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Inventing Medical Devices: Five Inventors' Stories Development of Technicon's Auto Analyzer EDWIN C. WHITEHEAD In 1950 Alan Moritz, chairman of the department of pathology at Case Western Reserve University and an old friend of mine, wrote to tell me about Leonard Skeggs, a young man in his department who had developed an instrument that Technicon might be interested in. I was out of my New York office on a prolonged trip, and my father, cofounder with me of Technicon Corporation, opened the letter. He wrote to Dr. Moritz saying that Technicon was always interested in new developments and enclosed a four-page confidential disclosure form. Not surprisingly, Dr. Moritz thought that Technicon was not really interested in Skeggs's instrument, and my father dismissed the matter as routine. Three years later Ray Roesch, Technicon's only salesman at the time, was visiting Joseph Kahn at the Cleveland Veterans Administra- tion Hospital. Dr. Kahn asked Ray why Technicon had turned down Skeggs's invention. Ray responded that he had never heard of it and asked, "What invention?" Kahn replied, "A machine to automate chemical analysis." When Ray called me and asked why I had turned Skeggs's idea down, I said I had not heard of it either. When he told me that Skeggs's idea was to automate clinical chemistry, my reaction was, "Wow! Let's look at it and make sure Skeggs doesn't get away." That weekend, Ray Roesch loaded some laboratory equipment in his station wagon and drove Leonard Skeggs and his wife Jean to New York. At Technicon, Skeggs set up a simple device consisting of a peristaltic pump to draw the specimen sample and reagent streams through the system, a continuous dialyzer to remove protein molecules 13

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14 MEDICAL DEVICE INNOVATION AND HEALTH CARE that might interfere with the specimen-reagent reaction, and a spec- trophotometer equipped with a how cell to monitor the reaction. This device demonstrated the validity of the idea, and we promptly entered negotiations with Skeggs for a license to patent the Auto Analyzer. We agreed on an initial payment of $6,000 and royalties of 3 percent after a certain number of units had been sold. After Technicon "turned-down" the project in 1950, Skeggs had made arrangements first with the Heinecke Instrument Co. and then the Harshaw Chemical Co. to sell his device. Both companies erro- neously assumed that the instrument was a finished product. However, neither company had been able to sell a single instrument from 1950 until 1953. This was not surprising, because Skeggs's original instru- ment required an expensive development process to make it rugged and reliable, and to modify the original, manual chemical assays. Technicon spent 3 years refining the simple model developed by Skeggs into a commercially viable continuous-flow analyzer. A number of problems unique to the Auto Analyzer had to be overcome. Because the analyzer pumps a continuous-flow stream of reagents interrupted by specimen samples, one basic problem was the interaction between specimen samples. This problem was alleviated by introducing air bubbles as physical barriers between samples. However, specimen carryover in continuous-flow analyzers remains sensitive to the formation and size of bubbles, the inside diameter of the tubing through which fluids flow, the pattern of peristaltic pumping action, and other factors. Development of the Auto Analyzer was financed internally at Technicon. In 1953 Technicon had ongoing business of less than $10 million per year: automatic tissue processors and slide filing cabinets for histology laboratories, automatic fraction collectors for chroma- tography, and portable respirators for polio patients. Until it went public in 1969, Technicon had neither borrowed money nor sold equity. Thus, Technicon's patent on Skeggs's original invention was central to the development of the Auto Analyzer. Without patent protection, Technicon could never have afforded to pursue the expensive devel- opment of this device. Early in the instrument's development, I recognized that traditional marketing techniques suitable for most laboratory instruments would not work for something as revolutionary as the Auto Analyzer. At that time, laboratory instruments were usually sold by catalog salesmen or by mail from specification sheets listing instrument specifications, price, and perhaps product benefits. In contrast, we decided that

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INVENTING MEDICAL DEVICES: FIVE INVENTORS' STORIES 15 Technicon had to market the Auto Analyzer as a complete system- instrument, reagents, and instruction. Technicon's marketing strategy has been to promote the Auto Analyzer at professional meetings and through scientific papers and journal articles. Technicon employs only direct salesmen. The company has never used agents or distributors, except in countries where the market is too small to support direct sales. To introduce technology as radical as the Auto Analyzer into conservative clinical laboratories, Technicon decided to perform clin- ical evaluations. Although unusual at that time, such evaluations have since become commonplace. An important condition of the clinical evaluations was Technicon's insistence that the laboratory conducting the evaluation call a meeting of its local professional society to announce the results. Such meetings generally resulted in an enthusiastic en- dorsement of the Auto Analyzer by the laboratory director. I believe this technique had much to do with the rapid market acceptance of the Auto Analyzer. Other unusual marketing strategies employed by Technicon to promote the Auto Analyzer included symposia and training courses. Technicon sponsored about 25 symposia on techniques in automated analytical chemistry. The symposia were generally 3-day affairs, attracting between 1,000 and 4,500 scientists, and were held in most of the major countries of the world including the United States. Because we realized that market acceptance of the Auto Analyzer could be irreparably damaged by incompetent users, Technicon set up a broad-scale training program. We insisted that purchasers of Auto Analyzers come to our training centers located around the world for a 1-week course of instruction. I estimate that we have trained about 50,000 people to use Auto Analyzers. Introduction of Technicon's continuous-flow Auto Analyzer in 1957 profoundly changed the character of the clinical laboratory, allowing a hundredfold increase in the number of laboratory tests performed over a 10-year period. When we began to develop the Auto Analyzer in 1953, I estimated a potential market of 250 units. Currently, more than 50,000 Auto Analyzer Channels are estimated to be in use around the world. In reviewing the 35-year history of the Auto Analyzer, I have come to the conclusion that several factors significantly influenced our success. First, the Auto Analyzer allowed both an enormous improve- ment in the quality of laboratory test results and an enormous reduction in the cost of doing chemical analysis. Second, physicians began to

