Willem J. Kolff, M.D.

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ARTIFICIAL ORGANS  FORTY YEARS AND BEYOND

W. J. Kolff

DEDICATION

I dedicate this lecture to Mrs. Vna Loy stark for her unseZfish and total dedication to her husband, Dr. Barney CLark, and for her courage, her understanding and for the support she has given our artificial heart team.

 

THE ARTIFICIAL KIDNEYS

I am not really the inventor of the artificial kidney. The artificial kidney was described by Abel, Rowntree and Turner, 3 Americans, in the City of Groningen, The Netherlands, during a Physiological Congress in 19131. I was 2 yrs old at that time, and I do not remember it, but in that same city I began to work on artificial kidneys in 1939.

In the City of Kampen, I later induced the industrialist, Mr. H. Th. J. Berk to build the first artificial kidney that was clinically useful 2,3 (Figure 1). And, so it has been during the rest of my very interesting life. I have induced other people to make and invent things, and in many cases, I have assisted with the invention. In all cases, my younger coworkers have had the opportunity to write a scientific publication with their name as the first author.

I have remained committed to the artificial kidney. Figure 2 is a photograph of the Wearable Artificial Kidney (WAK). It was designed in Dr. Steve Jacobsen's Laboratory at the University of Utah along with his coworkers, Todd Johnson, David Knutti, Barry Hanover, and many others. This photograph shows the newest model of the WAK which is now beginning to be manufactured in Japan (Mr. Fumio Uno, President, Junken Company, Ltd., 82427 Higashidaira, HigashimatsuyamaCity, SaitamaKen, Japan). We have obtained FDA approval to sell it in this country. We have not found any of the major companies involved in artificial kidneys interested in manufacturing it. It is like the automobile, until you import a small one from Japan, the established companies are not interested.

The aim of the WAK is to make kidney patients more independent, to increase their selfreliability and to make them better adjusted and happier. Mr. John Warner and Mrs. Lauraine Stephen organize "Dialysis in Wonderland" trips (Figure 3) with this in mind.

Since introducing the washing machine kidneys (Figure 4) and the "windthemyourself" kidneys5, I have fought a losing battle against the increased cost of dialysis. One of the reasons for the high cost of dialysis (2 billion dollars per year from Social Security alone), can be seen in Figure 5 and Figure 6 which compare the cost of home or center dialysis with hospital dialysis. The physician who makes the decision whether or not socalled "acute dialysis" (which means any dialysis inside a hospital) is indicated, is often the same physician who earns $240 more for hospital dialysis than for home dialysis. A delay of one month before a patient is referred to a dialysis center costs the Social Security Service $6,000 extra. With the advent of better immunosuppression (Cyclosporin A, etc. ), which make kidney transplantation easier, chronic dialysis for EndStage Renal Disease is on the way out. Fortunately for manufacturers, membrane separation of plasma proteins will strongly increase. Plasmapheresis was described by Abel, Rowntree and Turner in the same journal in which they published hemodialysis1. Dr. U. R. Shettigar in our department is developing cascade filtration by separating undesirable globulins from desirable albumin. An entirely new field of application lies open: rheumatoid arthritis, myasthenia gravis, cancer, burn patients. Figure 7 shows a diagram of cascade filtration using first a filter to separate plasma and then a filter to separate globulins from albumin6.

THE ARTIFICIAL HEART

Early Hearts. In 1957, in his Presidential Address to this Society, Dr. Peter Salisbury gave a clear description of an implantable artificial heart'. In December of that same year at the Cleveland Clinic, Dr. Tet Akutsu and I implanted the first artificial heart in a dog8. To the best of my knowledge, this was the first implantation of an artificial heart in the Western World. Demichov in Russia implanted an artificial heart in the chest of a dog, the drive shaft of which came through the sternum. This happened in Russia before World War II in 19379.

We counted all the scientific coworkers that have worked with me on artificial hearts and they totaled 247. These are only the names of those that have been listed as authors or coauthors of scientific articles.

From the Division of Artificial Organs, Department of Surgery, School of Medicine and the Institute for Biomedical Engineering, College of Engineering, University of Utah, Salt Lake City, Utah.

Supported in part by the NIH via NHLBI, Grant Nos. 2ROIHL24561 and 2ROIHL24338, and by the Development Fund of the Division of Artificial Organs to which contributions have been made by many including: American Health Assistance Foundation, Beatrice Foods, BurroughsWellcome Fund, Digital Equipment Corporation, Ernest W. Hahn, Lawrence Harvey, William Randolph Hearst Foundation, Iris Margolis, Ben Matthews, Square D Foundation, Mr. Wallace Rassmussen and Stichting Alfred Heineken Funds.

