Artificial Cells - American Chemical Society

11 Artificial Cells THOMAS MING SWI CHANG

Downloaded by PRINCETON UNIV on November 13, 2014 | http://pubs.acs.org Publication Date: June 8, 1984 | doi: 10.1021/bk-1984-0256.ch011

Artificial Cells and Organs Research Centre, McGill University, Faculty of Medicine, 3655 Drummond St., Montreal, PQ, Canada H3G 1Y6

Artificial c e l l s were first prepared i n 1957. Since then, there has been increasing basic, applied and clinical research i n this area. At present, artificial c e l l s are being investigated clinically as blood substitutes; artificial kidney; detoxifier; artificial l i v e r ; drug c a r r i e r s ; immunosorbent; hemoperfusion and other areas. They are also being investigated for their a p p l i cations in biotechnology in the areas of immobilized enzymes, b i o l o g i c a l s , and cells.

Since artificial c e l l s were first prepared by the author i n 1957 [1,2] an increasing number of approaches to their use are now available. Thus, artificial c e l l membranes can now be formed using a variety of synthetic or b i o l o g i c a l materials, resulting i n variations of permeability, surface properties and blood compatibility. Almost any material can be included within artificial cells. These include enzyme systems, c e l l extracts, b i o l o g i c a l cells, magnetic material, isotopes, antigens, antibodies, vaccines, hormones, adsorbents and others. A number of potential a p p l i cations, suggested e a r l i e r , have now reached the clinical trial or clinical application stage. Detailed reviews are available [4-7]. RED BLOOD CELL SUBSTITUTE Since 1956 we have investigated the f e a s i b i l i t y of using a r t i f i c i a l red blood c e l l s for use i n blood transfusion [1-3]. I n i t i a l l y , we prepared a r t i f i c i a l c e l l s i n the form of microencap0097-6156/84/0256-0171S06.00/0 © 1984 American Chemical Society

In Polymeric Materials and Artificial Organs; Gebelein, C.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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s u l a t e d hemoglobin. I n - v i t r o , these a r t i f i c i a l c e l l s d i d not i n t e r a c t w i t h blood group a n t i b o d i e s , but they c o u l d t r a n s p o r t oxygen and carbon d i o x i d e . However, a f t e r i n f u s i o n , they were removed r a p i d l y from the c i r c u l a t i o n . We a l s o prepared a r t i f i c i a l red blood c e l l s w i t h an organic m a t e r i a l , s i l i c o n e rubber, as the major component [8,9]. S i l i c o n e rubber microspheres can t r a n s p o r t oxygen. However, they were removed r a p i d l y from the c i r c u l a t i o n . Other groups were t e s t i n g a s i m i l a r m a t e r i a l i n the form of s i l i c o n e o i l and f l u o r o c a r b o n f l u i d f o r t r a n s p o r t i n g of oxygen. L a t e r , they prepared a f i n e emulsion of f l u o r o c a r b o n o i l as a red blood c e l l s u b s t i t u t e [10]. By c o a t i n g the s u r f a c e w i t h p h o s p h o l i p i d s to form an a r t i f i c i a l c e l l membrane, the f l u o r o c a r b o n emulsion could become s t a b i i l i z e d and blood compatible. C l i n i c a l t r i a l s have been i n i t i a t e d i n Japan and U.S.A. However the long-term i n - v i v o e f f e c t s of f l u o r o c a r b o n are not known. We e a r l i e r demonstrated t h a t hemoglobin could be c r o s s - l i n k e d by u s i n g a b i f u n c t i o n a l agent, forming a l a r g e polyhemoglobin. This permitted the a r t i f i c i a l c e l l s to be made much s m a l l e r than microencapsulated hemoglobin [2-4,9]. This has now been developed f u r t h e r so t h a t hemoglobin can be c r o s s - l i n k e d i n t o an even s m a l l e r polyhemoglobin which remains i n s o l u t i o n . S t u d i e s , being c a r r i e d out at t h i s Research Centre, have shown t h a t the s m a l l polyhemo g l o b i n s u r v i v e d much longer i n the c i r c u l a t i o n , as compared t o stroma-free hemoglobin [11].