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16 MEDICAL DEVICE INNOVATION kD HEALTH CAM realize that accurate laboratory data are useful in diagnosis. Last reimbursement policies increased the availability of health care. Plasmapheresis EDWIN C. WHITEHEAD l In the early 1940s, I read a provocative article by Arthur Wright, professor of surgery at New York University. Dr. Wright observed that by removing the plasma from a blood donation and then reinfusing red blood cells in the donor, one could bleed the donor twice a week instead of once every 7 weeks. At the time, Technicon Corporation was doing some work with William Aaronson, who was a pathologist at Morrisania Hospital in New York and also had a private laboratory. He and I discussed Wright's article and decided that the process would be practical only if it were automated. Otherwise, taking a blood donation, separating the cells from the plasma, and reinfusing the red blood cells in the donor would be too laborious. This was during World War II, and every newspaper and advertise- ment called for donations of plasma, which was sorely needed by the military. Dr. Aaronson and I reasoned that, since most of the soldiers in the United States were young and healthy, bleeding soldiers twice a week might be a better way of obtaining plasma than depending on donations from the civilian population. If we could make a small, portable, rugged, relatively inexpensive device to automate the process described by Wright, the military and the Red Cross should have great need for it. Aaronson and I experimented to determine the most efficient way to separate blood and plasma. The design we finally settled on was a cone-shaped container with radially extending blades that divided the container into separate compartments. Blood was drawn from the donor through a needle and injected directly into the center of the spinning container. Red cells were packed by centrifugal force at the outer edges of the container and plasma formed a layer closer to the center. We started removing plasma as soon as we had drawn 100 ml of blood. By the time the 400-ml blood donation was drawn, the plasma had been removed into a plastic bag. Saline solution was then added to the donor's red blood cells and the cells were fed back to the donor by gravity through the same needle used to draw the blood. In 6 months we had developed an operating prototype. We decided

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INVENTING MEDICAL DEVICES: FIVE INVENTORS' STORIES 1 ~7 to try it out by hiring a professional blood donor, bleeding the donor twice a week, and doing weekly blood chemistry studies to see if the donor experienced any ill effects. We managed to find a donor, but when we explained what we intended to do, he looked first startled, then frightened, and quickly picked up his hat and walked out. Aaronson and I tried to enlist other paid donors with the same result and finally decided to test our prototype by bleeding each other. I would stop at Aaronson's laboratory on my way home from work each Monday and Friday afternoon, and we would bleed each other. In 1944, after 6 months of observing no adverse effects, we decided that it was time to market the device. We made appointments with Red Cross, Army, and Navy offices in Washington, D.C., to demonstrate the device. Aaronson and I boarded the train from New York to Washington carrying a large box that contained substantial quantities of donated whole blood packed in ice. Feeling pleased with ourselves, we had reserved seats in the club car. We plunked down our large box and took our seats. Near Philadelphia, we noticed a thin, red stream of blood running from the box. Although our fellow passengers were too polite to comment, we were so embarrassed that we pretended the box did not belong to us until we got to Washington. Fortunately, only one of the bottles had broken. When Aaronson and I arrived in Washington, we were told by the Red Cross, the Army, and the Navy that, despite public appeals, the one thing the military had in abundance was blood plasma! In fact, both the Navy and the Army made a point of telling us that the first thing to be jettisoned in time of battle was blood plasma. Thus, our "market" completely disappeared and we abandoned our project, having spent a considerable amount of effort and receiving a patent for our invention. Pneumatic Extradural Intracranial Pressure Monitor ALAN R. KAHN Intracranial pressure (ICP) is monitored to detect dangerous pressure increases in patients with head or spinal trauma, craniotomies, Reye's syndrome, and certain drug intoxications. Before the invention of the pneumatic extradural ICP monitor in 1980, monitoring of ICE was generally accomplished by means of fluid-filled catheters (or other similar appliances) with one end in direct contact with the patient's

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18 MEDICAL DEVICE INNOVATION AND HEALTH CARE cerebrospinal fluid and the other end connected to a conventional pressure transducer. A device that detects ICP from a site outside the aura (the outermost and toughest membrane covering the brain) had been on the market for several years, but the pressure sensor in that device is very complicated and fragile, is slow to respond to changes, and is limited in accuracy. Thus, although that device established the usefulness of extradural ICP monitoring and has found application in certain medical centers, its use has been limited because of the complexity and inaccuracy of its sensing system. In contrast, the pneumatic extradural ICP monitoring system makes it possible to measure ICP simply, accurately, and at low cost. The invention includes a disposable sensor that is accurate, rugged, and inexpensive to construct. The invention also includes a pneumatic system in a monitoring module that powers the sensor and provides self-checking and failure detection. The system has been designed as a sophisticated microprocessor-based instrument and has been intro- duced to the market by Meadox Instruments, Inc. THE INVENTION PROCESS The invention of the ICP monitor was not the result of new technological developments but was rather the application of a basic physical principle that had been overlooked in the area of pressure measurement. In recent years, advances in technology have been made primarily in the field of electronics, and scientists and engineers tend to ignore other physical modalities such as pneumatics. Most of my inventions have been in the area of sensing and measurement and make use of basic physics rather than new technological developments. The necessary technical information can be found in any basic physics textbook. I first had the idea for the pressure management technique used in this instrument in 1964 as a way to measure the elasticity of human skin for a study on aging. At the time, I worked for a major corporation that did not see a market for a device with that application, and no product was ever developed. In 1980, during a discussion on ICP monitoring, I realized that my old idea could be modified for use in this new application. I offered the company with which I was employed the opportunity to develop this product under a royalty arrangement, but the company declined. Subsequently, I left that company to join a research and development consulting firm as an equal partner with the two existing partners, and we invested our time and personal funds to develop a prototype ICP

