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Cardiopulmonary bypass in the clinical setting is barely 40 years old. Yet worldwide, it is used in the operating room in more than 500,000 cases a year. This broad acceptance is a tribute to the vision of gifted investigators who could see beyond the mere technical problems of perfused isolated organs. They integrated mechanical concepts, knowledge of materials, and sheer inventiveness with an appreciation of physiological issues to address the clinical needs of open-heart surgery.

Two types of spongy polyurethane-polydimethylsiloxane blend (Cardiothane 51, Kontron Instruments, Inc., Everett, Mass.) vascular grafts with an internal diameter of 1.5 mm were fabricated by a spray, phase-inversion technique. Low-porosity grafts with hydraulic permeability of 2.7 ± 0.4 ml/min per square centimeter and medium-porosity grafts with hydraulic permeability of 39 ± 8 ml/min per square centimeter displayed good handling properties and suturability. Twelve straight low-porosity grafts, 17 straight medium-porosity grafts (1.5 to 2.0 cm in length), and one loop medium-porosity graft (10 cm in length) were implanted by the same surgeon end to end in the infrarenal aorta of 30 male Sprague-Dawley rats. Three months after implantation, patency was 8% for low-porosity grafts (1/12) and 76% for straight medium-porosity grafts (13/17). The loop medium-porosity graft was also patent. The sole patent low-porosity graft showed neointimal hyperplasia and incomplete endothelialization. All but one of the patent straight medium-porosity grafts showed a glistening and transparent neointima with complete endothelialization and no anastomotic hyperplasia. The loop medium-porosity graft displayed endothelialization from each anastomosis and in many islands in the middle portion of the graft, totaling 47% of the luminal surface by morphometric analysis. Thick mural thrombus, anastomotic hyperplasia, or aneurysm formation were not observed in any patent medium-porosity graft. These data indicate that in the rat aortic replacement model it is possible to achieve patency and a high degree of endothelialization in very small-diameter prostheses of appropriate porosity.

Worldwide, 30–50 million men and women benefit from implanted devices. Therefore, the clinical experiences with synthetic materials in intimate contact with human cells and tissues exceeds by three orders of magnitude the number of laboratory animals sacrificed in the elusive quest for “biocompatibility.” Furthermore, the much longer duration of observation characteristic of human implants, compared to animal studies, adds two orders of magnitude to the superiority of clinical and anatomopathological experience over laboratory animal studies. This glaring disparity must be kept in mind in the assessment of materials through in vitro and small animal studies, and the regulatory agencies’ pronouncements based on such evidence. Another sobering fact is that over 95% of the materials utilized for implants are standard commercial substances originally developed for industrial purposes. Those products which have been found to be appropriate for a specific medical device are labeled “biomaterials” (or more modestly, materials for medical use) on the grounds of established specifications and quality control, supported by continuing feedback from the clinical experience. The major obstacle to the advent of custom-designed biomaterials is that the medical device market is so small (not in numbers of implants and impact on health care budgets, but in the quantity of material used per implant) that large-scale production and amortization of industrial production expenditures is well nigh impossible for truly novel substances. In litigious countries such as the USA, suppliers are pulling out of the market because of the excessive cost of defending against legal action when materials allegedly fail in the body environment. Against this background, biomaterials science is bravely searching for new solutions to old problems. The ill-defined property of biocompatibility is slowly making way for the notion of bio acceptance as we expand our knowledge of the cellular aspects of tissue-material interactions. Bioacceptance can seek two diametrically opposed end points: biointegration, meaning that the material and the surrounding living structures form a continuum with stable, low-grade interactions; and biopassivation, meaning that the material is hardly recognized by surrounding body fluids or tissues and that its stealth characteristics can persist for clinically meaningful periods of use.

The expression "medical device" covers any diagnostic or therapeutic means which involves a specific object and exerts its effects by mechanisms other than pharmacological. As such the term "device" includes a broad variety of instrumentation ranging from artificial organs to dental and orthopedic prostheses, biomaterials, biosensors, implants of various kinds, tissue engineering products, tools for minimally invasive procedures, imaging and patient monitoring equipment, telemedicine, hospital support systems (organizational and managerial) used for screening, diagnostic or therapeutic purposes, and systems for human rehabilitation.

The American public's perception of biomedical engineering is fuzzy, and consequently, the expectations for services provided by the profession vary widely. This becomes apparent whether one talks to scientists in academia; manufacturers of medical products who employ biomedical engineers; doctors who either see technology through the narrow view of their specialization or as generalists are one step removed from technological innovation; patients who under the stress of disease cannot distinguish between standard and experimental forms of treatment; and finally government agencies which in the main have failed to define a place for biomedical engineering in their programs, and therefore oscillate between the extreme perspectives of biomedical engineering as a basic medical science and that of a service profession. As President of AIMBE, the American Institute for Medical and Biological Engineering, an umbrella organization which groups the majority of bioengineering societies (Table 1), I have witnessed and rationalized this confused perception as the uneasy coexistence of two realities: a scientifically mature field of inquiry impacting in both medicine and engineering, and a globally perplexed, almost balkanized profession, scattered among so many subgroups that no global identity can be defined and presented to the public.

