Artificial Organs 9(1):7-11, Raven Press, New York 0 1985 International Society for Artificial Organs

Therapeutic Artificial Organs: Future Perspectives

Yukihiko Nose

Department of Artificial Organs, Cleveland Clinic Foundation, Cleveland, Ohio, U.S .A .

“We have achieved the maximum limit of surgical removal. The future surgery is organ replacement either by transplantation or artificial organs.”

When Professor Jiro Mikami of the University of Hokkaido made this statement to me in 1957, when I was enrolled in his Department of Surgery, there had been no successful artificial kidneys, oxygen- ators, or even transplantations. Since 1957, many advances have been made in the field of artificial organs and organ transplantations.

Today, patients with end-stage organ failure can be restored to useful life by artificial organ or trans- plantation technologies. It is now possible to re- move, replace, or substitute for the heart, lung, pan- creas, or small intestine. It is also possible to re- move 8 0 4 5 % of the liver (Table 1). Heart valve replacement, vascular substitution, and pacemaker implantation have become routine procedures. Temporary heart assist devices, auxiliary heart transplant, and heart transplantation have become acceptable clinical methods of treatment (Table 2). Temporary partial-heart and pneumatically driven assist devices have been used in 250 cases, and total artificial hearts have been used for short-term (1) and for long-term replacement (2).

The pneumatic replacement of actuation by a to- tally implantable driving system for artificial hearts will eventually become a reality. Totally implant- able, electrically driven pusher-plate-type left ven- tricular assist devices are examples of this tech- nology that are currently being used in experiments with animals ( 3 ) .

There are 30,000 heart valves and 150,000 pace- makers implanted annually. Additionally, there are 350,000 cases of vascular graft implants per year.

Received November 1984. Address correspondence and reprint requests to Dr. Y. Nos6

at Department of Artificial Organs, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44106, U.S.A.

This study was presented, in part, at the Fourth Congress of the International Society for Artificial Organs, November 14- 17, 1983, Kyoto, Japan.

Pump oxygenators are used at least 200,000 times a year, and in the United States, 10,000,000 dialysis procedures are carried out each year (Table 3 ) .

Orthopedic implants are also very routinely placed. For example, 110,000 hips, 65,000 knee joints, and approximately 50,000 other joints are re- placed annually in the United States. Other surgical implants include dental implants, breast prostheses, nose and other facial prostheses, and penile im- plants. The number of ophthalmic implants in the United States has also increased substantially in re- cent years.

Transplantation also is becoming a well-accepted therapeutic practice. In the United States, 5,000 kidney transplants are performed annually (Table 4). Cornea transplantations number 22,000 per year. Heart and liver transplants have become more common during the last few years.

Spare-parts medicine, a term associated with the application of artificial organ and transplantation technologies, is now routine, as was predicted over 20 years ago. The applications for this technology are on the increase.

Techniques such as the artificial kidney or kidney transplantation, total artificial heart, or heart trans- plantation are used in cases of end-stage organ failure. The direct cost for maintenance of the fed- erally funded end-stage renal disease program in the United States is over $2 billion annually, and is ex- pected to at least double before levelling off (4). The cost of a heart or liver transplant is approximately $100,000. What will be the cost for total artificial heart implants, and who will be able to afford this procedure? Considering the high cost of its end- stage renal failure program, will the United States federal government ever subsidize another program of similar magnitude? Can society be expected to take over this burden in light of the rapid pace of technologicd advancement?

Despite the high costs of end-stage organ tech- nologies such as dialysis, the alternatives are not without disadvantages. Natural organ replacement carries with it certain medical complications. Arti-

7

8 Y . NOSE

TABLE 1. Surgical removal of organ systems: present status

Heart Total removal and replacement Lung Total removal and replacement Kidney Total removal and functional,

Pancreas Total removal with functional

Small Total removal with parenteral

Liver 8045% removal

anatomical replacement

assist

intestine nutrition

ficial organs are not fail-safe and are not perfect substitutes for their natural counterparts. Im- proving artificial organs will mean making them more complex. Will increased complexity add to their costs?