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INVENTING MEDICAL DEVICES: FIVE INVENTORS' STORIES 19 monitoring system. It took 6 months to build and test the first prototype in our laboratory and to perform preliminary tests in animals. FINANCING AND MARKETING Perhaps the most difficult step we encountered was in obtaining funding for design and marketing of the product. This was complicated by the fact that my partners and I were primarily interested in the R&D process and did not wish to get involved in marketing. Negoti- ations with venture capital firms and other conventional sources of capital proved unsuccessful, because acceptance of the extradural method of ICP monitoring was limited by the existing product, and it was difficult to project just how an improved product would affect market growth. Therefore, conservative sales projections were used in the business plan. These projections made the venture less attractive and affected our ability to obtain funding. We finally established a joint venture with Meadox, a biomedical company that had facilities for manufacturing the sensors and saw our ICP monitoring device as an efficient way to enter the market for electronic products. Each of the three partners in our R&D firm owned 9 percent of the new joint venture company and shared a royalty on product sales. Our R&D company received a contract from the joint venture company to develop the product and subsequently to manu- facture the electronic portion of the system until such time as the contractors learned more about the product and could take over all of the manufacturing. Although sales of the ICP monitoring systems in the United States proceeded as anticipated in our conservative pro- jection, the monitoring device was foreign to the Meadox product line and was subsequently discontinued. Invention of an Electronic Retinoscope ARAN SAFIR Following a year at Cornell University as an engineering student, I entered the U.S. Navy when I turned 18. On the basis of an aptitude test, I was placed in a training program for electronic technicians. The training lasted nearly a year and was rigorous and thorough. My Navy training and World War II ended almost simultaneously, and I spent another year in the Navy working on aircraft radio and radar systems. /

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20 MEDICAL DEVICE INNOVATION AND HEALTH CAME During that year, I decided that a career in medicine might offer a good combination of science, technology, and the social disciplines. I entered New York University as a premedical student majoring in English; later I entered medical school. Medical school was not much funrote memorization is not my strongest skill. In retrospect, I can see the early indications of some factors that would later assume great importance in my life. In high school, I had been seriously interested in photography- both the technology and the art. I had neither time nor money for it in medical school, but I turned to optics to help me learn pathology. Each student was given hundreds of slides of pathology specimens to be studied under the microscope so that the features of various diseases could be memorized. While studying my slides, I discovered that I could place my microscope on the floor underneath a small table that had a ground glass top. When I darkened the room, I could see the projected image of the microscope slide on the tabletop. Thus, I set about making my microscope into a projector. I bought the most powerful truck headlight bulb I could find, attached it to a transformer through an adjustable resistor so that I could operate the bulb well above its rated voltage, purchased some surplus lenses, and soldered together various rectangular and cylindrical tin cans to form a powerful substage lamp for my microscope. A small prism deflected the beam onto a white poster board on the wall, giving an image about 2 feet in diameter. With this device, several friends and I often studied our slides together and helped each other to learn. Still, I thought of this as only a passing diversion, almost occupational therapy, because I had always been a good mechanic and enjoyed building things. About 2 years later, I had a brief exposure to ophthalmology, which is all that most medical students get. But even during that brief exposure, I realized that I had to make almost no effort to memorize those parts of the textbook that dealt with the formation of images by the eye. When we went to the ophthalmological clinics and could look into the eyes of patients through widely dilated pupils, I was thrilled by the magic of the eye as an optical instrument. It was not until many months later, during my internship, that I had any opportunity to try my hand at surgery. When I found that I was good at surgery and enjoyed it, I began to think seriously of ophthal- mology as a career. Still, it was my intention at the time to become a practitioner of ophthalmology and to return to my hometown to establish a private practice. I clearly recall that at my residency interview at the New York Eye and Ear Infirmary, when the governing board of six senior surgeons asked me whether I intended to do

