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GENERAL ARTICLES Synthetic Polymers in Artificial Hearts: A Progress Report Michael Szycher" and Victor L. Polrler Biomaterials Research, Thermedics Inc., Weltham, Massachusetts 02254
One of the most demanding uses of polyurethane elastomers is in artificial hearts. Polyurethane elastomers are the synthetic polymer of choice in artificial hearts because of their inherent blood compatibility, flexure endurance, and abrasion resistance. At present, the artffical hearts in clinical use can be divlded into two types: first, temporary devices designed to assist the pumping function of a damaged heart, and second, if the damage is irreparable, use of permanently implantable ventricular assist devices (left or right) or in combination to form a bilateral support system. All of these devices utilize polyurethane elastomers fabricated in the form of ventricles to provide the necessary blood pumping action of the artificial hearts.
Background The pain begins under the breastbone and on the left side of the chest. Within a few seconds the pain becomes a crushing sensation, as if an elephant were sitting on the chest, interfering with normal respiration. As the chest pain becomes excruciating, secondary referred pain darts up the left interior portion of the neck and down the left arm. The skin blanches, pupils dilate, and nausea becomes evident. Inside the patient's chest, one or more of the vital heart coronary arteries, clogged by atherosclerotic palques, no longer transmit blood. The tissues of the heart, deprived of blood, have begun to die; the pain (angina) is the physical manifestation of dying heart muscle. The patient is undergoing a myocardial infarction, or what is commonly known as a heart attack. Cardiovascular disease, the precursor of myocardial infarction, afflicts 41 million Americans, accounting for more deaths than any other disease. Half of the fatalities spring from myocardial infarctions (about 500 000 yearly), and another 17% from cerebral strokes. Although since 1970 the death rate from heart attacks and strokes has plummeted by 25%, presumably as a result of lower smoking, exercise, and lower cholesterol intake, cardiovascular disease is still America's number one killer. To wipe out this national scourge, medical research spends nearly $40 billion a year to better understand and treat the human heart. Eleven ounces of contractile muscle tissue, the human heart is the size and shape of a large pear; it contracts a prodigious two and a half billion times in the span of an average life. This muscular activity is designed to circulate blood to all tissues of the body; in the average adult the normal heart pumps an astounding 2160 galons of blood per day. Thus, the human heart, that remarkable organ known to poets as the seat of the soul, is in reality a magnificently perfect pump, made up of contractile muscle, valves, partitions, and arteries. When damaged, valves can be surgically replaced; when obstructed, arteries can be bypassed. These spectacular advances in cardiac surgery over the past decade have
made a significant difference in the quality of life for many people. By contrast, the frontier that holds the greatest challenge in cardiac surgery today (and accounts for the greatest mortality) is presented by the myocardium, the heart muscle itself. When the heart muscle dies as a result of poor blood flow, it cannot be simply repaired by standard surgical procedures. The only hope is to allow healing of the damaged myocardium by placing it at rest, to replace the entire organ with a donor heart, or to replace it with an artificial heart. Donor heart transplantation, although increasing in popularity as a result of important advances in immunosuppressive therapy, may not be the optional answer to the overwhelming majority of cardiac patients because of the problems presented by logistics and an inadequate supply of donor hearts. Thus, the ultimate goal of cardiac research remains the development and widespread clinical application of artificial heart devices. For instance, it is estimated that there are only 1500 to 2000 biologic hearts available for transplants while there are 100000 patients per year requiring them. Obviously there exists a need for an alternative. This paper reviews the current clinical use of temporary and permanent artificial heart devices. In addition, we will also focus on the crucial role played by synthetic polymers in the development of artificial hearts, particularly the polyurethane elastomers, because the polyurethanes are among the few elastomers capable of withstanding the dual requirements of hemocompatibility and long-term flexure endurance, necessary for the successful use of artificial hearts. Biomedical-Grade Polyurethane Elastomers One of the most crucial requirements since the inception of the artifical heart program has been the need to develop biomaterials specific to chronic implantation. Major problems include the propensity for thrombus formation at the blood-materials interface, long-term flexing reliability, and the tendency of the body to reject foreign objects.