When somebody in our Division of Artificial Organs works on an artificial heart, it carries his name for easy identification. Thus, we have had Akutsu hearts, Norton hearts, Nose's giant atria, Lyman hearts, Donovan hearts, KwanGett hearts, Unger hearts, and Jarvik hearts. The man who worked on the heart published it under his name as first author. The only thing we have not had is a Kolff heart.

In 1957, our artificial heart was made of a thermosetting polyvinyl chloride called Plastisol inside hollow molds so that there were no seams (Figure 8). We followed the technique invented by a genius, Dr. Selwyn McCabe, who worked in Dr. Bowman's laboratory and the National Institutes of Health in Bethesda, MD. The valves were also made of polyvinyl chloride and were of the tricusp semilunar type imitating the natural aortic valves. They had sinuses of Valsalvae as well as we could make them. This artificial heart was driven with compressed air and used the principle we have honored ever since; that is to provide sufficient pressure to expel the blood from the ventricles and use as little suction as possible so that the venous filling determines the cardiac output (Starling's Law of artificial heart). For the drive system, we used 4 belloframs compressed with a cam and pulled back for diastolic filling with extremely flimsy springs, used only to overcome the slight resistance to movement of the belloframs. This artificial heart was published in the ASAIO Transactions in 19588.

Shortly thereafter, we made artificial hearts driven by electric motors10~l2 and an electrohydraulic heart driven by solenoids13 (with S. Harry Norton).

Air Driven Heart. We became restless with this slow progress, and it was Dr. Kirby Hiller of NASA who made a strong plea to return to artificial hearts drivenby compressed air. He and his associates at the Lewis Research Laboratory at NASA in Cleveland built a magnificent drive system in which one could program the shape of the air pressure waves, the rate, the duration of systole and diastole and, in addition, it could be guided by position transducers which would at least in theory prevent the crushing of blood cells14'15. The drive system was magnificent, but I once said that one needed a pilot's license to drive it. It would fail from timetotime due to such simple things as a surgical suture sticking in a programmed air valve. We began to look for simpler drive systems. From then on, one can say that simplicity has been the hallmark of our major attempts.

This made funding very difficult because it is relatively easy to obtain funding for complicated computerized drive systems with which one can simulate a thousand things. It is nearly impossible to obtain funding for something simple. Therefore, over the years my laboratory has teetered along, always on the rim of bankruptcy, always having too many ideas and too little money to carry them out.

Control and Drive Outside. We subscribe to the idea that for the time being, only the blood handling parts should be inside the body and that the control mechanism and the drive system should be outside the body 16'17. When one accepts this principle, then energy requirements, durability of drive system and control mechanism become much less pressing since one can repair or replace them if they are on the outside. E one has them inside the chest, one would have to open the chest to get at them.

We further believe that for the next few years, an air drive tube through the skin will have to be accepted, although electric wires through the skin would be a little more convenient. We tried to prevent infection along the drive lines by a special skin flange with a telescoping mechanism that relieves the stress from the point where the skin seals the entrance 18 (Figure 9).

Figure 10 is a diagram of a very simple drive system 19. A simple valve located in a 3way design exposes the artificial heart either to pressure or to the atmosphere (or a low subatmospheric pressure if that is required).

The Detroit Coil Company in Detroit made commercially available solenoid controlled air valves. Dr. Frank Hastings of the NIH (or his predecessor, Dr. C. William Hall) had 10 of these drive systems built by the Detroit Coil Company and distributed them to various laboratories in this country. that drive system 20.

Dr. Clifford KwanGett moved with me from Cleveland, Ohio to Salt Lake City in 1967. He made improvemeets to this system, the most essential being a larger valve opening and surge tanks between the pressure regulator and the valve. A young Chinese engineer (Hung K. Wong, who later died in an automobile accident), made further improvements to the drive system. Steve Nielsen, an electrical engineer who is still with us, further perfected it. It is now commonly called the Utah Heart Driver. Dr. KwanGett published his artificial heart and drive system in 7 articles under his name as the first author21~22. In at least 22 publications, we have referred to his articles. The Utah Heart Driver was used for Dr. Barney Clark. When one uses a slight vacuum (a slightly subatmospheric pressure of the order of magnitude up to 15 cm of water), then one shifts the Starling's curve to the left. We used 9 cm of water in Dr. Barney Clark most of the time.