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INVENTING MEDICAL DEVICES: FIVE INVENTORS' STORIES ~1 research, my reply was: "I don't know. I think I would like to try, to see whether I'm any good at it." I became a resident at the New York Eye and Ear Infirmary in 1956. That institution was known mostly for the excellent opportunity it gave the trainee to observe, learn, and participate in the practice of ophthalmology, but offered little experience or opportunity in research. There was a small scientific program, but residents were rarely involved. I reported for duty as a resident at the infirmary on July 1, 1956. After being issued white uniforms, I was shown to the clinic. There I was put in the care of a second-year resident who was clearly too busy with his own clinical problems to spend much time with me. He sat me down on a stool in a little booth where a patient sat next to a box of ophthalmological trial lenses. This was to be my first experience with refraction of the eye. Handing me a small instrument that resembled a flashlight, which he told me was a retinoscope, the second- year resident explained that I was to look through the little hole in the mirror and direct the beam of light into the patient's pupil. When I shined the light into the patient's eye, he explained, I would observe the patient's pupil glowing with light reflected from inside the eye. By tilting the mirror, I could make the reflected light move across the pupil. I was to sit at arm's length from the patient and observe whether the light coming back out of the pupil moved in the same direction as the light I shined on the patient's face, or in the opposite direction. If the light moved in the same direction, I was to take lenses from one side of the box, while if the light moved in a contrary direction, I was to take them from the other side of the box. I was to select lenses that would make the light appear to stop moving. Wishing me good luck, the resident went off to his own tasks. I worked very hard at this first refraction and was quite upset by it. Like other young physicians, I had spent years learning to be competent in difficult matters. To be thrust suddenly back into complete incom- petence and at the same time to have responsibility for patient care was disturbing to me. I recall going to lunch that day and sitting across the table from that same second-year resident. I told him, "If I can see those lights moving in the pupil, I'll bet I can make a photoelectric device that will see them better and faster." That was the conception of my idea of an automatic retinoscope. The retinoscope is basically a small lamp that shines light on a mirror with a hole in its center. Light reflected from the mirror enters the patient's pupil and illuminates the retina at the back of the eye. Nearly all the light is then absorbed, but a small fraction is reflected

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22 MEDICAL DEVICE INNOVATION AND HEALTH CARE: back, passes through the pupil, and leaves the patient's eye. The light that is reflected by the retina goes through the optical system of the patient's eye and acquires characteristics of that system. The light rays leaving the eye can be either convergent, parallel, or divergent. If a patient's eye has excessive converging power, as it does in myopia (nearsightedness), the light rays leaving the eye will converge to a point in space at some distance in front of the eye. The distance from the patient's eye to that point is a measure of the amount of myopia (the closer the point to the eye, the greater the degree of myopia). An eye with no refractive error sends out parallel rays, and a farsighted eye sends out divergent rays. The retinoscopist sits in front of the patient, looks through the sight hole in the center of the mirror, and decides whether the emerging light rays have reached a convergent point between him and the patient or have not yet converged by the time they get to his eye. The patient, merely has to hold fairly still and gaze at a distant target. The examiner puts lenses in front of the patient's eye to bring the convergent point to a standard place, at the examiner's eye. The lenses needed to accomplish this are a measure of the eye's refractive state. With this objective measurement, the examiner can go to the next phase of the examination, in which the patient's subjective responses to various lenses are elicited. There is usually good agreement between retinoscopic measurements and the patient's subjective responses. Because retinoscopy depends on the examiner's skill, which varies considerably among practitioners, and the patient's subjective re- sponses, are affected by the patient's personality, the final judgment of the patient's visual status often requires complex decision making. Shortly after beginning my work in the clinic, I drew up plans for the construction of an electronic retinoscope and presented my ideas to the research committee of the New York Eye and Ear Infirmary. I asked them for sufficient laboratory space and a budget for some equipment so that I might try out my idea. They gave me about 6 feet of bench space in someone else's laboratory, allowed me to borrow a double-beam oscilloscope, and gave me a drawing account of about $500. I set to work building an instrument. The hospital had a lathe and a drill press that were gathering dust for want of a machine shop, so I was asked to build one for them. With the aid of one of the hospital's engineering staff, I constructed a machine shop to which I was subsequently given free access. The chief administrator of the hospital recommended that I obtain a patent on my invention and suggested that I go to a former West Point classmate of his who had become a senior partner in a well-

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INVENTING MEDICAL DEVICES: FIVE INVENTORS' STORIES ~3 known New York patent firm. I did this, and the senior patent attorney assigned my case to a young patent attorney who had just joined the firm. That was when I found out that patent attorneys have degrees both in law and in a scientific discipline. In the young attorney's case, it was electrical engineering. The New York Eye and Ear Infirmary gave me a key to the library and research building and, over the course of about a year and with the aid of my attorney friend, I built a working model of the electronic retinoscope. The instrument was crudethe photocells were housed in the film carrier of an old view camera, the image of the subject eye was formed by a telescope made from the mailing tube that had held my diploma from medical school, and many of the parts were surplus that I had purchased at the outdoor hardware stalls on Canal Street in New York. But 18 months after I started, I had a working model that demonstrated the feasibility of the method and was able to measure the refractive state of schematic eyes, which are metal and glass simulations of human eyes and are commercially available to students of refraction who are learning retinoscopy. An important scene stands out in my memory of those times. As soon as the retinoscope was operating satisfactorily, I invited a few close friends to come and see it. Rather late one evening we gathered in the lab: my patent attorney, my girlfriend, and three or four ophthalmological buddies. I explained the device and what to look for on the oscilloscope, dimmed the room lights, and put the instrument through its paces. The outputs of the photocells could be easily seen on the oscilloscope. As the schematic eye was changed from nearsighted to farsighted, the oscilloscope tracing showed the change and clearly identified the crucial neutral point when the convergent point of the rays emerging from the eye was brought to precisely the correct distance, exactly as in clinical retinoscopy. The instrument had a rotating light beam deflector for creating the scan of light across the eye. There were mirrors and lenses that cast moving patterns of light, not only on the schematic eye, but on the walls of the lab as well. The oscilloscope face flickered with green evanescent tracings. In the darkened lab, it was dramatic. As others got interested in the apparatus and began to operate it themselves, I stepped back to the far side of the room and watched them. A new feeling swept over me and I verbalized it internally: "Look at what I have done. What started as an idea in my head has created a new machine and has gathered these people here and captured their interest." I had a feeling of power and wonder, a very good feeling, and though I have experienced it again since then, it has never been so poignant. Surely, there are many reasons for people to