THE ROLE OF ARTIFICIAL CELLS IN ARTIFICIAL ORGANS The r a t e of e q u i l i b r a t i o n i n 10 ml of 20 μ diameter a r t i f i c i a l c e l l s i s 400 times higher than f o r a standard hemodialysis machine [3,5,8]. Furthermore, membrane p r o p e r t i e s of a r t i f i c i a l c e l l s can be v a r i e d over a wide range to a l l o w f o r changes i n p e r m e a b i l i t y c h a r a c t e r i s t i c s and s u r f a c e p r o p e r t i e s . The very s m a l l volume of a r t i f i c i a l c e l l s r e q u i r e d , and the v a r i a t i o n s p o s s i b l e , r e s u l t i n d i f f e r e n t types of m i n i a t u r i z e d a r t i f i c i a l organs. Both t h e o r e t i c a l analyses and animal s t u d i e s have demonstrated the f e a s i b i l i t y of u s i n g the p r i n c i p l e of a r t i f i c i a l c e l l s to form extremely compact, e f f i c i e n t and simple a r t i f i c i a l organs. By v a r y i n g the contents of the a r t i f i c i a l c e l l s (adsorbents, d e t o x i c a n t s , enzymes, c e l l e x t r a c t s , c e l l s and other b i o l o g i c a l l y a c t i v e m a t e r i a l s ) , the a r t i f i c i a l organs can be adjusted to c a r r y out d i f f e r e n t biochemical or d e t o x i f i c a t i o n f u n c t i o n s . The p r i n c i p l e of a r t i f i c i a l c e l l s has already been used to form blood compatible c h a r c o a l and r e s i n hemoperfusion systems f o r use i n p a t i e n t s , as a blood d e t o x i f i e r ( p o i s o n i n g ) , a r t i f i c i a l kidney, a r t i f i c i a l l i v e r , or immunosorbent. These w i l l be d e s c r i b e d below.


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ARTIFICIAL CELLS FOR ARTIFICIAL KIDNEY The l a r g e s u r f a c e t o volume r e l a t i o n s h i p and t h e u l t r a t h i n membrane allows r a p i d e q u i l i b r a t i o n o f m e t a b o l i t e s i n t o the a r t i f i c i a l c e l l s . By p l a c i n g enzymes, i o n exchange r e s i n and a c t i v a t e d c h a r c o a l i n s i d e a r t i f i c i a l c e l l s , i t was demonstrated that the a r t i f i c i a l c e l l s could be used f o r hemoperfusion, a new form of a r t i f i c i a l kidney [ 8 ] . The p r i n c i p l e o f a r t i f i c i a l c e l l s , cont a i n i n g a c t i v a t e d c h a r c o a l f o r hemoperfusion, was developed f u r t h e r to a stage f o r c l i n i c a l a p p l i c a t i o n [12,13]. I n t r e a t i n g uremic p a t i e n t s , we have r e p o r t e d improvements i n nausea, v o m i t i n g , p r u r i t i s , f e e l i n g of w e l l - b e i n g , and i n p e r i p h e r a l neuropathy [ l 4 , 1 5 ] . T h i s approach i s much more e f f i c i e n t i n removing o r g a n i c uremic waste m e t a b o l i t e s than standard h e m o d i a l y s i s . However, i t does not remove water, e l e c t r o l y t e s o r urea. As a r e s u l t , hemop e r f u s i o n has been combined i n s e r i e s w i t h hemodialysis. This approach s o l v e s the problems of e l e c t r o l y t e , urea and f l u i d removal [16]. We i n i t i a l l y demonstrated t h a t a 2-hour ACAC hemoperfusionhemodialysis can r e p l a c e 6 hours of standard hemodialysis. Furthermore, t h i s approach r e s u l t e d i n improvements i n nerve conduction v e l o c i t y . T h i s has s t i m u l a t e d i n t e r e s t i n t h i s combined approach and, i n the most recent l a r g e - s c a l e s t u d i e s c a r r i e d out i n I t a l y , the e f f e c t i v e n e s s of t h i s approach has been c l e a r l y demons t r a t e d [17]. Another approach i s the combined use of hemoperfusion and a s m a l l (0.2 m ) u l t r a f i l t r a t o r , the l a t t e r f o r removal o f water and sodium c h l o r i d e [16]. I n t h i s approach, no hemodialysis equipment i s r e q u i r e d and the u l t r a f i l t r a t o r i s used only t o remove and d i s c a r d a l l the f i l t e r e d f l u i d (up t o 2.7 l i t e r s ) , based e n t i r e l y on the h y d r o s t a t i c pressure c o n t r o l l e d by the blood pump. A p r e l i m i n a r y long-term c l i n i c a l e v a l u a t i o n has demonstrated the s a f e t y and e f f e c t i v e n e s s of t h i s approach [18]. The completion of t h i s system w i l l have t o wait f o r the development o f a urea removal system. R e c e n t l y , a composite a r t i f i c i a l kidney has been formed, combining a r t i f i c i a l c e l l s and d i a l y s i s o r a r t i f i c i a l c e l l s and an u l t r a f i l t r a t o r [19]. 2