0196-4321/83/1222-0588$01.50/00 1983 American Chemical Society
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Table I. Commercially Available Biomedical-Grade Polyurethane Elastomers description name supplier Biomer Ethicon, Inc., Somerville, N J linear, segmented, aromatic, polyether-based;ethylenediamine extended Cardiothane Kontron, Inc., Everett, MA cross-linked, aromatic, polyether-based;urethane silicone Pellethane
Upjohn Chemical, North Haven, CT
processing solution casting solution casting
copolymer
linear, segmented, aromatic, polyether-based;butanediol extended
extrusion injection molding solution casting Tecoflex Thermedics Inc., Waltham, MA linear, segmented, aliphatic extrusion polyether-based;butanediol extended injection molding solution casting Fortunately, some synthetic polymers can be designed another binding force. The more weakly attractive van to appear innocuous to living organisms, thus circumder Waals forces are also operative in all parts of the venting any adverse immunologic response that may be polymer chains. The polymer chains are long enough to inimical to life. Flexing surfaces necessary in most pump get entangled in each other. designs present special problems since the flexing charThe lateral effect of all the foregoing states and forces, acteristics of the polymer must be outstnding to survive particularly paracrystallinity and hydrogen bonding, is to 42 million flexes per year; this requirement, coupled to tie together or “virtually cross-link” the linear primary nonthrombogenicity, introduces a secondary level of compolyurethane chains. That is, the primary polyurethane plexity. Polymers intended for cardiac implantations chains are cross-linked in effect, but not in fact. Conlasting for ten years must reliably flex over 400 million currently, of course, the virtual linkages also lengthen the times, a requirement that may extend beyond the capaprimary polyurethane chains. The overall consequence is bilities of most biomaterials. a labile infinite network of polymer chains which displays In spite of these difficulties, the search continues for the superficial properties of a strong rubbery vulcanizate biomaterials that can successfully meet the stated reover a practical range of use temperatures. quirements, and, indeed, in the past few years a family of Virtual cross-linking is a phenomenon that is reversible polymers has emerged that shows unusual promise: the with heat and, depending upon polymer composition,with polyurethanes. These versatile elastomers have been fasolvation, offering many attractive processing alternatives bricated into bladder shapes and continually flexed in a for thermoplastic polyurethanes. Thermal energy great mock circulatory loop, with the oldest bladder now exenough to (reversibly) break virtual cross-links, but too low ceeding 500 million flexes, the equivalent of more than 10 to appreciably disrupt the stronger covalent chemical years of pumping. bonds that link the atoms in the primary polymer chains, Polyurethane elastomers are rubbery reaction products can be applied to extrude or mold the polymers, and a of organic isocyanates, high molecular weight polyols, and solvent which solvates the polymer chains, reversibly inlow molecular weight chain extenders. The products are sulating the virtual cross-links, carriers the primary the condensation reaction between a reactive moiety, the polymer chains into solution separate and intact for such isocyanate, and compounds containing active hydrogen applications as coating or scientific study. sites, such as hydroxyl and amine groups. Typcially, the At present, four commercially available virtually crossreaction proceeds in two sequential steps. In step one, the linked, polyurethane elastomers are described as biomedisocyanate is prereacted with a high molecular weight ical grade: Biomer, Cardiothane, Pellethane, and Tecoflex, polyol to form a “prepolymer.” In step two, the chain listed in Table I, with corresponding molecular architecture extender, or curative, is added to the prepolymer, resulting shown in Figures 1 through 4. in a rubbery, thermoplastic polyurethane elastomer. In this context, biomedical grade means “a systemic, Thermoplastic polyurethane elastomers consist of espharmacologicallyinert substance designed for implantasentially linear primary polymer chains. The structure of tion within living systems.” Thus, these polyurethanes are these primary chains comprises a preponderance of relasynthesized by the manufacturers under strict Good tively long, flexible, “soft” chain segments which have been Manufacturing Practice (GMP), and unprecedented joined end-to-end by rigid “hard” chain segments through standards of high quality and chemical purity. covalent chemical bonds. The soft segments are diisoResearch by Thermedics Inc. (previously the Biomedical cyanate-coupled, low-melting polyether chains. The soft Systems Group of Thermo Electron Corporation) began segments include single diurethane bridges resulting when in 1965, when the National Institutes of Health awarded a diisocyanate molecule couples two polyether molecules, the company contracts for the research and clinical use of soft segments formed by the reaction of diisocyanate with artificial hearts. Since then, one of our highest priorites the small glycol chain extender component. has been the development of a biomedical-grade polyurethane elastomer capable of