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24 MEDICAL DEVICE INNOVATION AND HEALTH CARE; experience such feelings, but invention is one that I have known, and I suspect that those who do not invent do not often appreciate the emotional importance of the act. The young patent attorney was rather excited about this project because his review of the patents in existence had led him to conclude that we were opening up an entirely new field. The idea of dynamic scanning to measure an optical system had not been patented before. After about 2 years of effort, we filed a patent application in 1958. The patent was not granted until 1964, after several rejections and a hearing. The entire 6-year proceeding, which cost me a great deal of money and effort, seemed to be designed to test my persistence rather than my inventiveness. In 1964 I received a letter from Bausch & Lomb asking me if I was interested in licensing my patent to them. A contractual agreement was arranged between the Bausch & Lomb Company and me. It was 8 years from the time we signed the contract until Bausch & Lomb offered an instrument for sale. In that time, another company came out with an automatic refracting machine, and the Bausch & Lomb retinoscope never achieved a significant share of the market. Now there are several automatic refracting machines on the market. Most of them are made in Japan, and one of them made by a major Japanese company uses the principle that I patented. For this, the company paid me royalties during the last year of the life of my patent. I made very little money from this invention. If I were to reckon my income from it in dollars earned per hours spent, I would have been far better off to have spent my time practicing ophthalmology. The First Successful Implantable Cardiac Pacemaker WILSON GREATBATCH On April 7, 1958 Dr. William C. Chardack, Dr. Andrew Gage, and I implanted the first self-powered implantable cardiac pacemaker in an experimental animal. In October of that year, Dr. Ake Senning in Stockholm attempted the first human implant. That device worked for only 3 hours and then failed. A replacement device worked for 8 days, after which the patient survived unstimulated for 3 years. Two years later, in 1960, Dr. Chardack, Dr. Gage, and I implanted the first successful cardiac pacemaker in a human.

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INtJENTl~G MEDICAL DEVICES: FIVE INVENTORS' STORIES ~5 At the time, we predicted an annual use of perhaps 10,000 pacemakers per year. Soon thereafter, however, the implantable pacemaker became the treatment of choice for complete heart block (impairment of conduction in heart excitation) with Stokes-Adams syndrome (a con- dition caused by heart block and characterized by sudden attacks of unconsciousness). Today nearly 30 years laterpacemakers have assumed forms and functions that we never dreamed of, and the world pacemaker market is approaching 300,000 units per year. When World War II was over in 1945, I decided to register at the School of Electrical Engineering at Cornell University in Ithaca, New York. As an undergraduate at Cornell, I got my first exposure to medical electronics. To feed my family, I occasionally worked as an electronics technician, building intermediate-frequency amplifiers for what was later to become the Arecibo, Puerto Rico, radiotelescope. One day, in an adjacent lab, I saw Cornell graduate student Frank Noble measuring blood pressure in a rat by recording the change in tail size as a pulse of blood traversed it. Frank's electronic plethys- mograph belonged to the psychology department's Animal Behavior Farm at Varna, New York, near Ithaca. Research at the Animal Behavior Farm dealt with conditioned reflex under neurosis, and Frank was responsible for measuring heart rate and blood pressure in some 100 sheep and goats there. I became very interested in this work, and when Frank left to become head of an electronics laboratory at the National Institutes of Health, I inherited his job. During the summer of 1951, two New England brain surgeons spent their summer sabbatical at the farm performing experimental brain surgery on the hypothalamus of goats. At lunchtime we would sit on the grass in the bright Ithaca sun and talk shop. I learned much practical physiology during our discussions. One day, the subject of heart block came up. When the surgeons described it, I knew I could fix it but not with the vacuum tubes and storage batteries then available. By the time the first commercial silicon transistors became available (at $90 each) in 1956, I had become an assistant professor of electrical engineering at the University of Buffalo, I was also spending time with Dr. Simon Rodbard and Dr. Robert Cohn at the Chronic Disease Research Institute in Buffalo. Sy Rodbard was interested in fast heart sounds, which we recorded with an oscilloscope and a movie camera. I wanted a 1-kilohertz marker oscillator and built one out of a single transistor and a United Transformer Company model DOT-1 (UTC DOT-1) transformer. My marker oscillator used a 10-kilohm base-bias resistor. One day, I