ARTIFICIAL CELLS IN POISONING Hemoperfusion, using a r t i f i c i a l c e l l s c o n t a i n i n g a c t i v a t e d c h a r c o a l , i s e f f e c t i v e i n t r e a t i n g severe acute drug p o i s o n i n g f o r those drugs which can be adsorbed, and which have a s m a l l volume d i s t r i b u t i o n [20]. High drug clearances have been obtained: g l u t e t h i m i d e 230 ml/min, phénobarbital 228 ml/min, methyprylon 230 ml/min, methaqualone 230 ml/min, and s e c o b a r b i t a l 200 ml/min. The e f f e c t i v e n e s s of hemoperfusion f o r those drugs w i t h a h i g h volume d i s t r i b u t i o n , e.g., t r i c y c l i c a n t i d e p r e s s a n t s and d i g o x i n , i s s t i l l controversial.


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T h i s approach has a l s o been used i n the treatment of acute i n t o x i c a t i o n i n p e d i a t r i c p a t i e n t s [21]. The a m b e r l i t e r e s i n hemoperfusion system has a h i g h clearance f o r many drugs [ 2 2 ] . However, the problem of p l a t e l e t d e p l e t i o n was noted w i t h t h i s system. More r e c e n t l y , our approach of u s i n g an albumin-coating t o make the p a r t i c l e s u r f a c e more blood compatible f o r hemoperfusion [12] has been a p p l i e d to the c o a t i n g of r e s i n s . As a r e s u l t , hemoperfusion w i t h albumin-coated a m b e r l i t e does not deplete platelets.


