Rationale and Strategies for the Therapeutic Applications of Immobilized Enzymes

  • T. M. S. Chang


Except for digestive enzymes and some proteins and enzymes, the majority of enzymes and proteins in the body function in an intracellular environment. The simplest intracellular form is a high concentration of hemoglobin and complex enzyme systems in the red blood cells. The other extreme in the complexity of intracellular organizations are liver cells, each of which contains extremely complex enzyme systems which are further compartmentalized by being immobilized into intracellular membranes and intracellular organelles. Complex enzyme systems immobilized within these intracellular environments of varying complexities carry out their function by acting sequentially on substrates, including those which cross the cell membranes by passive movement or by special transport mechanisms.


Immobilize Enzyme Artificial Pancreas Artificial Cell Artificial Kidney Dialysis System 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Allison, J. P., Davidson, L., Gutierrer-Hartman, A., and Kitto, G. B., 1972, Insolubilization of Lasparaginase by covalent attachment to nylon tubing, Biochem. Biophys. Res. Commun. 47: 66.CrossRefGoogle Scholar
  2. Apple, M., 1971, Hemodialysis against enzymes as a method of “gene replacement” in cases of inherited metabolic diseases, Proc. West. Pharmacol. Soc. 14:125.Google Scholar
  3. Asher, W. J., Bovee, K. C., Frankenfeld, J. W., Hamilton, R. W., Henderson, L. W., Holtzapple, P. G., and Li, N. N., 1975, Liquid membrane system directed toward chronic uremia, Kidney Int. 7:S409.Google Scholar
  4. Bessman, S. P., and Schultz, R. D., 1973, Prototype glucose oxygen sensor for the artificial pancreas, Trans. Amer. Soc. Artificial Internal Organs 19:361.CrossRefGoogle Scholar
  5. Broun, G., Selegny, E., Minh, C. T., and Thomas, D., 1970, The use of proteic and enzymatic coatings and/or membranes for oxygenators, FEBS Letters 7:223.CrossRefGoogle Scholar
  6. Chang, T. M. S., 1957, Hemoglobin corpuscles, report of research project for B.Sc. Honours, McGill University.Google Scholar
  7. Chang, T. M. S., 1964, Semipermeable microcapsules, Science 146:524.CrossRefGoogle Scholar
  8. Chang, T. M. S., 1965, Semipermeable aqueous microcapsules, Ph.D. thesis, McGill University.Google Scholar
  9. Chang, T. M. S., 1966, Semipermeable aqueous microcapsules (“artificial cells”): with emphasis on experiments in an extracorporeal shunt system, Trans. Amer. Soc. Artificial Internal Organs 12:13.Google Scholar
  10. Chang, T. M. S., 1969a, Asparaginase-loaded semipermeable microcapsules for mouse lymphomas, Proc. Can. Federation Biol. Sci. 12:62.Google Scholar
  11. Chang, T. M. S., 1969b, Removal of endogenous and exogenous toxins by a microencapsulated adsorbent, Can. J. Physiol. Pharmacol. 47:1043.CrossRefGoogle Scholar
  12. Chang, T. M. S., 1971, The in-vivo effects of semipermeable microcapsules containing L-asparaginase on 6C3HED lymphosarcoma, Nature 229:117.CrossRefGoogle Scholar
  13. Chang, T. M. S., 1972a, Artificial Cells, Charles C. Thomas, Publisher, Springfield, Ill.Google Scholar
  14. Chang, T. M. S., 1972b, Effects of local applications of microencapsulated catalase on the response of oral lesions to hydrogen peroxide in acatalasemia, J. Dental Res. 51:319.CrossRefGoogle Scholar
  15. Chang, T. M. S., 1973a, Biomedical applications of artificial cells, Bio-med. Eng. 8:334.Google Scholar
  16. Chang, T. M. S., 1973b, L-Asparaginase immobilized within semipermeable microcapsules: in-vitro and in-vivo stability, Enzyme 14:95.Google Scholar
  17. Chang, T. M. S., 1975, Microencapsulated adsorbents for uremia, liver failure, and intoxication, J. Kidney Int. 7:5378.Google Scholar
  18. Chang, T. M. S., and Loa, S. K., 1970, Urea removal of urease and ammonia adsorbents in the intestine, Physiologist 13:70.Google Scholar
  19. Chang, T. M. S., and MacIntosh, F. C., 1964, Semipermeable aqueous microcapsules, Pharmacologist 6:198.Google Scholar
  20. Chang, T. M. S., and Malaya, N., 1970, The development and first clinical use of semipermeable microcapsules (artificial cells) as a compact artificial kidney, Trans. Amer. Soc. Artificial Internal Organs 16:141.Google Scholar
  21. Chang, T. M. S., and Migchelsen, M., 1973, Characterization of possible “toxic” metabolites in uremia and hepatic coma based on the clearance spectrum for larger molecules by the ACAC microcapsule artificial kidney, Trans. Amer. Soc. Artificial Internal Organs 19:314.CrossRefGoogle Scholar