For the control of artificial hearts, until the necessity will prove that it shall be otherwise, we follow extreme simplicity. We follow Starling's Law of the artificial heart. The venous filling (which is related to venous pressure) determines the filling of each stroke and when that stroke volume is discharged with every beat, the result is that the venous pressure determines cardiac output. The rate can be set by hand, but in Dr. Clark we did not have to touch the drive systems for weeks, even when he exercised and got in and out of bed. The same is true in our animals who are allowed more vigorous exercise on a treadmill.

The Pumps Inside the Chest. Our first artificial hearts were the sactype 23, but soon we also had artificial hearts that used a diaphragm  that means only one side of the ventricle was activated, and the other side

remained stationary. A special variation was the artificial heart with special antisuction bellows which followed Starling's Law better than any other device I have ever seen (Figure 12) 0. Diaphragm artificial hearts were used in combination with the NASA machine since we had one stationary coil on one side and a moving coil as a position transducer on the diaphragm. Mr. John Holter of the Holter Company made some diaphragm ventricles of the same principle but by injection molding. He had one set pump in the entrance hall to his office for many years without breaking until an unfortunate successor removed it, for no other reason than he was not interested. We implanted some of these artificial hearts (Figure 13)24.

Dr. KwanGett came with an important innovation. To prevent tunneling of the compressed air, he tied the moving diaphragm around a metal or other hard base. Also, the KwanGett diaphragm was relatively small so that it would never touch the other side of the ventricle and it would not crush red blood cells (Figures 14 and 15). Holding the diaphragm between 2 metal constrains is not new. It was done by Dr. Ted Stanley who came with his ventricular assist pump from Michigan in 1967 25.

Dr. KwanGett designed an innovation in 1975 after he had already left us, by first making the housing with the blood ports of the artificial heart and then by fitting a metal cavity under it. It is then possible to make a membrane heart without a seam, using the conventional urethanesolution casting technique. His contribution is herewith acknowledged. This was incorporated into the JarvikV ventricle which uses a pumping diaphragm of 4 layers to offer better flex life (published by Jarvik in 1977 26).

The Fit Inside the Chest. I felt we had problems with the fitting of the KwanGett heart between the sternum and vertebral column. I blamed the rise in venous pressure which we saw with improper fit. Therefore, I asked Robert Jarvik, who at that time was a premedical student, to make the pancake heart, also called the JarvikII (Figure 16). It was very flat. The left and right ventricles were Iying against the rib cage, and the entire area between the sternum and the vertebral column was free for the atria and the large vessels 27. Indeed, the calf that had this heart implanted did not have any recognizable problems with elevated left atrial pressure. I then asked Robert Jarvik to create a modification of the KwanGett heart which would have a lower ventrodorsal diameter. The result was the Jarvikm (Figure 17) 28. As was seen in xrays, it left space between the trachea and the heart valves free for atria and vessels. The JarvikV had a circular contour for easy machining of the molds and was larger to serve larger calves 29. The JARVIK 7 heart (Figure 18) is smaller than the JarvikV (Figure 19). It is designed for fit inside the human chest and it did fit in Dr. Barney Clark30.

The placement of the JARVIK 7 heart inside the chest, however, deserves some careful consideration and practice in cadavers for surgeons who have not implanted it before. After 3 mos of pumping, no one can deny that it did fit inside Dr. Barney Clark, but Dr. Clark was a large man. Dr. DeVries moved the left ventricle fairly far out to the left side. My oldest son, Dr. Jack Kolff at Temple University in Philadelphia, has done implantations of the JARVIK 7 heart in braindead cadavers. This is as close as one can come to the real thing. In his braindead patient number 4, Jack found that the JARVIK 7 heart fits easier when the left ventricle is moved further towards the left. It is also possible to use the JARVIK 7 heart in a smaller patient. One then has a choice of whether to put one ventricle orthotopically and the other ventricle heterotopically, or both ventricles heterotopically  one on the left side and one on the right side. In a small braindead patient, weighing only 96 pounds, Dr. Jack Kolff made the right atrium into a blindpouch by oversewing the tricuspid orifice. The right artificial ventricle was placed on the right side and connected to the lateral side of the natural atrium; the left ventricle could be placed on the left side of the chest. The critically narrow area between the sternum and vertebral column could be reserved for connections only (Figure 21). Dr. Jack Kolff was able to sustain the circulation of the fifth braindead patient for 3 days with good lung function until the experiment had to be terminated so as not to interfere with the funeral arrangements 31.

Based on our fittings in the human cadavers and on the experience with Dr. Barney Clark and the braindead patients, the conclusion is that the JARVIK 7 artificial heart will indeed fit in the human chest, but carefully and if necessary, one ventricle to the right and one ventricle to the left side of the chest.

