and elongation of polyethylene and silicone rubber tubing decrease with the exposition time13. A decrease to about 30% of the original value of the tensile strength of the silicone rubber tubing after 1 1 years of implantation has been reported. The modulus at 200% elongation of silicone rubber, which is a measure of the crosslink density, slowly increases in the initial period of implantation and drastically decreases after about 1 year of exposition (up to 50% of its original value after 11 years implantation). The change in crosslink density with implantation time, determined by the equilibrium swelling in toluene of the retrieved insulations, has provedI that the modulus (or stiffness) change of silicone rubber results from the decrease in the concentration of elastically effective crosslinks in rubber. It has also been found that the extractable fraction (sol) obtained by toluene swelling from the retrieved clinically used pacemaker lead insulation implanted for time periods from 7 to 4000 d increases linearly with implantation times’4. It is questionable whether the extractable sol consists of the absorbed lipids or predominantly of low-molecular weight polysiloxanes due to some degradation of the crosslinked silicone rubber matrix. This question seems to be indirectly answered by the experimental finding that the increase in sol fraction is accompanied by the decrease of crosslink density from equilibrium toluene swelling, as shown in Figure 2. Biolsi et al.“, however, did not find any linear polysiloxanes in heart valve poppets after an extended implantation period (58 months) by unspecified extraction/ spectroscopic techniques. These poppets were reported to have about 20% of solvent extractables and they
sl >Z
w
.20
J 0
5
15
IO
EXTRACTABLE
SOL
20
1%)
Figure 2 Volume fraction ofsilrcone rubberin the equihbnum swollen state (swollen in toluene) as a function of the sol fraction extracted by toluene ,n pacemaker lead Insulations retneved at various ,mplantation periods’4.
contained several per cent of unreacted linear polymer before body exposure. Therefore, one can assume that the low-molecular polysiloxanes originally present, and those which are generated from the silicone rubber network by some degradation processes, most probably based on hydrolytic decomposition (see the following paragraph), are washed out by blood lipids absorbing into the material. This situation is quite different from that found in implants positioned in body sites where they are not in contact with circulating blood. It can be stated that silicone rubber in applications where it is exposed to the permanent flexing while in contact with circulating blood will suffer a change of its structure and properties, like polyethylene~3. This change is especially significant in implantation periods longer than 1 year. However, the deterioration of mechanical properties of silicone rubber pacemaker lead insulations is not critical from the point of view of its functional reliability, since the implantation will not generally exceed a period of 15-20 years.
Hydrolytic
stability
of silicone
rubbers in model studies
Ward and Perry” have recently published results of their relatively short-term model study of silicone rubber stability in a simulated extracellular fluid. They conclude that some, not specified, structural changes occurred in silicone rubber manifesting themselves through the altered dynamic properties. Ward and Perry found the storage modulus G’ of silicone rubber to increase with immersion time in the pseudo-extracellular fluid within a relatively short time (approximately 15% increase in 6 weeks of immersion). This finding seems to have some relationship with the modulus increase found in pacemaker lead insulations in the initial period of impiantation13. The dynamic logarithmic decrement of silicone rubber immersed in the pseudo-extracellular fluid or distilled water at 37°C was found to decrease by approximately 25% after 4 months of immersion. Evidence has been put forward for slow hydrolytic
Biomaterials
1984,
Vol 5 July
211
Biostability
of elastomers:
I? Vond&ek
and B. Dolesel
decomposition of very lightly crosslinked polydimethyl siloxane16 under relatively mild conditions, When a previously extracted sample of lightly crosslinked unfilled silicone rubber was stored under laboratory conditions, a considerable amount of approximately 1% of soluble material was generated in 300 h. This process was accelerated somewhat at higher temperatures and strongly by the presence of ammonia vapours (4% of new soluble fraction after400 h in NH, vapours at 25°C). As it did not appear to take place under dry conditions, it was attributed to a hydrolytic decomposition catalysed by ammonia. It should be noted that this tendency was greatly reduced with the crosslinked vinyl-containing silicone polymer and with increasing crosslink density. Nearly all silicone rubber used in medicine and surgery contains a substantial portion of a silica filler and is highly crosslinked. Therefore, it is possible that the tendency to a hydrolytic decomposition is suppressed in commercial formulations of silicone rubber and can manifest itself only after a very long time of contact with the biological environment To prove or refuse this hypothesis, one would need to study a change in properties of a strictly defined material during implantation for more than 5 years.
siloxane rubber (Silastic 372 or Silastic MDX 4-4515) used originally for manufacturing finger joint implants with the additionally cured vinyl-terminated polydimethyl siloxane (Silastic MDX 4-4210) which possesses substantially improved tear resistance”. The latter silicone rubber is cured by reacting its vinyl-terminated groups with a silane-terminated polysiloxane using a chloroplatinic acid catalyst. The improved tear propagation characteristics are important in implants which are expected to flex and bear stress in contact with bones which may produce small defects in the implant surface. Clinical follow-up of a group of 496 patients with the improved finger joint implants has shown 13% with clinical complications but only 1.9% of implant fractures after 22 months”. Recently, a new type of finger joint prostheses has been introduced by Lord Corporation which consists of titanium alloy stems sized to fit the medullary cavity of the phalange or metacarpal and connected with the polyolefin elastomer flexible elemen?‘. The elastomeric member is made of Bion, a synthetic polyolefin elastomeP3 with an exceptional flex-life.