being fabricated in large The polar nature of the recurring rigid, hard, urethane quantities, thus reducing the cost of the material, without chain segments results in their strong mutual attraction, compromising its biocompatibility or utility. aggregation, and ordering into crystalline and paracrystalline domains in the mobile polymer matrix. The The culmination of the research was the introducton of abundance of urethane hydrogen atoms, as well as carbonyl Tecoflex in 1982. Unlke aromatic polyurethanes previously and ether oxygen partners in polyurethane systems, perused in many medical devices, Tecoflex, an aliphatic-type mits extensive hydrogen bonding among the polymer polyurethane, does not give off decomposition products chains. This hydrogen bonding apparently restricts the such as methylene dianiline, a known carcinogen. This mobility of the polyurethane chain segments in the domaterial has been proven nontoxic and when in direct mains and thus their ability to organize extensively into contact with circulating blood, its unique molecular crystalline lattices. As a consequence, semi-orderedregions structure enables it to preferentially adsorb albumin, a natural serum protein. This feature results in passivation result, which are described as “paracrystalline.” Associaof the material surface to prevent undesirable blood tion of the electrons of the polymer structures represents
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Ind. Eng. Chem. Prod. Res. Dev., Vol. 22, No. 4, 1983 OCN O C H 2 0 N C O +H-0-Lf(CH2CH2CH2CH2),-OfH Methylene Dilsocyanate
(MDI)
H
I
PolyTetraMethylene Ether Glycol (PTMEC)
O
O
H
Isocyanate-Terminated Prepolymer
1
H2N-cH
2
CH2-NH2
(Ethylene Diamine Chain Extender)
‘Linear, Segmented Elastomer, Composed of Urethane and Substituted Urea Linkages
Figure 1. Molecular architecture of biomer. O
H
H
O
O
1 -O-C-N-:-CH,-.-td-C-OT(CH I 1 2 4
-lCH
H
H
O
1 -OfC-N-,-CH2-b-N-d-O-
2 4
Bare Polyurethane Polymer X
X
1x1
= Hydrogens in Hydrocarbon Portions O f Molecule
0
CHI
0-C-CH]
0 Base Polymer
Acetoxy-Terminated Silicone Crosslinking Agent
0
CH 73
~
dSi-Si-CH, i
-
+ HO-d-CH,
I
C H 3 OH Crosslinked Polymer
Acetic Acid
Figure 2. Cross-linking of Cardiothane.
clotting. Pilot production quantities of Tecoflex have been supplied to device manufacturers to satisy a variety of special medical products requirements. Clincal Evaluation of Temporary Ventricular Assist Devices Because death and disability from heart disease are most commonly due to the pumping inadequacy of an infarcted left ventricle, with the remainder of the heart providing sufficient function, an effective Ventricular Assist Device (VAD) was considered a major priority a t Thermedics. Other research groups, both in America and abroad, have focused their attention on total heart replacement. Major impetus for these clinical trades comes from statistics which show that more than 750000 Americans die annually of cardiovascular disease. In addition, another 150000
adult patients undergo open heart surgery every year. A substantial fraction of these deaths are caused by inadequate cardiac function. Many of these individuals have otherwise intact organ systems and cannot be helped by current or projected methods of conventional medical and surgical treatment. Most of these patients could be saved by mechanical intervention; it is for this patient population that VAD’s are intended. The left ventricle is the portion most often damaged by heart attack and is the source of 75% of all heart failure. For a VAD, the period of intended application may be expected to range from just a few hours up to permanent implantation. For some patients, the vicious cycle of cardiac inadequacy (i.e., failure of the heart ot nourish itself leading to myocardial infarction) might be reversed in a matter of hours or days and only temporary or short-term circulatory systems would be needed. In other cases, where heart disease may be so advanced and extensive that adequate myocardial healing proves impossible, a permanently implantable device might be used. In the early seventies Thermedics, in conjunction with the Children’s Hospital Medical Center in Boston and the Texas Heart Institute in Houston, developed a series of implantable axisymmetric assist pumps. The basic design is shown in Figure 5, which depicts the Model 11ventricular assist pump. The device is surgically connected between the apex of the left ventricle and the aorta. The arrangement facilitates unloading of the ventricles, making it a passive rather than active pumping chamber. In late April and early May 1978, two University Hospital (Boston, MA) patients, became the first and second Americans with severe coronary artery disease to be saved by a VAD designed and built by Thermedics. Both patients recovered, and were discharged from University Hospital, returning only for exercise and rehabilitation sessions. The VAD was the successful culmination of years of cooperative research effort between Thermedics and Dr. William F. Bernhard, Professor of Surgery a t Harvard
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Methylene DiIsocvanate
H
PolyTetraMethylene E t h e r Glycol
O
O
1
HO-CH
H
2CH2CH2CH2-OH
1,4 Butane diol
Pellethane Polymer
Figure 3. Molecular architecture of Pellethane. OCN
QC H ~ Q N C O
+ H - O + C H ~ C H ~ C H ~ C H ~ )n - ~ f n
PTMEG
HMDl
4
OH-CH2CH2CH2CH 2-OH
Tecoflex HR
Figure 4. Molecular architecture of Tecoflex.