ARTIFICIAL CELLS AS ARTIFICIAL LIVER Our i n i t i a l o b s e r v a t i o n that hemoperfusion can r e s u l t i n the temporary recovery of consciousness i n grade IV h e p a t i c coma p a t i e n t s [23] i s now c o n c l u s i v e l y supported by other centers [5-7]. However, i t s e f f e c t on long-term s u r v i v a l has not y e t been establ i s h e d . A galactosamine-induced fulminant h e p a t i c coma r a t model has been used t o study i n d e t a i l the e f f e c t s of c h a r c o a l hemop e r f u s i o n on the s u r v i v a l r a t e s of the animals [24-28]. ACAC hemoperfusion has been c o n c l u s i v e l y demonstrated to i n c r e a s e both s u r v i v a l time and s u r v i v a l r a t e of r a t s i n the e a r l y stages of h e p a t i c coma. ACAC hemoperfusions c a r r i e d out i n the l a t e r stage of h e p a t i c coma increased the s u r v i v a l time but not the s u r v i v a l r a t e . The same r e s u l t s were obtained through homologous l i v e r p e r f u s i o n which increased the s u r v i v a l r a t e of r a t s i n the e a r l y stages of h e p a t i c coma, but not those i n the l a t e r stage of coma. The present r e s u l t s would i n d i c a t e that hemoperfusion p l a y s an important r o l e for the support of e a r l y stages of h e p a t i c coma. I n a l a t e r stage of coma, perhaps i r r e v e r s i b l e changes have a l r e a d y taken p l a c e . The r e s u l t s o f experimental s t u d i e s i n animals from t h i s l a b o r a t o r y [2428] demonstrating the need f o r e a r l i e r treatment have now been corroborated by an i n i t i a l c l i n i c a l t r i a l [29]. Thus, l a r g e r s c a l e c l i n i c a l t r i a l i s now ready t o i n v e s t i g a t e t h i s a r t i f i c i a l l i v e r concept f u r t h e r , based on a r t i f i c i a l c e l l s , f o r the treatment o f p a t i e n t s i n the e a r l i e r stages of fulminant h e p a t i c f a i l u r e [30]. We have a l s o i n v e s t i g a t e d the use of a r t i f i c i a l c e l l s cont a i n i n g t y r o s i n a s e t o c a r r y out some metabolic f u n c t i o n s of the l i v e r [31]. R e s u l t s i n animals show that t y r o s i n a s e a r t i f i c i a l c e l l s , r e t a i n e d i n e x t r a c o r p o r e a l shunts perfused by blood, can e f f e c t i v e l y lower the systemic blood t y r o s i n e l e v e l s of l i v e r f a i l u r e r a t s . A r t i f i c i a l c e l l s , t o c a r r y out other metabolic f u n c t i o n s of the l i v e r , are a l s o being s t u d i e d . For i n s t a n c e , u s i n g a r t i f i c i a l c e l l s c o n t a i n i n g multienzyme systems w i t h c o f a c t o r r e c y c l i n g [32], we have s t u d i e d the i n - v i t r o conversion of ammonia s e q u e n t i a l l y i n t o d i f f e r e n t types of amino a c i d s . T h i s way, ammonia


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has been converted i n t o glutamate and then s e q u e n t i a l l y i n t o a l a n i n e or other amino a c i d s .


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The ACAC hemoperfusion system developed by the author c o n s i s t s of a l b u m i n - c o l l o d i o n coated c h a r c o a l [12]. Albumin makes the s u r f a c e blood compatible and a l s o takes part i n i n t e r a c t i n g w i t h m a t e r i a l i n the c i r c u l a t i n g blood, i n c l u d i n g the f a c i l i t a t e d t r a n s p o r t of l o o s e l y protein-bound substances [ 5 ] . Terman reported the i n t e r e s t i n g f i n d i n g that these ACAC microcapsules can a l s o be used to remove a n t i b o d i e s to albumin from dog plasma [33]. He proceeded f u r t h e r to i n c o r p o r a t e other types of antigens or a n t i b o d i e s onto the surface of t h i s ACAC a r t i f i c i a l c e l l system, r e s u l t i n g i n immunosorbents f o r d i f f e r e n t types of a p p l i c a t i o n s . In very p r e l i m i n a r y s t u d i e s he found t h a t , by r e p l a c i n g the albumin of the ACAC system w i t h p r o t e i n A f o r use i n plasma p e r f u s i o n , he was a b l e to s i g n i f i c a n t l y reduce the s i z e of breast carcinomas i n patients. Another area i n v o l v e s the use of s y n t h e t i c immunosorbents. In order to prevent the problem of p a r t i c u l a t e r e l e a s e and blood i n c o m p a t i b i l i t y , we coated s y n t h e t i c immunosorbents f o r blood group A & Β w i t h albumin and c o l l o d i o n . I t was demonstrated that the s y n t h e t i c immunosorbent could s t i l l remove the a n t i - A and a n t i - B blood group but d i d not a f f e c t p l a t e l e t s or r e l e a s e p a r t i c u l a t e s [33]. An albumin-coated system has s i n c e been used c l i n i c a l l y by another centre to remove a n t i - A and a n t i - B from plasma of p a t i e n t s p r i o r to bone marrow t r a n s p l a n t a t i o n .