The application of artificial organ and organ transplantation technology creates its own set of problems. For example, acute and chronic bio- chemical, hematological, and immunological imbal- ances can result. The chronic renal failure patient population shows higher incidences of certain forms of cancer, heart disease, and immunodeficiency symptoms when compared with their age-matched normal counterparts.

Many ethical and legal issues have been raised. It appears that the best approach for spare-parts medicine is to emphasize equally the disease-pre- ventative applications so that the number of end- stage organ failures can be reduced and thus the more expensive technologies can be used in a smaller number of chronic-care patients. Limiting the number of patients who need the most sophis- ticated technologies will help mitigate the eco- nomic, social, legal, ethical, and medical dilemmas we face.

GOALS

The objective is to reduce the numbers of end- stage organ failure patients through application of artificial organ technologies at much earlier stages in the disease process than has heretofore been pos- sible. This will be more cost effective. The reduc-

TABLE 2. Heart replacement: present status

Partial replacement Heart valve (mechanical and biological) Pacemaker Temporary assist device Auxiliary heart transplant

Total artificial heart Heart transplantation

Total replacement

TABLE 3. Implant procedures and cardiovascular replacements in the United States in 1983

Procedure Number

Cardiovascular implants Heart valves Pacemakers Vascular grafts

Extracorporeal devices Oxygenators Dialysis procedures

Surgical implants Dental implants Plastic and reconstructive

Breast prostheses Cosmetic surgery After mastectomy Nose, chin and other

Penile prostheses

implants

prostheses

Orthopedic prostheses and implants Hips Knees Shoulders, finger joints,

other Ophthalmic implants

Lenses Retinal surgery Other prostheses

Insulin infusion pumps Other

30,000 150,000 150,000

200,000 1o,o0o,ooo

20,000

100,000 80,000 20,000

10,000 5,000

110,000 65,oM)

50,000

25,000 up to 50,000 up to 8,000

5,000

tion in numbers of such patients will decrease the need for dialysis and transplantation. Reducing the incidence of end-stage heart failure and occlusive arterial disease due to atherosclerosis, vasculitis, or cardiomyopathy will lessen the need for artificial hearts and vascular or valve replacement. Pre- venting or slowing end-stage bone and joint dete- rioration as related to long-standing rheumatoid ar- thritis will decrease the need for artificial joints.

A review of the underlying disease process gives evidence of metabolic and immunologic abnormal- ities ( 5 ) . Might not earlier sustained biochemical and immunological control prevent or at least delay the onset of these chronic disorders?

APPROACH TO PREVENTIVE MEDICINE WITH ARTIFICIAL ORGANS

How will the reduction of end-stage organ failure be accomplished? With the availability of artificial organ technologies, it is now possible to modulate

TABLE 4. Transplantations, in 1982

Bone and joint 300 (world) Cornea 22,000 (U.S.A.) Kidney 5,000 (U.S.A.) Heart 170 (world) Liver 100 (world)

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FUTURE PERSPECTIVES FOR ARTIFICIAL ORGANS 9

TABLE 5. Normal fibrinogen values in humans

Value (mgidl)

10-19 20-29 30-39 30-44 50-59

Over 60

185- 300 185-340 177-365 2 15 -400 235-455 260 - 5 00

the biochemical and immunological systems of the body. Chronic immunological diseases, including autoimmune diseases, atherosclerosis, cancer, and infection, can be treated by artificial organ tech- nologies that regulate the body’s bio-immunological chemicals, thereby halting and possibly reversing the disease process. While certain patients can be cured with or without the help of conventional med- ical or surgical therapy, in some groups of patients the number requiring treatment will certainly be re- duced.

How can immunomodulation be carried out? Macromolecular kinetics in the body are not well understood. Certainly, abnormally increased levels of macromolecules represent an immunological re- sponse. If the physiological system is deficient in removing or reducing the macromolecules, they will gradually accumulate in the body. Plasmapheresis, and the more recently introduced plasmapheresis coupled with plasma filtration, is one method to re- move macromolecules from the body.