APICAI INLET
-. Figure 5. Model 11s axisymmetric left ventricular assist device (Thermedics).
Medical School. Dr. Bernhard, in conjunction with Dr. Robert L. Berger, Professor of Surgery at Boston University School of Medicine, headed the surgical team in both cmes. Dr. Berger, after the successful outcome of the cases, commented on two important implications: “first, the cases show that a mechanical device can maintain life in man; second-and equally important, in my mind-they present the first convincing evidence in man that, with early intervention, the damage from massive heart attacks can be reversed, and some of the so-called dead or injured heart muscle can recover.” Prophetic words. These early successes in Boston spurred the medical interest in temporary VAD’s. As of
March 1981,170 patients worldwide underwent temporary ventricular assistance. Of these, 66 were weaned from the device, indicating that their compromised natural heart had recovered sufficiently to take over normal pumping function, and more than 55% (36 patients) are considered long-term survivors. Although still considered experimental, the temporary VAD’s have proven their surgical utility and, as clinical experience has been gained, survival rates have concomitantly increased. The next phase in the development of VAD’s will be to arrive at a permanently implantable, fully ambulatory, electrically powered artifical heart. This new system, shown in Figure 6, will address a larger population of cardiac patients than the temporary heart assist. This research being conducted at Thermedics, and at several participating Boston and Houston hospitals, is supported by the Devices and Technology Branch, National Heart, Lung, and Blood Institute, of the National Institutes of Health. We are following a plan whose end goal is the development, and clinical application, of artificial heart devices that will not require large external support systems and, thus, restore cardiac patients to a high quality of life. Over the past 17 years, our laboratories have progressed from pneumatically powered temporary assist devices to electrically driven heart pumps that can be powered by miniature portable battery packs and will not require a noisy, external support console. Total Artificial Hearts Since the first human heart transplantation was performed by Dr. C. N. Barnard at Groote Schuur Hospital in 1967, a mjor limitation of the technique has been that
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Figure 6. Components of Thermedics' artificial heart include: the pump housing: the internal battery pack: the low-speed torque motor: and the fivelayer printed circuit hoard (containing the electronic modules) which controls the beat rate of the artificial heart.
it was available primarily for elective use only, and not on an emergency basis. To overcome this obstacle, Dr. Denton A. Cooley of the Texas Heart Institute proposed a twostage cardiac transplantation with a Total Artificial Heart (TAH) as the first stage to maintain the patient's life, until a human donor heart could be located and readied for transplantation (cardiac allografting). In his report to the 1969 American Heart Association meeting, Dr. Cooley described the clinical course of a 47year old man whose life was sustained for 64 h with a TAH, until a suitable heart transplant could be found. Although the patient died 32 h after receiving the donated human heart, it was nonetheless proven that, even with desperately ill cardiac patients, it was possible to sustain life temporarily with a totally man-made artificial heart. During the years since 1969, investigations at the Cullen Cardiovascular Research Laboratories of the Texas Heart Institute continued, leading to the development of an improved artificial heart; by 1981, cardiothoracic surgeons had developed an artificial heart considered suitable for clinical application. The implantable heart, the Akutsu Model 111, series 3 TAH, combined two pneumatically powered, doublechambered pumps which utilized the principle of a reciprocating hemispherical diaphragm. The seamless one-piece pumping chambers were fabricated from Avcothane 51 (now called Cardiothane); Bjork-Shiley disk valves maintaine undirectional blood flow through the artificial heart. Arterial connectors were fabricated from silicone rubber, with a velour cuff; pulmonary and aortic flexible connectors were fabricated from 25-mm low-porosity polyethylene terephthalate grafts. In July 1981, this artificial heart was implanted in a Dutch patient, brought to Texas on a special airlift. Atherosclerosis had turned this patient, a t 36, into an old man who could no longer walk acrws a room without pain. On July 23, the patient underwent a triple coronary bypass, but could not be weaned from cardiopulmonary bypass.