ARTIFICIAL CELLS CONTAINING ENZYME SYSTEM The i n j e c t i o n of f r e e enzyme of heterogenous o r i g i n may r e s u l t i n h y p e r s e n s i t i v i t y r e a c t i o n s , production of a n t i b o d i e s , and r a p i d removal and i n a c t i v a t i o n . Furthermore, f r e e enzymes cannot be kept at the d e s i r e d s i t e s of a c t i o n and are l e s s s t a b l e at a body temperature of 37°C. The use of a r t i f i c i a l c e l l s c o n t a i n i n g enzymes and p r o t e i n s has been i n v e s t i g a t e d [3,4]. Some examples of research being c a r r i e d out w i l l be b r i e f l y mentioned. The f i r s t demonstration of the use of a r t i f i c i a l c e l l s f o r enzyme replacement i n h e r e d i t a r y enzyme d e f i c i e n c y c o n d i t i o n s i n v o l v e d the i m p l a n t a t i o n of a r t i f i c i a l c e l l s c o n t a i n i n g c a t a l a s e to r e p l a c e the h e r e d i t a r y c a t a l a s e d e f i c i e n c y i n acatalasemic mice [3.4]. We have a l s o demonstrated that a r t i f i c i a l c e l l s c o n t a i n i n g asparaginase are e f f e c t i v e i n the experimental suppression of lymphosarcoma i n animal s t u d i e s [3.4]. As described e a r l i e r , the



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f e a s i b i l i t y of using a r t i f i c i a l c e l l s c o n t a i n i n g t y r o s i n a s e f o r the i n - v i v o conversion of t y r o s i n e and phenols i n fulminant h e p a t i c f a i l u r e r a t s has a l s o been s t u d i e d [31]. Our work i n the area of a r t i f i c i a l c e l l s w i t h c o f a c t o r r e c y c l i n g and multienzyme systems [4] l e d t o the development of a r t i f i c i a l c e l l s c o n t a i n i n g multienzyme systems f o r s e q u e n t i a l s u b s t r a t e conversion [32]. For i n s t a n c e , i n the same a r t i f i c i a l c e l l , urea can be converted by urease i n t o ammonia; ammonia i s then converted by glutamate dehydrogenase i n t o glutamic a c i d ; glutamic a c i d can be f u r t h e r converted by t r a n s aminase i n t o other amino a c i d s . The c o f a c t o r NADH required i s r e c y c l e d using glucose dehydrogenase o r a l c o h o l dehydrogenase. The c o f a c t o r can be r e t a i n e d w i t h i n the a r t i f i c i a l c e l l s by covalent l i n k a g e t o s o l u b l e macromolecules l i k e dextrans [4] o r by the use o f a r t i f i c i a l c e l l s w i t h l i p i d complexed membrane [35].

ARTIFICIAL CELLS CONTANING BIOLOGICAL CELLS A r t i f i c i a l c e l l s were prepared t o c o n t a i n b i o l o g i c a l c e l l s [2,3]· We suggested t h a t , t h i s way, the microencapsulated b i o l o g i c a l c e l l s , when implanted, can be separated from immunol o g i c a l r e j e c t i o n and proposed the use of t h i s f o r the i n - v i v o i m p l a n t a t i o n of endocrine c e l l s [ 3 ] . A recent development has r e s u l t e d i n i n - v i v o experiments demonstrating that t h i s suggestion i s p o s s i b l e . F o r i n s t a n c e , r a t - i s l e t c e l l s have been microencaps u l a t e d and then implanted i n t r a p e r i t o n e a l l y i n t o d i a b e t i c r a t s [36]. I n t h i s way the microencapsulated i s l e t c e l l s can f u n c t i o n t o m a i n t a i n normal glucose l e v e l s i n the d i a b e t i c animals. Artificial c e l l s c o n t a i n i n g f i b r o b l a s t s o r plasma c e l l s have a l s o been used i n i n - v i t r o t e s t s f o r the production of i n t e r f e r o n and monoclonal a n t i b o d i e s [37].

GENERAL DISCUSSION The b i o l o g i c a l c e l l i s the fundamental u n i t of a l l organs. I t i s thus not too s u r p r i s i n g that i t s s y n t h e t i c counterpart, the a r t i f i c i a l c e l l , i s p l a y i n g an i n c r e a s i n g r o l e i n a r t i f i c i a l organs. The present paper only b r i e f l y describes a few examples t o i l l u s t r a t e the a p p l i c a t i o n o f a r t i f i c i a l c e l l s i n medicine, biotechnology and other areas.