Simple filters, introduced in the last 5 or 6 years, are now available for the separation of plasma from whole blood. The plasma, which contains accu- mulated macromolecules, is discarded and is gen- erally replaced with an albumin solution. By dis- carding the plasma, the macromolecules are also discarded. Plasma exchange is becoming an ac- cepted method of treatment and is also used in de- veloping treatments for various diseases (6). For ex- ample, if this method of treatment is applied in the early stages of anti-glomerular basement membrane disease, the disease process can be controlled, pre- venting chronic renal failure. Non anti-GBM glo-

TABLE 7. Hematologic and biocheinical changes in a patient with sclerosing cholangitis who underweiit 95

plasma treatments

Pretreatment Posttreatment

White blood cell count ( x 109/L) 8.0 5.1 Platelet count ( x IOP/L) 340.0 199.0 Fibrinogen (mg%) 400.0 310.0 Cholesterol (mg%) 2,195.0 315.0 Triglycerides (mg%) 118.0 194.0 Lipoprotein

t Normal

P t t Pre p 1 LI No band Trace

merulonephritis can also be treated with this method, as can the acute rejection phase of organ transplantation and lipid disorders. Rheumatoid dis- eases have also been treated by plasma exchange. Rheumatoid arthritis has not, however, been shown to respond well to simple plasma exchange. How- ever, Raynaud’s syndrome, scleroderma, dermato- myositis, and rheumatoid vasculitis can be effec- tively treated by this method, as can multiple my- eloma, and macro- and cryoglobulinemias.

Plasma exchange replaces only a portion of the body fluid. It not only removes the pathological macromolecules, but also the essential macromol- ecules. In addition, this method cannot be applied as intensively as the disease treatment may require. The ideal method of plasma treatment is that which does not require any substitution fluid and which can be performed as extensively and intensively as may be required.

Cryofiltration was developed to overcome some of the disadvantages of plasma exchange (7). In this procedure, separation and cooling of plasma and secondary filtration semiselectively removes the “pathological” macromolecules in the form of cry- ogel. Cryogel consists of cryoprotein, immune com- plexes, immunoglobulin, fibronectin, fibrinogen, activated complement, endotoxin, antibodies, al- bumin, and other components. The exact compo- sition will be a function of the plasma treated, the filtration temperature, the anticoagulant used, and the filter module employed (8). This procedure is

TABLE 6. Sizes of lipoproteins

Ultracentrifuge Electrophoresis Size

Very low density

Intermediate

Low density

High density

lipoprotein Pre P 300-700 A (carry most of triglycerides)

density lipoprotein pre P to p 300 p\

lipoprotein P 250 A (60% of cholesterol is carried)

lipoprotein a 75-200 A

Arrf Organs, Vol. 9, No. 1 , 198.5

10 Y. NOSE

TABLE 8. Immunosuppressive agents in malignancies

Specific blocking factors Free tumor-associated antigens Free antibody Immune complexes

ol,-acid glycoprotein a,-antitrypsin a-fetoprotein Immunoregulatory a-globulin Carcinoembryonic antigen Fibrinogen degradation product Immunosuppressive acidic protein a2H-globulin

Nonspecific blocking factors

safe and can be applied as intensively as required- every day if necessary.

Controlled trials of plasma exchange in rheuma- toid arthritis did not result in significant improve- ment (9), but leukopheresis did improve results. However, in uncontrolled trials, cryofiltration showed better results than did leukopheresis (10). More than 85% of patients showed improvement (1 1). This difference is probably due to the selective nature of the macromolecule removal, lack of re- placement fluid requirement, and the capacity for more intensive treatments.

How can atherosclerosis be treated? Atheroscle- rosis may be an autoimmune disease, so normali- zation of immunologically active macromolecules is important. It is also important to achieve normali- zation of lipoproteins, cholesterol, and triglycer- ides. In addition, it may be important to remove pathological fibrinogen, for which the so-called normal range increases with age (Table 5 ) . The fi- brinogen in the aged population may be excessive, and some might be pathologic, which may con- tribute to the atherosclerotic process. The various types of lipoproteins are of different sizes (Table 6). Very low density and low density lipoproteins are much larger than the high density lipoprotein. Be- cause the larger lipoproteins are more pathologic, membrane technology is well suited for separating the larger lipoproteins from the smaller ones. In a patient with sclerosing cholangitis who was treated for more than 2 years once weekly or biweekly (12), cholesterol and lipoprotein levels normalized (Table 7). White blood cell, platelet, and fibrinogen con-