Silicone rubber inclusions in haemodialysis
Segmented
Evidence of the deteriorating effect of combining dynamic flexing and blood contact on properties of silicone rubber has been recently published by various authors, reporting a deposition of microscopic inclusions of silicone rubber in parenchymatic organs of long-term haemodialysis patients. For example, Leohapand et al.” have found particles of silicone rubber in 37% of the group of 78 longterm haemodialysis patients. The refractile particles of silicone rubber” have been most frequently found histologically in liver and spleen”,‘*. The probability of the occurrence of such particles, which apparently is not an important cause of chronic liver disease”, depends on the duration of maintenance haemodialysis. Their accumulation seem to be a stochastic process”. Apparently, the source of the silicone rubber inclusions is the inner wall of silicone rubber tubing exposed to flexing in contact with blood in peristaltic roller pumps used for dialysis. The inclusions were found to be identical with particles of silicone tubing exposed to roller pumps’*.
Attention has been recently focused on methodology of fatigue-life testing of elastomers working in a biological environment in connection with a selection of materials for constructing various cardiac assist systems and artificial blood pumps. The highest attention has been paid to segmented polyether urethanes (e.g. Biomer, Pellethane, Tecoflex, Avcothane), promising the best balance of performance characteristics such as blood compatibility, suitable manufacturing properties, and mechanical durability. Biostability of segmented polyether urethanes in vivo has been proved, e.g. by testing mechanical properties of Biomer used as blood sacks for the left ventricular assist device and total artificial heart after 2-3 months of functioning in calve.sz4. No statistically significant reduction in tensile strength or flexibility after this period of use in the biological environment has been found. There seems to be no obvious degradation due to exposure to blood, gas or vacuum during relatively shortterm experiments. Even though survival times of some artificial blood pumps have exceeded 10 months we may have reached the mechanical limit of the segmented polyether urethanes. Bucher125 recently reported that 70% of 10 consecutive totally artificial heart terminations with survival over two months were related to pump material failure. It seems that long-term (greater than 2 years) reliability of blood pumps will probably have to wait for another generation of biocompatible polymers26. There are also known cases of polyurethane pacemaker lead insulations failing in long-term service due to hydrolytic degradation2’.
Finger joint implants Despite the tendency to a hydrolytic decomposition and deterioration by flexing in contact with blood, silicone rubber is still one of the best polymeric materials for longterm implantations. One of its successful applications is to the replacement of finger joints where its durability and stability has been of great concern. In contrast to heart valve poppets the lipid absorption does not seem to affect significantly the flex-life of finger joint endoprostheses”. A reliable finger joint endoprosthesis should withhold 10 million flex cycles by approximately 90”‘. Results of model in vitro experiments on the Swanson-type of finger joint replacements have proved that silicone rubber endoprostheses fulfil this requirement’s-2’. For example, Czechoslovak finger joint implants produced by Rubena showed a flex-life of more than 50 million flex cycles by 83” in the simulated plasma at 37°C”. In 1975, Dow Corning replaced the peroxide cured polydimethyl
212
Biomaterials
1984,
Vol 5 July
BIOSTABILITY
Polyolefin
OF ELASTOMERS
FOR BLOOD PUMPS
polyurethanes
rubber
Lately, a new type of biomedical elastomer has been introduced, which seems to be a promising one for constructing heart blood pumps. The rubber, originally called Hexsyn by Goodyear, now renamed Bion by Lord
Biostabilitv
Corporation, is a synthetic polyolefin elastomeP3. The polymer backbone is a straight chain saturated hydrocarbon (like polyethylene) resistant to oxidation and ozonization, bearing olefinic pendants of 4-5 carbon atoms on every second carbon of the backbone. Some of the side substituents contain unsaturated double bonds through which sulphur cure can be accomplished. Hexsyn is produced by a copolymerization of 1 -hexene with a mixture of 4-methyl-1,4-hxadiene and 5-methyl-l, 4hexadiene23. When compounded and cured the rubber produces a low-modulus, soft-vulcanizate with exceptional fatigue properties. The flex-life of Hexsyn measured by ASTM D 430 De Mattia test is better than 300 million flex cycles2’* 28. In clinical applications, this material is prepared with a porous surface to which is attached a blood compatible gelatinous Iaye&*.