Portable Drive System. Dr. Barney Clark moved about with his drive system 32 (Utah Heart Driver) all through the hospital, to the xray department to have scans done, to sun rooms, through the halls and in the elevators. Although a person with the present drive system could go shopping if he wanted to, pushing the drive system along with him, a far more elegant solution is the H. Peter Heimes' drive system as seen in Figure 22 3.

The only reason why it was not used in Dr. Clark was that it did not have any redundancy. This means that if it would break down, one would have to replace it in minutes. The newest Heimes' driver, however, has this redundancy. It consists of 2 motors, 2 pumps and there are 2 of every component. If onehalf of the system breaks down, the other half will continue to operate sufficiently to sustain life although there could not be any vigorous exercise.

Monitoring. The monitoring of our air driven artificial hearts inside the chest is done with a combination of air drive line pressure curves and the COMDU (Cardiac Output Monitoring and Diagnostic Unit  invented by Peter Willshaw and Steve Nielsen)34. This measures the flow of the air that is expelled from the ventricle during

diastole by the inflow of blood. We believe it to be accurate within 10%, and it gives a wealth of diagnostic information. Every third stroke, we see the stroke volume and the calculated cardiac output for the right and left side (Figures 23 and 24). Since the COMDU operates with the exhausted air drom the drive system, no transducers of any type are required inside the chest. We wouldn't dare treat a patient now without it. The Heimes' Driver has its own inbuilt computer and monitoring system (Figure 25). Indeed, the experimental data obtained from a Heimes' Driver are transmitted by modern telephone by Steve Nielsen in Salt Lake City to Dr. Peter Heimes in Aachen, Germany, for further perfection of this driver.

Electrohydraulic Hearts. For the future of totally implanted electrically driven artificial hearts we are also aiming at extreme simplicity. The one system presently in the works that has the most promise for this is Jarvik's electrohydraulic heart. Figure 26 is a picture of the electrohydraulic heart 35'36.

Since the blood handling ventricles are basically the same as the ones used in the air driven hearts, we do not expect any unknown difficulties there, but instead of air, it pumps a hydraulic fluid from left to right and right to left. The enfine has only one moving part  an electric motor to which a propeller is welded. It reverts from 12,000 revolutions one way to 12,000 revolutions the other way in 1/12,000's of a second. The propeller does not churn up the blood because it is only the hydraulic fluid that moves back and forth. The motor is cooled by the hydraulic fluid that surrounds it and hydrodynamic bearings will not wear at all. We have met disbelief by peer review committees, but both the possibility and the durability of the bearings have been proven beyond a doubt. It will be a few years before this electrohydraulic heart is ready for clinical implantation. All of the electrical controls can be initially outside the chest.

Biomaterials. In Utah, cooperation with a strong Biomaterials group has been of invaluable assistance to us. In this group we have among others, Dr. Don Lyman, Dr. Joe Andrade, Dr. S. W. Kim, Dr. Dennis Coleman, Dr. Lee Smith, Dr. Don Gregonis and Dr. Jim McRea37. I once made the statement that when the design is good, nearly any material works 38. However, better materials and anticlotting surfaces allow us to make some deviations from the optimum design which may be required because of other constraints. While this group has been invaluable to us to point out our shortcomings, their greatest impact is still to come when the grafting of prostaglandins, anticoagulants and antibiotics to the polymers becomes practical. Dr. Kim and coworkers have shown that immobilized heparin39 and prostaglandins40 are effective. If heparin is grafted on a stalk of 8C atoms to the surface of the polymer, it is most effective (Figure 27).

Permission from the FDA. It took Dr. William DeVries 7 mos to obtain permission for implantation of the artificial heart in a human patient who could not be weaned off the heartlung machine. It took our company, Kolff Associates, Inc., 7 mos to answer all the questions the FDA wanted answered for its approval. It took another 8 mos, thereafter, before we were approved by the Institutional Review Board to do artificial heart implantations in patients with cardiomyopathy. The FDA then took only a few weeks. The major objection anywhere has been the fact that we remove the natural heart. The symbol of love, the site of life and the habitat of the soul still has a magical attraction even when it is no good. I do admit that it is an irrevocable step, and if the sick heart does not commit any mischief, it might even take over in case of noncatastrophic failure of an artificial heart. I was convinced of this after seeing the results of Dr. Christian Barnard's group in South Africa with the socalled heterotopic transplantation (or piggyback implantation) of a donor heart where the right atrium was connected to the right atrium and the left atrium to the left atrium, the aorta to the aorta and the pulmonary artery to the pulmonary artery. With the 2 hearts in parallel, the heart that is the strongest pumps the most; the other coasts along 41.