Cardiopulmonary bypass (CPB) is used so routinely in hospitals around the world that most of the participants — surgeons, anesthesiologists, perfusionists, operating room nurses and, above all, patients — forget that this landmark in clinical technology is not even 40 years old. In fact, many of the pioneers are still active in the field. Yet, so much has been done to transform a once-hazardous procedure into standard medical practice — through basic science, quality control, and good manufacturing — that one hardly remembers the days (not so long ago) when “pump-oxygenators,” as they were graphically called, were assembled just outside the operating room by tinkerers with a dream. The purpose of this chapter is to recall the inventiveness displayed by a small coterie of gifted investigators to whom we owe the mechanical and physiologic foundations of open-heart surgery, and to reflect on the new demands that continuing clinical advances will undoubtedly make on this technology.

EPLACING R a defective component of the body or substituting for a deteriorated organ function by a natural or man-made counterpart is one of the major contributions of modern science to clinical medicine. My objective in this essay is to draw some lessons from the experience with organ replacement in the last 40 years, and to project where substitutive and reparative medicine may lead us in the decades ahead. If the generalized practice of organ replacement is a recent phenomenon, the idea of substituting in some manner for body parts lost by accident or worn out by disease is apparently as old as mankind. Witness for man-made implants the use of gold plates to cover traumatic skull defects in several ancient civilizations. Witness for external support systems the technology for grinding rock crystal into the vision-correcting lenses allegedly used by the emperor Nero, and quite widespread in the western world since the 13th century. Witness, in the case of transplantation, the geographic transfer of knowledge regarding pediculated skin flaps to reconstruct the nose from ancient origins in India seven centuries before Christ, to Alexandria in the Ptolemaic period, and then through Arabic conquest of the Mediterranean coast, to a lineage of barber-surgeons in Southern Italy in the late Middle Ages, and finally to Tagliacozzi who, in the 16th century, codified in Bologna an operation that is still practiced today. What is new to our times is not so much the impact of modern science and technology on organ replacement procedures. as the epic scale on which substitutive and reparative medicine are now, rather suddenly, being practiced.

Mechanical systems to oxygenate blood outside of the body were first employed in clinical medicine as a component of the «heart-lung machine». The artificial lung has been an essential component of the technology underlying the progress of cardiovascular surgery since 1950. Its impact on clinical medicine can be measured by the widespread acceptance of cardiac surgery for the treatment first of congenital malformations, then valvular lesions, and more recently, coronary artery disease. Whereas the use of the artificial lung during temporary exclusion of the pulmonary circulation for surgical purposes is now well established, the chronic application of extracorporeal membrane oxygenation in end-stage respiratory failure is still controversial. Internally implantable lung prostheses are still at the conceptual or developmental stage, and are unlikely to impact on clinical medicine for another decade.

Since hypothermia is commonly used to lower local and general metabolism during cardiopulmonary bypass, we attempted to identify its specific effects on glucose-insulin interactions. A group of nondiabetic patients undergoing hypothermic (28 degrees C) cardiopulmonary bypass with ischemic (cold) cardiac arrest was compared to a similar group operated on under normothermic conditions with potassium cardioplegia. In the absence of exogenous dextrose administration, hypothermia blocked insulin secretion for the duration of the operation. It also inhibited insulin secretion in response to an exogenous dextrose load (e.g., the priming fluid of the cardiopulmonary bypass circuit) or a glucagon injection, but this inhibition was lifted by rewarming. Blood glucose levels, which during normothermia were mildly elevated even in the absence of dextrose administration, remained normal during the hypothermic phase of cardiopulmonary bypass. By the end of the rewarming period, however, blood glucose levels had reached the same level as observed under normothermic bypass, a fact suggesting that the cold inhibition of hepatic glucose production had been only temporary. Cold inhibition of hepatic glucose production also explains why glucose clearance after a sudden dextrose load was initially faster at low body temperature than at normal temperature. Glucose-clamp studies indicated that insulin resistance was initiated by anesthesia and surgical trauma, and further accentuated by cardiopulmonary bypass, in association with elevated levels of hormones indicative of surgical stress. Regardless of body temperature changes, the assimilation of glucose by nondiabetic subjects during and immediately after bypass called for the infusion of large doses of insulin. A comparison with diabetic subjects showed that insulin-dependent patients (type I diabetes) required no more insulin during cardiopulmonary bypass than normal subjects, whereas patients with type II diabetes exhibited a marked insulin resistance during the operation and in the immediate postoperative period.