Model flex-life testing Various model testing experiments of fatigue or flex-life provide different results for different materials. For example, the De Mattia test method, commonly used in the rubber industry, will indicate Hexsyn as the most durable material in flexing (more than 300 million cycles). Segmented polyurethane Biomer will show its flex-life reduced by an order of magnitude (18 million cycles), while silicone rubber will have the flex-life reduced by two orders of magnitude (0.8 million cycles)22~28. On the contrary, silicone rubber shows a value for flexural fatigue-life comparable with polyurethanes when tested in cyclic tension (approximately 10 million cycles at 100% elongation)2s. The life-time of Hexsyn in uniaxial creep has been found to be considerably lower than that of segmented polyurethanes (Biomer, Avcothane)30. One must be very careful therefore in interpreting fatigue data for different polymeric materials obtained by different testing methods. The following example shows clearly how one can obtain misleading conclusions by testing the fatigue durability of elastomeric materials in an unsuitable way. Szycher et d3’ have chosen a bending flex method, working at -40°C for screening evaluation of flexure endurance of the candidate materials for use in blood pumps. The results obtained by the accelerated testing of flexural fatigue-life at cryogenic temperature cannot be universally extrapolated to the temperature of application (i.e. body temperature) for different materials with various Tg values. The repeated studys2, this time performed at 39°C in the diaphragm and bladder configuration testing modes in saline, have provided quite different conclusions as to the flex endurance of the considered candidate materials. The latter work has resuited in fiexural survival probability functions for 7 candidate materials tested. This seems to be currently the best published guidance for selection of elastomeric materials for manufacturing artificial heart pumps and assist devices from the point of view of their respective flexural durability. Segmented polyurethanes (Pellethane. Biometj and polyolefinic rubber (Hexsyn) have been indicated here as suitable materials for constructing the systems, the flexural endurance of which is a critical, lifesaving or life-threatening property.
f? Vond&ek
and B. Dolesel
chemical structure of the elastomer used, but also on the application conditions. The same material can show different biostability characteristics and life-time in different applications. The evaluation of silicone rubber behaviour in dynamic applications (heart valve poppets, pacemaker lead insulation, haemodialysis roller pump tubing) in contact with circulating blood shows much higher variance in properties than in subcutaneous, intramuscular or intraosteal silicone rubber implants. This is probably related to the different oxygen concentration at various body sites, and to different modes of mechanical stressing. There is no universal in virra testing procedure for the assessment of elastomer in viva fatigue properties. There are various experimental data in the literature, obtained by different in vitro model testing procedures, which should be interpreted very carefully, expecially in relation to in viva conditions. The same probably applies for interpreting in viva data obtained in animals, This seems to be especially true in the case of blood pumps elements. When selecting the suitable polymeric material for a specific application and testing its life-time by simulated in vitro experiments, one must bear in mind the application conditions to obtain relevant results and conclusions. Biostability of an elastomeric implant may depend not only on stability of the basic elastomer, but also on secondary factors, such as filler content or crosslink density. The review shows that silicone rubber, segmented polyurethanes and polyolefinic rubber are suitable for many medical implant applications, but that they can suffer from some property changes during their service life. Therefore, one cannot expect unlimited reliable lifetime of such implants. This is the reason why the authors regard biostability research as very important. Biostability research is still in its infancy and it is necessary to focus attention, in this field of biomaterial science, not only to obtain the empirical knowledge of biostability of specific materials at specific applications but also on the mechanisms contributing to the deterioration of the implanted polymers. This would provide the possibility of an active improvement in biostability of polymeric biomaterials. As biostability testing of elastomeric implants retrieved from human patients provides the most valuable data, we recommend that more implant retrieval and evaluation programmes should be organized to get a higher quantity of relevant experimental data. In an ideal case, all clinically used polymeric implants should be retrieved and evaluated from the point of view of biostability. Such an ideal situation should be the aim of all who are interested in this interdisciplinary field of polymer science, technology and medicine.
ACKNOWLEDGEMENT The authors wish to thank Dr. J. Kopecek of the Institute of Macromolecular Chemistry, Czechoslovak Academy of Sciences, for reviewing the manuscript and for valuable comments.
REFERENCES
CDNCLUSIONS The biostability and life-time term implantation depends
of elastomers:
of elastomers in the longnot only on the type of
1 2
Anderson, J.M., Polymeric implants in the human, in /UPACZ&h Macromol. Symp. Papers, Amherst, 1982, p 338 Leininger, R.I., Markovit~h, V., Peters, A. and Hawks, W.A..
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t984.
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Biostabiiity
of elastomers:
P. Vond&ek
and 8. Doke.?el
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