Implant ~ Transplant. Olsen 42 has convincingly shown that the circulation can first be sustained with an artificial heart and later the animals can live with a heart transplant. We believe, however, that the artificial heart has justification for existence all by itself, mainly because we will never have enough donor hearts for transplantation.

Permanent LRVADs. On this basis, I have worked on Left Ventricular Assist Devices (LVADs) and Right Ventricular Assist Devices (RVADs) which can leave the natural heart in place but yet can take over the total heart function. They can also be implanted under the skin or inside the chest with their backs against the rib cage. These LVADs and RVADs are made by an entirely new technique. The valves are homemade tricusp semilunar valves to avoid the extraordinary cost of other mechanical valves. Figure 28 is a picture of a sheep with an LVAD apparently none the worse for it. However, we are not ready for clinical use yet4 .

Electrical coordination with the natural heart is not necessary, and it is probably a disadvantage since it might decompress the natural ventricle to the point where it will atrophy. With an LVAD on the left and an RVAD on the right side, the entire circulation can be taken care of. The insertion in animals does not require a pump oxygenator. To the best of my knowledge this and a modified JARVIK 7 are the only air driven LRVADs that are designed for permanent use. For the word "permanent", compare its meaning in the connection with permanent wave provided by one's wife's hairdresser. We adhere to the same policy expressed earlier for total artificial hearts, only the blood handling parts are inside the chest. Air tubes go through the chest wall; control and drive system are outside the chest where they can be serviced and, if necessary, replaced.

Intraaortic Balloon Pump. The term "counterpulsation" originated in a brainstorming session in Dwight E. Harken's laboratory in 1958. In 1961, Moulopoulos, Topaz and Kolff invented the intraaortic balloon pump.

It was published in 1962 44~45. We are forever indebted to Adrian Kantrowitz for having introduced its clinical application in 196667 46'47. Dr. Jack Kolff obtained a grant from the NIH to adapt the intraaortic balloon pump in babies. They used cats and very small dogs to practice with incredibly small balloons (2. 5 ml). Dr. Veasy and coworkers have now the first babies whose lives were saved by these very small balloons 48.

OTHER RESEARCH ADVANCES

Insulin Via the Portal System. Most insulin pumps to regulate diabetes deliver the insulin in the systemic circulation like any other insulin that is injected. This is most unfortunate since it gives a high insulin concentration in the periphery where it is blamed (rightly or not) for degeneration of retina, capillaries, arteries and kidneys, and it gives one a relatively low concentration in the liver where one wants it. After all, the Lord or nature put the pancreas in the portal circulation, not in the systemic circulation. Dr. Robert Stephen, Dr. Carl Kablitz, Dr. Jeff Harrow, Dr. Steve Jacobsen and coworkers are delivering insulin via the portal system by instilling it into the peritoneal cavity via an access device  the insulin button or SPAD (Figure 29). This is a natural consequence of our work with peritoneal ravage and the use of the indwelling "mouse" as a port of access to it. Brittle juvenile diabetics can be regulated with ease with intraperitoneal insulin. Moreover, we have the first patients with beginning renal failure on the basis of juvenile diabetes, where the disease is actually halted or improved 49'50. Sometimes the insulin buttons have been overgrown by mesothelium, but this can now be relieved with a laser beam directed through a peritoneoscope. In view of the numbers of diabetics to be helped, and the dismal long range prognosis of most juvenile diabetics, the intraperitoneal administration of insulin may become the most important contribution our laboratory has made (patients are pending).

Artificial Arm. The Artificial Arm by Dr. Steve Jacobsen and his colleagues in the Center for Biomedical Design of the College of Engineering in the University of Utah is without any doubt the most sophisticated artificial arm around. Since its movements are controlled by myoelectrical pickups attached to either the stump or the muscles of the shoulder girdle, the arm already moves when the amputee thinks he wants to do something 51. It was a particular problem to make sure that this quick moving arm would not knock out the teeth of its owner so it slows down whenever it approaches the owner's lips. It is now being combined with an artificial hand made by Otto Bock in Germany. Movements are careful enough to hold a tomato when one cuts it, yet strong enough to crack a nut when one wants it (Figure 30).

The Artificial Eye. After Dr. William Dobelle left our Institute for Biomedical Engineering to go to Columbia University in New York City, 2 more arrays of electrodes made in Utah have been implanted on the visual cortex of totally blind people in New York City. When one stimulates an electrode, the blind man sees a light point here and when one stimulates another electrode, he sees another light point there. With a television camera in his hand, the blind man can recognize a simple letter like "A" or "L". When he reads Braille by stimulation of his brain, he understands what he is reading. With the enormous advance in electronics and particularly with the availability of gate arrays, we hope to resume work on the artificial eye again where we left off 7 years ago52.