After several attempts to restore the patient's own heart (which was suffering severe biventricular failure-a flaccid, motionless muscle), the only recourse was to utilize a total artificial heart, until a suitable donor heart could be found. On July 23, 1981, total artificial heart pumping was initiated a t 45 beats/min and increased through 60 to 80 beats, as cardiopulmonary bypass was discontinued after a total of 1.5 h. The search for a donor was instituted immedicately following the artificial heart implantation. A donor was located in another state and transported to Texas via a chartered jet aircraft. The donor and recipient were moved to adjacent operating rooms, where the donor heart was transplanted following removal of the artificial heart; the transplanted donor heart assumed total circulatory support on July 25. Thus,the second artificial heart in history again performed its life saving function. The patient was not destined to survive for long with his transplanted heart. Beaten by an infection and kidney and lung problems, Willebrordus Meuffels, the first man in history to have lived for a week with three different hearts, succumbed on August 2. The hemodynamic performance of the artificial heart during the 55-hour period was entirely satisfactory, with the device maintaining a relatively stable circulatory status. A gratifying feature of this record clinical application of two-staged cardiac transplantation was the absence of hemolysis. In the previous attempt, in which a fabric-lined artificial ventricle was used, initial hemolysis was extreme, rising to 300 mg/dL, a clinically unacceptable level. Meanwhile, half a continent way, in Utah, another audacious surgical team was readying a medical miracle that had been 50 years in the making. In February 1981, the Utah team spearheaded by Drs. William DeVries and Robert Jarvik applied to the Food and Drug Administraton for permission to implant the Jarvik 7 artificial hearts in human beings. The Utah artificial heart consists of two idependent pumps, each containing a flexible Biomer polyurethane ventricle which expands as the blood enters the devices, and then ejects blood into the peripheral circulation in response to pneumatic pressure provided by an external compressor. In contrast to the Texas TAH, the Utah TAH was intended to replace a damaged heart on a permanent basis. Once implanted, two 6 ft long tubes emerged from the left side of the patient's abdomen, just below the ribs, and were connected to an extemal console, called a heart driver, that regulates the flow of air from the compressor to the heart. The Utah team received approval from FDA in June 1982,just in time to consider implantation in a cardiomyopathy patient. The patient, Barney Clark, a retired dentist from Seattle, was referred to the University of Utah after suffering from unknown heart trouble that was gradually destroying his heart muscle. The patient at 61 was too old to be considered for heart transplantation; physicians a t Utah concluded Bamey Clark to be an ideal candidate for the "noble experiment." The elective operation was scheduled for Thursday morning, Dec 2, 1982, but by Wednesday morning, the patient's heart was deteriorating fast; several times his normally steady heartbeat disintegrated into ventricular tachycardia (a rapid, uncoordinated flutter that accomplished little pumping) and was thus life threatening. Suspecting that the patient might die before the scheduled operation, the team decided to operate immediately. Surgery on Clark began Tuesday night and by the next day, December 1, the surgical team was ready to begin connecting the implanted artificial heart. They had cut away the diseased ventricles; left in place were the atria
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which act as blood reservoirs. The team sutured the Dacron fittings onto the atria, and the two major blood vessels, the pulmonary artery and the aorta. The Jarvik 7 ventricles were connected onto the Dacron fittings; once the artificial ventricles were in place, they were held together by Velcro patches. When the artificial left ventricle was finally in place and actuated, it failed to pump blood adequately. After several unsuccessful attempts to readjust the ventricles, the team simply used a bionic solution-they replaced the failed ventricle with a backup spare which worked perfectly. The artificial heart was now performing all the functions of a normal, natural heart. Whatever the ultimate outcome, the operation succeeded, the technology was operational, and it saved a critically ill man from immediate death. And as the patient was wheeled from the intensive care unit, Barney Clark was now a hero, who courageously fought off death. No matter how long he survived, he had won a place of honor in the annals of thoracic surgery. After several complications, Clark died in late March 1983 of multiple organ failure. The artificial heart was a cumbersome,pneumatically powered device that left Clark with limited mobility because of the need to stay tethered to a large power and control console; nonetheless, it maintained a patient alive for almost four months. That effort, which was privately funded, yeilded important scientific and medical data, likely to reinforce general public confidence in the concept of implantable artificial hearts. Future Prospects When Dr. Christian Barnard performed the world's first heart transplant in 1967, he pioneered the modern era of cardiac surgical research. Barnard cut out the ailing heart of Dr. Louis Washkansky, a 55-year old South African dentist, and replaced it with the donated heart from a 25-year old woman who had been fatally wounded in an automobile accident. Washkansky lived for 18 days with his transplanted heart before dying of pneumonia. Since those pioneering days, and with little publicity, human heart transplants continue to be performed at selected cardiac centers, most notably at Stanford University, near San Francisco, where Dr. Norman Shumway has performed 248 transplant operations; of these, 98 patients are alive, and many have returned to work with a semblance of normal life. But while recipients of transplanted hearts may return to a more normal life than recipients of plastic artificial hearts, supply of donor hearts is totally inadequate. Of the 100000 Americans per year who could benefit from transplanted hearts, only a handfd can be saved, since only 1500 to 2000 donated hearts become available per year. Another limiting factor is the monstrous amount of money involved in the logistical support and initial surgical treatment. Thus, while a handful of patients may be saved by transplanted hearts, for the overhwelming majority of cardiac patients, the best hope lies in the development of artificial hearts made from hemocompatible synthetic polymers, such as the polyurethane elastomers.