Decreases in cardiac efficiency have been observed in experimental endotoxic shock, acute hemorrhage, and cardiopulmonary bypass. Diminished coronary blood flow, tissue anoxia, or metabolic alteration may affect the contractile protein which, in turn, causes cardiac inefficiency. To test this hypothesis, cardiac actomyosin and myosin were extracted with Guba-Straub solution, and intrinsic viscosity, ATP (adenosinetriphosphate) activity, ATP sensitivity, the rate of ATP hydrolysis, and myosin-ATPase activity were determined. Under these experimental conditions, both myosin and actin were altered. In order to exclude the possible effect of hypoxia of the arterial blood upon the cardiac contractile system, acute hypoxia was produced in dogs and the physicochemical properties of actomyosin and myosin were studied. During acute hypoxia, the myosin-ATPase was affected, but actin appeared to remain unaltered. These changes of actomyosin and myosin may cause insufficient energy utilization by the contractile system and thereby affect the cardiac efficiency.

Evidence is presented that reflex systemic vasodilatation occurs after stretching dog's lungs by either mechanical traction or positive pressure ventilation under conditions of separate pulmonary and systemic perfusion. This reflex is mediated by the vagus.

Hematological changes were measured in 14 dogs during partial heart-lung bypass procedures of 10 hr duration with an extracorporeal flow approximating 40% of the cardiac output. The changes occurring during the 1st hr of perfusion were identical to those previously reported for short periods of total heart-lung bypass, namely, thrombocytopenia and leukopenia. Later on, however, compensatory mechanisms were manifested by the appearance of a leukocytosis with a shift to the left, a leveling off of thrombocyte counts, and the appearance of nucleated red cells in the peripheral blood. Bone marrow studies revealed stimulation of myeloid tissues. These compensatory responses observed during perfusion were similar to changes which have been described as typical of the postperfusion period after shorter durations of extracorporeal circulation. The trauma inflicted on erythrocytes during extracorporeal blood handling became evident after perfusion as a marked anemia and an increased mechanical fragility of the red cells. Submitted on September 22, 1961

For a close observer of the National Institutes of Health Artificial Heart Program since its inception in 1964, the landmark report by DeVries et al.1 on the first long-term clinical use of the tot...

The goal for the hybrid artificial pancreas is chronic implantation in diabetics. In approaching this goal it is important to have animal models in which the effectiveness of the hybrid artificial pancreas, already proven in short-term studies, can be investigated over periods of weeks and preferably without anticoagulation. Scribner shunts have been implanted in beagles and exteriorized on their backs, giving flows of 150–200 ml/min. Pancreas prototypes with U-shaped tubes were inserted with a single loading dose of heparin, and three different tube sizes were used. Average life before occlusion by thrombi decreased as the tube diameter decreased, but 2.7 mm i. d. tubes can be maintained free of thrombus for at least three weeks.

Membrane oxygenation has recently become a reliable tool for routine cardiac surgery and an exciting instrument for investigating the concept of long-term respiratory assistance in man. Yet the technology underlying this modality of care is of relatively long standing. Indeed it was in the mid 1950s that Clowes and his team in Cleveland (Clowes et al. 1956) demonstrated the clinical feasibility of membrane oxygenation. Why then did it take 20 years to reach the stage of widespread clinical application? What were the obstacles on the road? What has finally made the difference? And where do we go from here? These are the questions to be considered in this overview of membrane oxygenation.

Publisher Summary This chapter describes an ultrasonic method that is being used to quantitate microemboli in blood during extracorporeal circulation. The system consists of a plexiglas ultrasonic chamber, a reflectoscope, and a PDP 11/40 DECLAB computer. The ultrasonic chamber is constructed such that the 5 MHz ceramic transducer is positioned external to the fluid flow. The curvature of the cylindrical chamber forms a planoconcave lens that focuses the ultrasonic beam at a point 1.36 cm from the crystal. Random nonpenetrating holes were drilled around the periphery of the transducer to break up the shear waves from the edges of the crystal. The chapter presents an ultrasonic microparticle detection system that has been designed to monitor the number and size of microparticles in fluid. The system has the capability to distinguish between gaseous and solid emboli.

A computerized ultrasonic particle detection system is capable of identifying microemboli in the 10 to 350 μ range. Data show that appropriate computer analysis of the reflected signals allows discrimination of size and type of emboli. All extracorporeal circuits have microemboli with a large variation in size and number, depending upon the apparatus and how it is run.