The Artificial Ear. There has been more progress towards the artificial ear. Unlike the artificial eye that directly stimulates the cortex of the brain, the artificial ear stimulates the acoustic nerve via 6 platinum electrodes threaded up into the cochlea of the inner ear of the deaf patient. Dr. Don Eddington who originally worked with Dr. William Dobelle, has returned after a period of extra training at MIT Peabody Laboratory, and the artificial ear has now reached the point where the electrodes fit in a package about the size of a pack of cigarettes. One totally deaf person is able to understand up to 85% of spoken words he has never heard before and without seeing the lips of the speaker. If he sees the speaker facetoface, he can hold a near normal conversation. A visitor from Geneva was introduced to a totally deaf bearer of Dr. Eddington's artificial ear. The deaf man told the visitor that although he was from Geneva, his accent sounded as if he came from a German speaking part of Switzerland. Indeed, he came from Zurich (Figure 31) 53~54.

COWORKERS IN THE EXPERIMENTAL LAB

While the invention, development and manufacturing of the actual art)ficial heart and assist devices of course is very important, one does not get anywhere unless one has an animal laboratory and personnel that can implant artificial hearts in animals and can study them without killing the animal. I have been extremely fortunate for the last 10 yrs to have Dr. Don Olsen as Head of our Experimental Heart Research Laboratory. He has implanted artificial hearts in animals in Utah and also Rostock, East Germany; Brno, Czechoslovakia; Lyon, France; Buenos Aires, Argentina; and a few other places. An East German calf "Rosie" in Rostock had the impertinence to live longer than any Soviet calf with an artificial heart. Dr. Olsen has had the assistance of a string of excellent and devoted Japanese surgeons. Some of them, like Dr. Hiro Fukomasu, worked with us for 3 yrs.

I express my thanks to all my former coworkers, many of whom came from foreign countries. They came from Europe, Finland, Rumania, Greece and Turkey in the East to England in the West. They came from

Australia and from Asia, India, Thailand, the Philippines, Korea, China, and Japan. They came from the United States, Central and South America. They all had one thing in common  they were all forced to speak English, be it with a Dutch accent, and they were all devoted to the cause of artificial organs. Milestones were reached by Dr. Tet Akutsu, Dr. Yuki Nose, Dr. Spyros Moulopoulos, Steve Topaz, Dr. Clifford KwanGett, Dr. Hans Zwart, Dr. Don Olsen, Dr. Hiri Fukumasu, and Dr. Jack Kolff. In our calf laboratory, we have the habit of appointing one principal investigator who is in charge of any calf with an artificial heart. This principal investigator has the full responsibility for the care of this calf, and no one else is to change the course of treatment or the management of the calf without the consent of the principal investigator.

In the case of Dr. Barney Clark, Dr. William DeVries was the principal investigator and Dr. Lyle Joyce was the coprincipal investigator. I am extremely happy with the entire team at the University of Utah and particularly with the principal investigators.

We have counted all the scientific coworkers involved with the development of the total artificial heart and assist devices over the years. There were 247. The following is an alphabetical list of those 247 people. Their names have been taken from the authors listed on scientific articles published from our laboratory.

LIST OF DR. WILLEM J. KOLFF'S 247 COWORKERS WHO HELPED TO DEVELOP THE

PERMANENT ARTIFICIAL HEART UNTIL IT WAS IMPLANTED IN THE FIRST

HUMAN PATIENT  DR. BARNEY CLARK  ON DECEMBER 2, 1982

REFERENCES

1. Abel JJ, Rowntree LG, Turner BB. On the removal of diffusible substances from the circulating blood of living animals by dialysis. J Pharmacol Exp Ther 5:275, 1913.

2. Kolff WJ, Berk HThJ, Ter Welle M, Van Der Ley AJW, Van Dyk EC, Noordwijk J. The artificial kidney: A dialyzer with a great area. Acta Med Scand 117:120, 1944.

3. Kolff WJ. First clinical experience with the artificial kidney. Ann Intern Med 62:608, 1965.

4. Kolff WJ, Jacobsen S, Stephen RL, Rose D. Towards a wearable kidney. Kidney Int 10S:300, 1976.

5. Khastagi B, Erben J, Shimizu A, Rose F, Nose Y, Van Dura D, Kolff WJ. The fourcoil artificial kidney for home dialysis. Trans Am Soc Artif Intern Organs 13:14, 1967.

6. Shettigar UR, Mann H, Gressner A. Continuous enrichment of albumin in relation to globulins in plasma. Artif Organs 6:163, 1982.