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Some widely publicized artificial hearts, such as the device used at the University of Utah, rely on a large external air compressor, essentially tethering the patient to the control console for the rest of his life. At Thermedics laboratories, we are developing, under NIH sponsorship, artificial hearts powered by rechargeable Ni-Cd batteries worn on a small belt. The advantages of these systems of course are that they do not need external control systems or large energy sources. Electrical energy can be conveniently transferred into the body without the fear of infection. In our research, we are joined by heart researchers, such as Dr. Benedict D. T. Daly, of Tufts New England Medical Center. Together we are currently investigating two alternative methods of transmitting electrical energy across the skin. One method is to use highfrequency radio transformers across the intact skin (Transcutaneous Energy Transmission); the second method is to transmit electrical power through the skin with a special porous prosthesis (Percutaneous Energy Transmission). When these systems become fully operational, recipients of artificial hearts will be able to move freely and return to a high quality of life. The artificial heart program represents the wedding of medicine and engineering at its best. In time, the fruits of joint research efforts by physicians and engineers will be applied to other organ systems, such as lungs, kidneys, and livers. Replacing a lung, kidney, or liver, which are very active biochemical organs, is infinitely more complex than replacing a heart, which is, in the final analysis, a simple pump. Therefore, the human heart will probably become the first major internal organ to be replaced by a totally artificial device. Physicians and engineers are busily at work to hasten the day when artificial hearts will become commonplace elective surgical procedures, for the benefit of mankind.
Literature Cited Bernhard, W. G.; LaFarge, C. G.; Liss, R . H.; Szycher, M.; Berger, R. L.; Poirier, V. "An Appraisal of Blood Trauma and the Blood-Prosthetic Interface During Left ventricular Bypass in the Calf and Man"; Presented at the Annual Meeting of the Society of Thoracic Surgeons, Orlando, FL, Jan 1978. Bernhard, W F.; Poirier, V.: LaFarge, C. G.; Carr, J. G. J. Thor. Card. Surg. 1975, 70(5), 880-895. Bernhard, W.; Poirier, V.; Carr, J. "A Paracorporeai Left Ventircuiar Assist Device"; "Modern Techniques in Surgery: Cardiac/Thoracic Surgery"; Futura Pubiishino Co.. 1979. Poiriei, V.; S z y c k , M.; Whalen, R. Trans. Am. Soc. Arfif. Intern. Organs 1879. 25. 319-324. Szycher; M.'; Poirier, V.; Dempsey, D. "Advances in Tectured Blood Interfaces", Proceedings, 38th Annual Tech. Conf., SPE. XXVI, 1980; p 662. Szycher, M. "Clinical Needs for Synthetic Polymers in Critical Care Devices", Keynote Address, ACS Symposium Innovation in Medical and Pharamceutical Uses of Rubber, Chicago, Oct 1982. Szycher, M.;Bernhard, W. F.; Poirier, V. L.; Franzblau, C.; Haudenschiid, C. C. Trans. Am. SOC.Artif. Intern. Organs 1980, 2 6 , 493. Szycher, M.; Poirier, V.; Dempsey, D. "Synthetic Polymers: Their Crucial Roles in Artificial Hearts", JACS, Annual Meeting, Rubber Division, Chicago, 1982. Szycher, M.; Daly, B. D. T.; Dasse, K. "Tissue/Porous Biomateriais Adherence: An Experimental Protocol", Chapter in "Biomateriais in Reconstructive Surgery"; Rubin, L. R.; Mosby. C. V., Ed.; 1983.
Received for review May 13, 1983 Accepted June 30, 1983