ACKNOWLEDGMENT This research has been supported by the M e d i c a l Research C o u n c i l o f Canada and, a t present, i n the form o f a s p e c i a l p r o j e c t grant (MRC-SP-4).


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LITERATURE CITED 1. Chang, T.M.S., Hemoglobin corpuscles, report of research project for Honours B.Sc., McGill University, 1957. 2. Chang, T.M.S., Semipermeable microcapsules, Science, 146, 524, 1964. 3. Chang, T.M.S., Artificial Cells, Charles C. Thomas, Publisher, Springfield, I11, 1972.


4. Chang, T.M.S., Biomedical Application of Immobilized Enzymes and Proteins, Vols. I & II, Plenum Press, New York, 1977. 5. Chang, T.M.S., Artificial Kidney, Artificial Liver, and Artificial Cells, Plenum Press, New York, 1978. 6. Sideman, S. and Chang, T.M.S., Hemoperfusion: Artificial Kidney and Liver Support and Detoxification, Part I, Hemis phere, Washington, D.C., 1980. 7. Bonomini, V. and Chang, T.M.S., Hemoperfusion, Contributions to Nephrology Series, S. Karger AG, Basel, 1982. 8. Chang, T.M.S., Semipermeable aqueous microcapsules (''artificial cells"): with emphasis on experiments in an extracorporeal shunt system, Trans. Amer. Soc. Artif. Internal Organs, 12, 13, 1966. 9. Chang, T.M.S., Artificial red blood cells, Trans. Amer. Soc. Artif. Internal Organs, 26, 354-357, 1980. 10. Mitsuno, T. and Naito, R., Perflurochemical Blood Substitutes, Excerpta Medica, Amsterdam, 1979, 469. 11. Keipert, P.M., Minkowitz, J . and Chang, T.M.S., Cross-linked stroma-free polyhemoglobin as a potential blood substitute. Int. J. Artif. Organs, 5, 383-385, 1982. 12. Chang, Τ.M.S., Removal of endogenous and exogenous toxins by a microencapsulated absorbent. Can. J. Physiol. Pharmacol., 47, 1043, 1969. 13. Chang, T.M.S. and Malave, N., The development and first clinical use of semipermeable microcapsules (artificial cells) as a compact artificial kidney. Trans. Amer. Soc. Artif. Internal Organs, 16, 141, 1970. 14. Chang, T.M.S., Gonda, Α., Dirks, J.H. and Malave, Ν., Clinical evaluation of chronic intermittent or short-term hemoperfusions


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in patients with chronic renal failure using semipermeable microcapsules (artificial cells) formed from membrane-coated activated charcoal. Trans. Amer. Soc. Artif. Internal Organs, 17, 246, 1971. 15.

Chang, T.M.S., Gonda, A., Dirks, J.H., Coffey, J.F. and Burns, Τ., ACAC microcapsule artificial kidney for the long term and short term management of eleven patients with chronic renal failure. Trans. Amer. Soc. Artif. Internal Organs, 18, 465472, 1972.

16.

Chang, T.M.S., Chirito, Ε., Barre, P., Cole, C. and Hewish, Μ., Clinical performance characteristics of a new combined system for simultaneous hemoperfusion-hemodialysis-ultrafiltration in series. Trans. Amer. Soc. Artif. Internal Organs, 21, 502-508, 1975.

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Stefoni, S., Coli, L . , Feliciangeli, G., Baldrati, L. and Bonomini, V., Regular hemoperfusion in regular dialysis treatment. A long-term study. Int. J. Artif. Organs, 3, 348, 1980.

18.

Chang, T.M.S., Chirito, E. Barre, Ρ., Cole, C., Lister, C. and Resurreccion, Ε., Long-term clinical assessment of combined ACAC hemoperfusion-ultrafiltration in uremia. Artif. Organs, 3, 127-131, 1979.

19.

Chang, T.M.S., Barre, P., Kuruvilla, S., Messier, D., Man, M.K. and Resurreccion, Ε., Phase 1 clinical trial of a new composite artificial kidney combining hemodialysis with hemoperfusion. Trans. Amer. Soc. Artif. Internal Organs, 28, 43-48, 1982.