7. Salisbury PF. Implantation of physiological machines into the mammalian organism. Identification of problems connected with the implantation of artificial hearts and of artificial kidneys. Experimental results to date. (Presidential Address) Trans Am Soc Artif Intern Organs 3:37, 1957.

8. Akutsu T, Kolff WJ. Permanent substitutes for valves and hearts. Trans Am Soc Artif Organs 4:230, 1958.

9. Demikhov VP. In: Haigh B, ed. Chapter 5 in Experimental Transplantation of Vital Organs. Moscow: Translation Medgiz, 1960, pp 212213.

10. Norton SH, Akutsu T, Kolff WJ. Artificial heart with antivacuum bellows. Trans Am Soc Artif Intern Organs 8:131, 1962.

11. Akutsu T, Houston ChS, Kolff WJ. Roller type of artificial heart within the chest: Preliminary report.Am Heart J 59:731, 1960.

12. Houston Ch, Akutsu T, Kolff WJ. Pendulum type of artificial heart within the chest: Preliminary report. Am Heart J 59 723' 1960.

13. Kolff WJ, Akutsu T, Dreyer B, Norton SH. Artificial heart in the chest and use of polyurethane for making hearts, valves and aortas. Trans Am Soc Artif Intern Organs 5:298, 1959.

14. Hiller KW, Seidel W, Kolff WJ. An electronicmechanical control for an intrathoracic artificial heart. Am J Med Electr 2:212' 1963.

15. Kolff WJ, Hiller KW, Seidel W, Moulopoulos S, Akutsu T, Mirkovitch V, Topaz SR. Results obtained with artificial hearts driven by the NASA servomechanism and the pathologic physiology of artificial hearts. Trans Am Soc Artif Intern Organs 8:135, 1962.

16. Jarvik RK. Electrical energy converters for practical human total artificial hearts  an opinion in support of electropneumatic systems. Artif Organs 7 21 ~ 1983.

17.Kolff WJ. Clinical use of artificial hearts in the l9oO's. Texas Heart Inst J (in press).

18. Hastings WL, Aaron JL, Deneris J, Kessler TR, Pons AB, Razzeca KJ, Olsen DB, Kolff WJ. A retrospective study of nine calves surviving five months on the pneumatic total artificial heart. Trans Am Soc Artif Intern Organs 27 71 ~ 1981.

19. Nose Y, Kolff WJ. Some experiences with artificial hearts inside the chest, driven with a simple inexpensive servosystem. J Cardiovasc Surg 9:22' 1968. lff WJ The intracorporeal mechanical heart. Vascular D'seasest;21. KwanGett CS, Wu Y, Collan R, Jacobsen S, Kolff WJ. Total replacement artificial heart anu ur~ving system with inherent regulation of cardiac output. Trans Am Soc Artif Intern Organs 15:245' 1969.

22. KwanGett C, Zwart HHJ, Kralios AC, Kessler T, Backman K, Kolff WJ. A prosthetic heart with hemispherical ventricles designed for low hemolytic action. Trans Am Soc Artif Intern Organs 16:409' 1970.

23. Akutsu T, Mirkovitch V, Stephen R, Topez S, Kolff WJ. Silastic sac type of artificial heart and its use in calves. Trans Am Soc Artif Intern Organs 9:281 ~ 1963.

24,  Kolff WJ. The artificial heart: Research, development or invention? Dis Chest 56:314' 1969.

25.  Stanley TH, Boam W. Use of the computer to monitor longterm cardiac assistance. J Thorac Cardio

26.  Jarvik RK, Olsen DB, Kessler TR, Lawson J, English J, Kolff WJ. Criteria for human total artificial heart implantation based on steady state animal data. Trans Am Soc Artif Intern Organs

27.Jarv~k R, Voider J, Olsen D, Moulopoulos S, Kolff WJ. Venous return of an artificial heart designed to prevent Ann Biomed Engr 2 335' 19/4.

28. Unger F, Olsen DB, Oster H, Kolff WJ. Material and design factors in thromboembolization in total artificial heart recipients living 100  2~000 hours. Eur Surg Res 8:105' 1976.

29. Jarvik RK, Olsen DB, Kessler TR, Lawson J, English J, Kolff WJ. Criteria for human total artificial heart implantation based on steady state animal data. Trans Am Soc Artif Intern Organs 23

30. DeVries WC, Joyce LD, Hastings WL, Olsen DB, Jarvik RK, Kolff WJ. The permanent clinical implantation of the Utah total artificial heart. (Abstracts) Am Soc Artif Intern Organs 12:2' 1983.