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26 MEDICAL DEVICE INNOVATION AND HEALTH CARE; reached into my resistor box to get a 10-kilohm resistor but misread the color codes, and instead of getting the brown-black-orange resistor, I got a brown-black-green (1 megohm) resistor. The circuit started to squeg (oscillate in bursts) with a 1.8-millisecond pulse followed by a 1-second quiescent interval. During the quiescent interval, the transis- tor was cut off and drew practically no current. I stared at the thing in disbelief and then realized that this was exactly what was needed to drive a heart. I built a few more. For the next 5 years, most of the world's pacemakers were to use a blocking oscillator with a UTC DOT-1 transformer just because I grabbed the wrong resistor! I found little enthusiasm locally for an implantable cardiac pace- maker. Each medical group I approached said, "Fine idea, but most of these patients die in a year or so. Why don't you work on my project?" In Buffalo we had the first local chapter in the world of the Institute of Radio Engineers, Professional Group in Medical Electronics (the IRE/PGME, now the Biomedical Engineering Society of the Institute of Electrical and Electronics Engineers). Every month, 25 to 75 doctors and engineers met for a technical program. Our chapter had a standing offer to send an engineering team to assist any doctor who had an instrumentation problem. One day in the spring of 1958, I went with such a team to visit Dr. William Chardack on a problem dealing with a blood oximeter. Dr. Chardack was Chief of Surgery at the Veterans Administration Hospital in Buffalo. Imagine my surprise at finding that his assistant was one of my old high school classmates, Andy Gage (later chief of staff at the hospital)! Our visiting team could not help Dr. Chardack much with his blood oximeter problem, but when I broached my pacemaker idea to him, he walked up and down the lab a couple of times, looked at me strangely, and said, "If you can do that, you can save 10,000 lives a year." Three weeks later in April 1958, Dr. Chardack, Dr. Gage, and I had our first model cardiac pacemaker implanted in a dog. Our experimental work was done on dogs that had been put into complete heart block by occluding the atrioventricular (AV) bundle with a tied suture. We had no heart-lung machine. The operating team stood poised like runners waiting for the starting gun. Upon a "go" signal, the team occluded the large vessels, opened the heart, occluded the AV bundle with the tied suture, closed the heart, and released the large vessels, all in 90 seconds! We were naive about early pacemaker designs. We initially thought that wrapping the module in electric tape would seal it. We soon

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IENTING MEDICAL DEVICES: FIVE INVENTORS' STORIES 27 found, however, that any void beneath the tape would fill with fluid, so we began to case our electronics in a solid epoxy block. Within a year, we had worked our animal survival time up from 4 hours to 4 months and felt ready to start looking for a suitable patient. Building pacemaker units began taking more of my time than my job would allow, so I quit my job to work full time on the pacemaker in 1960. I had $2,000 in cash and enough to feed my family for 2 years. I took the $2,000 and went up into my wood-heated barn workshop. In 2 years I had made 50 pacemakers, 40 of which went into animals and 10 into patients. The 10 patients had their pacemakers implanted by Dr. Chardack and his associates. Most of the patients were older people in their sixties, seventies, and eighties, typical of the usual heart-block patient. However, two of the patients were children and one was a young man with a wife and two children. The young man, I remember, had worked in a local rubber factory until he collapsed on the job one day. Soon thereafter, he had another severe attack in which his mother-in-law applied resuscitation and brought him back. Before implantation of the pacemaker, the young man's prognosis was grim. After recovery, he retrained as a hairdresser, worked full time, and joined a bowling team. This man was still alive and well in late 1987. Another patient I remember well, also in complete heart block with Stokes-Adams syndrome, was a woman in her sixties. She was our seventh patient. A few years ago, when our local engineering society named me "Engineer of the Year," she came to my award dinner. The news media called her the "Pacemaker Queen." She died not too long ago, in her eighties, after having been paced for over 20 years. In early 1961, Jim Anderson and Palmer Hermundslie of the Med- tronic Company, which manufactured external, hand-held pacemakers, hew into Buffalo from Minneapolis. At a luncheon table in the Airways Hotel at the Buffalo airport, we worked out a license agreement for the implantable cardiac pacemaker. The next day we had it notarized at a local bank. This agreement was the beginning of the Medtronic Chardack-Greatbatch Implantable Cardiac Pacemaker, which domi- nated the field for the next decade. The license agreement was a very tight one. I assumed design control for all Medtronic implantable pacemakers. I signed every drawing, every change, and had to approve every procurement source. The device had to be called a "Chardack-Greatbatch Implantable Cardiac Pacemaker" in all company brochures, advertising, and communica- tions, both within the company and without. The quality control program reported directly to me for 10 years. I sat on the board of directors and had a major (and noisy) input to all company affairs,

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28 MEDICAL DEVICE INNOVATION ED HEALTH CAM pushing pacemakers and dropping unprofitable product lines like cardiac monitors and defibrillatory. Within 2 years Medtronic had become number one in pacemakers. Today, over two decades later, Medtronic is still number one, and has a sales volume of nearly $300 million a year. Dr. Chardack was just as active as I, but in an unofficial, behind- the-scenes way. His papers, his case reports, his spring-coil electrodes, and his personal recommendations really "sold" the Medtronic device to the profession. Dr. Chardack's professional stature and reputation in the field were unparalleled. He was Medtronic's most effective and most credible "salesman" in those critical early days. We soon found that the highest grade military components were not good enough for the "zero defect" requirements of pacemakers. The warm, moist environment of the human body proved to be a far more hostile environment than outer space or the bottom of the sea. We had predicted a 5-year pacemaker in our first 1959 paper, but even by 1970 we were getting only 2 years. The miniature DOT-1 transformers that we initially used were wound with exceptionally fine wire and proved troublesome. We continued to experience failures until we finally went to a transformerless design. The Medtronic 5862 (my last design for Medtronic) used a three- transistor, transformerless, complementary multivibrator circuit (after Roger Russell's patent) which could not "hang up." With diode- isolated, dual-battery packs and voltage-doubler output, it was probably the most reliable of the mercury-powered pacemakers of the 1960s. Early transistors were inconsistent. We identified several failure modes due to contamination and leaky seals. We adopted the policy of segregating the transistors into beta (current gain) classes and then heat-soaking them for 500 hours at 125C; they were transferred to dry ice five times during this period. Any transistor that developed leakage or drifted more than one beta class was discarded. This was followed by a shock test. We lost about 15 percent of the GE 2N335 transistors in this program, but never lost one subsequently in a pacemaker. (The Minuteman space program later adopted much the same approach for high-reliability missile components after we pub- lished our procedures.) In 1964 Barough Berkovits (also a member of our chapter of the Professional Group in Medical Electronics when the American Optical Company Medical Electronics Division was in Buffalo) published a series of papers on a new pacemaker concept in which the pacemaker "listened" to the heart and worked only when the heart did not. A "demand pacemaker" seemed like quite a good idea, and we began working on an implantable version. My laboratory notebook says that