TABLE 9. Survey of reports on plasma treatment for solid tumor as of October 1983

Published articles 32 Number of patients treated 138 Treatment effective 55 Treatment not effective 83

TABLE 10. Artificial heart applications projected for the year 2000

Expected application Temporary LVAD and BVAD Permanent LVAD Permanent biventricular ADS Total artifjcial heart

Temporary LVAD and BVAD Permanent LVAD Permanent biventricular ADS Total artificial heart

Ideal application"

Patientsiyear 50,000 12,500 6,250 6,250

4 ,OM) 1,000

500 500

LVAD, left ventricular assist device; BVAD, biventricular assist device;

a Assuming rates of disease will be reduced SO that the need for such ADS, assist device system.

applications is reduced.

centrations also became more normal. It is believed that methods of plasma treatment can be developed which may have the potential of reversing athero- sclerosis.

What about cancer? There are specific blocking factors or immunosuppressive substances for malig- nant tumors that exist in the patient's plasma, in- cluding free tumor-associated antigens, free anti- body, and immune complexes (Table 8). There are also nonspecific blocking factors that exist, such as aL,-acid glycoprotein, a,-antitrypsin, a-fetoprotein, immunoregulatory a-globulin, carcinoembryon- ic antigen, fibrinogen degradation product, a2-H- globulin, and immunosuppressive acidic protein. Plasma exchange has been used for the treatment of solid tumors (13,14). More than 32 articles have been published, and more than 138 patients treated. The effectiveness, at present, is not that impressive (Table 9). Tumor size reduction is claimed, but it is believed that chemotherapy, immunotherapy, and radiotherapy, coupled with plasma treatment, would be more effective. So far, all of the articles are anecdotal in nature, and intensity and treatment methods are not well defined; no specific or non- specific immunosuppressive factors were identified. Plasma exchange is not selective and, as in the case of rheumatoid arthritis, nonselective removal by the current level of exchange is not very effective. Var- ious investigators have now embarked on treatment protocols for cancer utilizing membrane plasma fil- tration. To prove its effectiveness, it will be neces- sary to have more frequent, intense and longer term treatments than are currently being applied to iden- tify the blocking factors and to clarify their immu- nosuppressive activity. After identification, a well- designed control study could be implemented. Plasma exchange and specific sorbents as immu- noadsorbents have been applied; however, it is the author's opinion that the selective removal of spe- cific immunosuppressive macromolecules will not

Artif Organs. Vol. 9, No. 1. 1985

FUTURE PERSPECTIVES FOR ARTIFICIAL ORGANS I 1

be the answer. It is probably necessary to remove not only the specific immunosuppressive agents but also the nonspecific ones. As a technology, cryofil- tration, coupled with specific sorbents, can best ful- fill these objectives at present.

Through biochemical and immunological modu-

Nielsen S, Hastings L , Anderson J , Anderson F, Menlove R. Lessons learned from Dr. Barney Clark, the first patient with an artificial heart. In: Atsumi K, Maekana M, Ota K , eds. Progress in artificial organs Cleveland, OH: ISAO Press, 1984 (in press).

3. Fujimoto LK, Smith W, Butler K, Kiraly R, Morimoto T, Harasaki H, Moise J, Nos6 Y. An LVAS with practical clin- ical features. Trans Am Soc Artif Intern Orpans 1984 (in

lation by-plasma treatment technologies, it is hoped that by the year 2000 the numbers (current esti- mates) of left ventricular assist devices and artificial heart patients will be reduced to less than 10% (Table lo), and that the hemodialysis population will also be reduced to below current levels.

CONCLUSION

There are many pioneers in the field of artificial organs. They have achieved a great deal. They have unlimited curiosity, enthusiasm, and optimism; they established goals years ago that have become to- day’s reality. It is the obligation of the artificial or- gans scientific community to continue their work. If the momentum of the pioneers is maintained, the impossibility of today will be the reality of to- morrow. The wave of the future is cost containment in medicine. This does not mean the elimination of expensive technologies, but rather the intelligent and reasonable use of them. Artificial organs have a bright future, but only if preventative as well as end-stage organ failure applications are empha- sized.

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