31. Kolff J, Dub G, Michael G, Riebman J. Human studies with a pneumatic artificial heart. Heart Transplantation (in press)

32.Kolff WJ. Old, new and revised aspects of artificial organs. Int J Artif Organs 3:94' 1980.

33.Heimes HP, Klasen F. Completely integrated wearable TAH drive system. Int J Artif Organs 5 157'

34.Willshaw P, Nielsen SD, Nanas J, Pichel RH, Olsen DB. A cardiac output monitor and diagnostic unit for pneumatically driven artificial hearts. Artif Organs (in press).Fukumasu

36. H, Smith L, Jarvik R, Lawson J, Nielsen S, Olsen DB, Iwaya F, Kolff WJ. Development ofelectric and electrobydraulic hearts for future human application. Jap Soc Artif Intern Organs

36.Jarvik RK. The total artificial heart. Scientific Am 244:74, 1981.

37. Coleman D, Lawson J, Kolff WJ. Scanning electron microscopic evaluation of the surfaces of art.ficial hearts. Artif Organs 2 166' 1978.

38. Kolff WJ, Stellwag F. Blood at artificial organ surfaces: Progress to date as stepping stones for the future. Ann NY Acad Sciences 283:443, 1977.

39.Ebert CD, Kim SW. Immobilized heparin: Spacer arm effects on biological interactions. Thromb Res 26.43, 1982.

40.Ebert CD, Lee ES, Kim SW. The antiplatelet activity ofimmobilized prostacyclin. J Biomed MaterRes 16.629, 1982.

41. Losman JG, Replogle RL, Kolff WJ. An alternative to the orthotopic artificial heart: A point of view. Artif Organs 6:319, 1982.

42. Olsen DB, DeVries WC, Oyer PE, Reitz BA, Murashita J, Kolff WJ, Daitoh N, Jarvik RK, Gaykowski R. Artificial heart implantation, later cardiac transplantation in the calf. Trans Am Soc Artif Intern Organs 27:132, 1981.

43. Kolff WJ. For the clinical application of the artificial heart. Point of view. Heart Transplant 1 :159, 1982.

44. Moulopoulos SK, Stephen R, Topez S, Kolff WJ. Extracorporeal assistance to the circulation and intreaortic balloon pumping. Trans Am Soc Artif Intern Organs 7:85, 1962.

45. Moulopoulos SD, Topez S, Kolff WJ. Diastolic balloon pumping (with carbon dioxide) in the aorta  a mechanical assistance to the failing circulation. Am Heart J 63:669, 1962.

46. Kantrowitz A, Tjonneland S, Krakauer J, Butner AN, Phillips SJ, Yahr WZ, Shapiro M, Freed PS, Jaron D, Sherman JL Jr. Clinical experience with cardiac assistance by means of intraaortic phaseshift balloon pumping. Trans Am Soc Artif Intern Organs 14:344, 1968.

47. Kantrowitz A, Phillips SJ, Tjonneland S, Freed PS, Butner AN, Sherman JL Jr. Initial clinical experience with intraaortic balloon pumping in cardiogenic shock. JAMA 203:113, 1968.

48. Veasy LG, Blaylock RC, Daitoh N, Fukumasu H, Orth JL. Preclinical evaluation of intraaortic balloon pumping for pediatric use. Trans Am Soc Artif Intern Organs 27:490, 1981.

49. Stephen RL, Jacobsen SC, Maxwell JG, Kablitz C, Maddock RK, Tyler FH. Longterm intraperitoneal insulin treatment: Preliminary studies in 12 diabetic patients. In: Friedman EA, L'Esperance FA, eds. Diabetic RenalRetinal Syndrome, Vol. 2, Prevention and Management. Grune S Stratton, Inc., 1982, pp 447461.

50. Jacobsen SC, Hanover BK, Stephen RK, Maxwell JG, Kablitz C, Harrow J. Longterm intraperitoneal (IP) insulin. In: Piskin E, Chang TMS, eds. Proceedings International Symposium on Hemoperfusion and Artificial Organs. 1982, pp 102104.

51. Jacobsen SC, Knutti DF, Johnson RT, Sears HH. Development of the Utah artificial arm. IEEE Trans Biomed Engr BME29:249, 1982.

52. Dobelle WH, Mladejovsky MG, Evans JR. Braille reading by a blind volunteer by visual cortex stimulation. Nature 259:111, 1976.

53. Eddington DK, Dobelle WH, Brackmann DE, Mladejovsky MG, Parkin JL. Auditory prostheses research with multiple channel intracochlear stimulation in man. Ann Otol Rhinol Laryogol (Suppl 53) 87, Part 2, 1978.

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