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INVENTING MEDICAL DEVICES: FIVE INVENTORS' STORIES ~9 we completed our first successful prototype on January 10, 1965. This design went on to become the Medtronic model 5841, which was the first implantable, inhibited-demand pacemaker to become commercially available. We gradually improved pacemaker reliability to the point that battery quality became the limiting factor. It was increasingly apparent that we would never achieve our objective of a "lifetime pacemaker" with the zinc-mercury battery. I terminated my license with Medtronic under friendly circumstances and established my own battery manu- facturing company, Wilson Greatbatch Ltd. Battery manufacturing, by the way, was another field about which I knew nothing. By 1972, after looking into several types of batteries, we had settled on a battery with a lithium anode, an iodine cathode, and a solid-state, self-healing, crystalline electrolyte invented originally by Catalyst Research Corporation in Baltimore. The development of the lithium battery eventually removed the battery as the limiting factor in pacemaker longevity. Today, nearly every pacemaker uses a lithium battery of some sort, and nearly every surgical intervention for a pacemaker problem is electrode-related rather than battery-related. Wheelchairs for the Third World RALF HOTCHKISS For the past 20 years I have been involved in wheelchair design and innovation. I became a paraplegic in 1966 and began by modifying my first chair. I now work full time on wheelchair design. For the past 12 years, I have been involved in making stair-climbing wheelchairs, stand/squat models, and high-speed sports chairs. My current focus is the design of lightweight folding wheelchairs for manufacture in developing countries. NICARAGUA WHEELCHAIR PROJECT In 1980 I was contacted by Bruce Curtis, a disabled man involved with the independent living movement. He had just returned from a trip to Caribbean and Central American countries, including Nicaragua. He was most enthusiastic about a group of disabled people he had met at a rehabilitation center in Managua, many of whom had become disabled during the revolution of 1979. These disabled Nicaraguans

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30 MEDICAL DEVICE INNOVATION AND HEALTH CARE: needed assistance with wheelchair repairs and wanted to learn to drive automobiles with hand controls. More important, they were very interested in the concept of independent living, which had given birth to numerous independent living centers in the United States. On my first trip to Nicaragua in 1980, I met many disabled people and began to assess their problems in obtaining and maintaining affordable wheelchairs that would meet their needs. I found that the disabled Nicaraguans who had managed to get wheelchairs used two types of chairs. The vast majority of people had second- or third-hand hospital-type chairs, which had hard tires and nonremovable armrests and footrests, and which gave the users little flexibility of use or mobility. Such wheelchairs had frequent breakdowns and were not very useful outdoors. The second type of chair was a U.S. prescription model, which few people had because it was very expensive by Nicaraguan standards. This type of chair was easier to use but had many of the same problems as the others. It was heavy, and the seat widths of the standard imported models tended to be far too wide for Nicaraguans. Many common replacement parts were impossible to get because American wheelchairs are not made from generic, inter- changeable parts. During my 1980 trip, I also worked with disabled people from the United States to provide information to disabled Nicaraguans about independent living. This visit set into motion the formation of an independent living center organized and run by disabled Nicaraguans from the rehabilitation center. The Nicaraguan government gave the group a house in Managua to use as an office. One of the group's top priorities was to set up a wheelchair repair shop and to obtain new wheelchairs that Nicaraguans could afford. The group also began to plan for the eventual economic self-sufficiency of the independent living center. After returning to the United States, I submitted a proposal to a Washington, D.C.-based group, Appropriate Technology International, which would allow me to provide technical assistance to the Managua independent living center for the establishment of a wheelchair repair and manufacturing shop. This proposal was funded for 1 year. During that year, I developed a prototype of a Third World-appropriate wheelchair at my shop in Oakland, California, and made eight trips to Nicaragua to help the independent living center organize its shop, purchase its tools and equipment, develop wheelchair repair and modification techniques, and begin making wheelchairs. Under a second contract with Appropriate Technology International, we com- pleted the Nicaragua project and began to spread the wheelchair design

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INVENTING MEDICAL DEVICES: FIVE INVENTORS' STORIES 31 and its technology to disabled people and their organizations in the Caribbean and Central and South America. EVOLUTION OF THE DESIGN The first prototype design for a Third World-appropriate wheelchair was based on features that wheelchair riders in the Western world often have learned to specify as modifications to the standard light- weight folding wheelchair to enable it to be used over rough terrain. When wheelchairs are used to climb curbs or follow rocky trails, for example, they bend and break if they are not properly reinforced. When they are propelled over rough ground, they lose traction and become impossible to push if they do not have pneumatic tires. Moreover, if they are any wider than necessary, they will not fit through many doorways; if they are too heavy, they will be hard to push and lift; if they do not fold, they will not fit in the aisle of a bus. With rare exceptions, full-time users needing a single vehicle for both indoor and outdoor use have found nothing better than four- wheeled, rear-drive wheelchairs with the following features: Width: 24 inches maximum for a 16-inch or greater seat width. Length: 42 inches. Weight: 45 pounds for a fully equipped chair with armrest/fenders, brakes, footrests, handrims. Lightweight aluminum folding chairs, weighing as little as 30 pounds fully equipped, are now available at high cost. Traction and Maneuverability: A skilled rider of a four-wheeled, rear-drive chair can easily shift all of his or her weight to the drive wheels, giving full traction over rough terrain. When combined with pneumatic tires and a flexible frame, the four-wheeled, rear-drive chair gives excellent propellability and better stability than a three-wheeled chair of comparable width. Ease of Assistance: The rear-wheel drive chair can be tipped back on the rear wheels by an assistant and pushed or pulled over curbs and rough terrain. Folds: To a width of 12 inches or less. Easy disassembly of the chair by the rider has also been demanded by some users. Accessibility: The chair must not interfere with pulling close to a worktable or, for users who cannot stand, making lateral transfers into and out of the chair. Durability: The chair must stand up to the shock of ramming curbs and chuckholes and withstand rough treatment in all types of