20.

Chang, T.M.S., Coffey, J.F., Lister, C., Taroy, E. and Stark, A. Methaqualone, methyprylone, and glutethimide clearance by the ACAC microcapsule artificial kidney: in vitro and in patients with acute intoxication. Trans. Amer. Soc. Artif. Internal Organs, 19, 87-91, 1973.

21.

Chang, T.M.S., Espinosa-Melendez, E., Francoeur, T.E. and Eade, N.R., Albumin-collodion activated coated charcoal hemoperfusion in the treatment of severe theophylline intoxication in a 3year-old patient. Pediatric, 65, 811-814, 1980.

22.

Rosenbaum, J.L., Experience with resin hemoperfusion. In Artificial Kidney, Artificical Liver, and Artificial Cells (Chang, T.M.S., ed.) Plenum Press, New York, 1978, 214-217.

23.

Chang, T.M.S., Haemoperfusion over microencapsulated adsorbent in a patient with hepatic coma. Lancet, ii, 1371-1372, 1972.


11.

CHANG

Artificial Cells

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24. Chirito, Ε., Reiter, B., Lister, C. and Chang, T.M.S., Artificial liver" the effect of ACAC microencapsulated charcoal hemoperfusion on fulminant hepatic failure. Artif. Organs, 1(1), 76-83, 1977.


25. Chang, T.M.S., Lister, C., Chirito, E., O'Keefe, P. and Resurreccion, Ε., Effects of hemoperfusion rate and time of initiation of ACAC charcoal hemoperfusion on the survival of fulminant hepatic failure rats. Trans. Amer. Soc. Artif. Internal Organs, 24, 243-245, 1978. 26. Mohsini, Κ., Lister, C. and Chang, T.M.S., The effects of homologous cross-circulation and in situ liver perfusion on fulminant hepatic failure rats. Artif. Organs, 4, 171-175, 1980. 27. Tabata, Y. and Chang, T.M.S., Comparisons of six artificial liver support regimes in fulminant hepatic coma rats. Trans. Amer. Soc. Artif. Internal Organs, 26, 394-399, 1980. 28. Chang, T.M.S., Hemoperfusion, exchange transfusion, cross circulation, liver perfusion, hormones and immobilized enzymes. In Artificial Liver Support (Brunner & Schmidt, eds.) SpringerVerlag, Berlin, 1981, 126. 29. Gimson, A.E.S., Braude, S., Mellon, P.J. and Canalese, J., Earlier charcoal haemoperfusion in fulminant hepatic failure. Lancet, Sept.25, 681683, 1982. 30. Chang, T.M.S., Earlier Haemoperfusion in fulminant hepatic failure. Lancet, Nov.6, 1982. 31. Shi, Z.Q. and Chang, T.M.S., Effects of hemoperfusion on blood and brain levels of tyrosine and middle molecules. Trans. Amer. Soc. Artif. Internal Organs, 28, 205-209, 1982. 32. Chang, T.M.S., Malouf, C. and Resurreccion, Ε., Artificial cells containing multienzyme systems for the sequential conversion of urea into ammonia, glutamate, then alanine. Artif. Organs, 3, S284-S287, 1979. 33. Terman, D.S., Tavel, T., Petty, D., Racic, M.R. and Buffaloe, G., Specific removal of antibody by extracorporeal circulation over antigen immobilized in collodion charcoal. Clin. Exp. Immunol., 28, 180, 1977. 34. Chang, T.M.S., Blood compatible coating of synthetic immunoadsorbents. Trans. Amer. Soc. Artif. Internal Organs, 26, 546549, 1980.


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35. Yu, Y.T. and Chang, T.M.S., Ultrathin lipid-polymer membrane microcapsules containing multienzymes, cofactors and substrates for multistep enzyme reactions, FEBS Letters, 125(1), 94-96, 1981. 36. Lim, F. and Sun, A.M., Microencapsulated islets as bioartificial endocrine pancreas. Science, 210, 908, 1980. 37. Bulletin on Tissue Microencapsulation, Damon Corporation, Needham Heights, Mass, 1981. April 23, 1984


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