In anesthetized dogs a fraction of the venous blood flow was diverted into a heart-lung machine (gas exchange bag) and from there infused by gravity into the arterial circulation. During such a partial heart-lung bypass an increase in extracorporeal perfusion rate resulted in a long lasting bradycardia and a decrease of right ventricular pressure and pulmonary blood flow. The decline of the aortic pressure caused by this maneuver could be compensated by adjustment of the infusion pressure into the arterial system. The external work of the heart was reduced thereby without compromising tissue perfusion. The procedure was compatible with survival of the animals. Submitted on February 24, 1959

Innervated, nourished and ventilated dog lungs were perfused in situ with a technic which afforded adequate control of blood flow, pressures, pH and temperature. Variations of the pulmonary (hut not of the systemic) blood temperature was followed by pronounced changes of the pulmonary vascular resistance, believed to be attributable to pulmonary vasomotion.

Summary Eight out of eleven dogs were long term survivors when submitted to 24 hours of partial heart-lung bypass using a membrane oxygenator with a low priming volume. It was possible to maintain an adequate metabolic balance in these animals and tests of hepatic and renal function after perfusion gave normal results. Blood damage during perfusion remained well within limits of compensation by the organism. However, the survival time of erythrocytes tagged at the end of the procedure was shortened, explaining the occurrence of hemolytic anemia in the first week after perfusion. Nonsurvivors showed pulmonary damage, water and electrolyte retention, splanchnic congestion and impairment of liver function. These experiments suggest that extracorporeal blood oxygenation can be offered safely for clinically useful periods with simple equipment requiring little or no priming blood.

Partial heart-lung bypass is one form of artificial circulation proposed for assisting the failing heart. Since it involves extracorporeal gas exchanges, respiratory as well as circulatory functions must be considered during the procedure. Our studies reveal that an accurate knowledge of the systemic blood volume is necessary to control the distribution of blood flow between the intracorporeal and extracorporeal circuits. The systemic blood content also influences the pulmonary ventilation. Partial heart-lung bypass can be performed in such a manner that it completely fulfills the metabolic requirements of the body tissues. Whether abnormal hemodynamic conditions in heart failure can be relieved by partial heart-lung bypass after the period of active circulatory assistance is still to be evaluated.

Partial heart-lung bypass was performed in open-chest dogs, using the gravity arterial in-fusion technique. Arterial infusion pressure, venous suction and pressures in the left ventricle, aortic arch, and airways were phasically recorded. The mean flow in the aortic arch and the blood content of the extracorporeal circuit were continuously recorded. According to the height of the bag oxygenator above the heart level, partial heart-lung bypass resulted in a shift of blood either from the extracorporeal circuit into the animal or vice versa. When the body blood volume was increased by the bypass procedure, the cardiac output decreased only slightly. When the body blood volume was diminished by the bypass procedure, the cardiac output dropped markedly. It was found that when the systemic arterial pressure was maintained at approximately normal levels, independent of cardiac output, the change in cardiac output was proportional to the change in the body blood volume.

A 5‐MHz ultrasonic sensing device which detects and monitors microparticles in a moving fluid stream has been described, constructed, and calibrated, The ultrasonic transducer is so placed that a thin section of plexiglas exists between the transducer and the fluid stream. This section is of piano‐concave shape and acts as a converging lens to focus the transducer at approximately 1.36 cm from the surface of the lens. The pulsed ultrasonic signal is transmitted into the fluid which flows through a calibrated and mapped sound radiation field. The calibration of the field for particle size was done through the use of carbonized microspheres, glass beads and air bubbles of known sizes. The device is calibrated to detect and monitor microparticles in the range of 7–400 μm in diameter. A formula was derived from these calibration studies which relates reflected amplitude to particle size. The radiation field was mapped using a target ball of 0.635 cm in diameter. The apparatus has been used successfully during in vivo extra‐corporeal studies done on sheep, and has recorded microparticles during these procedures. [Work supported by Rhode Island Heart Association.]

A 5‐MHz pulsed ultrasonic system has been designed which can detect microparticles in a free‐flowing liquid, monitoring particles between 10 and 400 μm in diameter. As in an earlier version by the same authors [J. Acoust. Soc. Am. 60, S53–S54(A) (1976)], the transducer is mounted in the plexiglass wall of a cylindrical dielectric cell (interior diameter 1.27 cm) so that a thin section of plexiglass of plano‐concave shape exists between the transducer and the liquid stream, serving as an acoustic lens and focusing the ultrasonic beam at a point 1.36 cm from the surface of the lens. The return reflections from density discontinuities within the liquid are converted to digital signals by use of a 100‐MHz A‐D converter. This information is then analyzed by means of a PDP‐11/40 computer. Both the video signal and the RF signal from the ultrasonic transmitter‐receiver are used to provide information on the size and type of particle detected. Air bubbles return a symmetric pulsed echo, while various solid particles examined return asymmetric pulses. The RF signal can also be used to provide phase information, thus distinguishing particles with acoustic impedance less than that of the flowing liquid from those with higher acoustic impedance.