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32 MEDICAL DEVICE INNOVATION AND HEALTH CARE transit. It must not be prone to breakdowns, which can strand the rider far from service facilities, and must perform with a minimum of routine maintenance. Commercial chairs vary widely in this regard. These criteriaimportant for active wheelchair riders in the Western worldare particularly important for riders in Third World countries where doors are narrower, turning spaces are smaller, roads are rougher, curbs and steps are higher and less uniform, assistance in getting over obstacles is needed more often, wheelchairs must be lifted more often, and access to repairs is far more restricted. Thus, my goal has been to design a wheelchair for manufacture and use in developing countries. It was to be at least as good as the best Western model but less expensive, made out of locally available materials, and built in workshops set up with a minimum of capital. During the first year, I did most of the work on designing and revising prototypes for a Third World-appropriate wheelchair. After that, one of the disabled Nicaraguans, Omar Talavera, made significant contributions to the design. A visit in 1981 to Tahanan Walang Hagdanan (house with no stairs) in the Philippines, where 20 wheelchair riders had built more than 1,000 low-cost chairs, led to more significant changes in our design. The major problems in developing a workable prototype stemmed from lack of materials and poor understanding of wheelchair use in Nicaragua. The economic situation in Nicaragua made it difficult, and sometimes impossible, for the wheelchair shop to purchase custom- made wheelchair parts from outside the country. We were forced to find ways to make wheelchair components out of standard Nicaraguan hardware, and the unavailability of materials in Nicaragua quickly began to dictate the design of our wheelchair. I had already decided to use zinc-plated electrical conduit instead of inch-sized seamed metal tubing, because the standard sizes of electrical conduit were more available in Nicaragua. The prototype design changed as I discovered what else was not available: hardened bolts, concentric tubing sizes, suitable ready-made hubs, and more. We are still trying to figure out how to make a high-resiliency, low-cost front wheel, but everything else is now made out of locally available materials. My naivete about the life-style of disabled Nicaraguans caused one major change in the prototype. My original design called for a wooden folding seat, which allowed me to use a simpler and stronger folding mechanism than that in the average U.S. chair. That design had to be scrapped, however, because I had not taken into consideration the fact that, unlike wheelchair riders in the United States, most Nicaraguan

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I^ENTING MEDICAL DEVICES: FIVE INVENTORS' STORIES 33 wheelchair riders do not sit on cushions. A wooden seat would cause decubitus ulcers for people with spinal cord injuries. During the first year, I bought some cushions and tried to convince the group to use them. As the cushions wore out and needed replacement, I finally realized why most Nicaraguans would never use cushionsthey cannot afford new ones. I had also overlooked the need in Nicaragua for a folding wheelchair that allows the rider to fold the chair partially without getting out of it. The Nicaraguans partially fold their chairs to squeeze through the narrow doorways that are common in that country. We now have enough barrier-free buildings in the United States that this is not considered an essential feature. As a result of these economic and practical problems, the current wheelchair design is almost completely original and is closely attuned to the needs of disabled people who live in rural areas and cannot afford anything but the cheapest wheelchairs. THE FUTURE The ability of the independent living center in Managua to proceed beyond prototype development into marketing of wheelchairs has been hampered by the problems the country has had in maintaining a general inventory of basic materials. Another problem is that the disabled people who run the independent living center and who grew up in poverty are not used to the concept of purchasing in bulk. Instead, they are used to buying today what they need today as a result, they sometimes lose opportunities to buy needed materials when they are available. The potential market for wheelchairs in Managua is great if measured by need. However, not many disabled Nicaraguans can afford to buy their own wheelchairs, even though the Managua-made wheelchair is much less costly than imported chairs. At present, materials for one wheelchair cost about U.S.$80, and =5 person-days are needed to complete each chair. The sales price is about U.S.$170. So far, 50 wheelchairs have been sold to private individuals in Nicaragua. Durability and ruggedness have been major characteristics built into our wheelchair's design, and it is hoped that the wheelchairs can be maintained indefinitely. We have begun to spread what we have learned. Under the spon- sorship of Appropriate Technology International, we held workshops in Jamaica, Peru, Costa Rica, Honduras, and California. Each mechanic

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34 MEDICAL DEVICE INNOVATION AND HEALTH CARE completed a wheelchair and took it home to use as a model for production. A 150-page production manual, Independence Through Mobility, is now available from Appropriate Technology International. A new project, Appropriate Technology for Independent Living, has begun in California to carry on the development and dissemination of our wheelchair design worldwide.