  22. Chang, T. M. S., and Poznansky, M. J., 1968, Semipermeable microcapsules containing catalase for enzyme replacement in acatalasemic mice, Nature 218:243.CrossRefGoogle Scholar
  23. Chang, T. M. S., Johnson, L. J., and Ransome, 0., 1967, Semipermeable aqueous microcapsules: IV. Nonthrombogenic microcapsules with heparin-complex membranes, Can. J. Physiol. Pharmacol. 45:705.CrossRefGoogle Scholar
  24. Chang, T. M. S., Pont, A., Johnson, L. J., and Malave, N., 1968, Response to intermittent extracorporeal perfusion through shunts containing semipermeable microcapsules, Trams. Amer. Soc. Artificial Internal Organs 15:163.Google Scholar
  25. Chang, T. M. S., Gonda, A., Dirks, J. H., and Malave, N., 1971, Clinical evaluation of chronic, intermittent, and short term hemoperfusions in patients with chronic renal failure using semipermeable microcapsules (artificial cells) formed from membrane-coated activated charcoal, Trans. Amer. Soc. Artificial Internal Organs 17:246.Google Scholar
  26. Chang, T. M. S., Gonda, A., Dirks, J. H., Coffey, J. F., and Lee-Burns, T., 1972, ACAC microcapsule artificial kidney for the long term and short term management of eleven patients with chronic renal failure, Trans. Amer. Soc. Artificial Internal Organs 18:465.CrossRefGoogle Scholar
  27. Chang, T. M. S., Coffey, J. F., Lister, C., Taroy, E., and Stark, A., 1973a, Methaqualone, methyprylon, and glutethimide clearance by the ACAC microcapsule artificial kidney: in-vitro and in patients with acute intoxication, Trans Amer. Soc. Artificial Internal Organs 19:87.CrossRefGoogle Scholar
  28. Chang, T. M. S., Coffey, J. F., Barre, P., Gonda, A., Dirks, J. H., Levy, M., and Lister, C., 1973b, Microcapsule artificial kidney: treatment of patients with acute drug intoxication, Can. Med. Assoc. J. 108:429.Google Scholar
  29. Chang, T. M. S., Migchelsen, M., Coffey, J. F., and Stark, A., 1974, Serum middle molecule levels in uremia during long term intermittent hemoperfusions with the ACAC (coated charcoal) micro-capsule artificial kidney, Trans. Amer. Soc. Artificial Internal Organs 20:364.Google Scholar
  30. Chang, T. M. S., Chirito, E., Barre, B., Cole, C., and Hewish, M., 1975, Clinical performance characteristics of a new combined system for simultaneous hemoperfusion-hemodialysis-ultrafiltration in series, Trans. Amer. Soc. Artificial Internal Organs 21:502.Google Scholar
  31. Cooney, D. A., Weetall, H. H., and Long, E., 1975, Biochemical and pharmacologic properties of Lasparaginase bonded to dacron vascular prostheses, Biochem. Pharmacol. 24:503.Google Scholar
  32. Gardner, D. L., Falb, R. D., Kim, B. C., and Emmerling, D. C., 1971, Possible uremic detoxification via oral-ingested microcapsules, Trans. Amer. Soc. Artificial Internal Organs 17:239.Google Scholar
  33. Gordon, A., Greenbaum, M. A., Marantz, L. B., McArthur, M.J., and Maxwell, M. H., 1969, Adsorbent based low volume recirculating dialysate, Trans. Amer. Soc. Artif. Intern. Organs 15:347.Google Scholar
  34. Gregoriadis, G., and Ryman, B. E., 1972, Fate of protein-containing liposomes injected into rats: an approach to the treatment of storage diseases, Eur. J. Biochem. 24:485.CrossRefGoogle Scholar
  35. Hersh, L. S., 1974, L-Asparaginase from Escherichia coli II and Erwinia carotovora bound to poly-(methyl methacrylate), J. Polymer Sci. 47:55.Google Scholar
  36. Horvath, C., Sardi, A., and Woods, J. S., 1973, L-Asparaginase tubes: kinetic behavior and application in physiological studies, J. App. Physiol. 34:181.Google Scholar
  37. Hyden, H., 1970, An extracorporeal shunt apparatus for blood detoxification, Arzneimittel-Forschung 21:1671.Google Scholar
  38. Ihler, G. M., Glew, R. H., and Schnure, F. W., 1973, Enzyme loading of erythrocytes, Proc. Natl. Acad. Sci. U.S. 70:2663.CrossRefGoogle Scholar
  39. Jay, A. W. L., and Edwards, M. A., 1969, Mechanical properties of semipermeable microcapsules, Can. J. Physiol. Pharmacol. 46:731.CrossRefGoogle Scholar
  40. Kusserow, B., Larrow, R., and Nichols, J., 1971, Urokinase-heparin bonded synthetic surfaces, Trans. Amer. Soc. Artificial Internal Organs 17:1.Google Scholar
  41. Kusserow, B., Larrow, R., and Nichols, J., 1973, Surface bonded, covalently cross-linked urokinase synthetic surfaces, Trans. Amer. Soc. Artificial Internal Organs 19:8.CrossRefGoogle Scholar
  42. Levine, S. N., and LaCourse, W. C., 1967, Materials and design consideration for a compact artificial kidney, J. Biomed. Mater. Res. 1:275.CrossRefGoogle Scholar
  43. Marconi, W., Guilinelli, S., and Morisi, F., 1974, Fiberentrapped enzymes, in Insolubilized Enzymes (M. Salmona, C. Saronio, and S. Garattini, eds.), p. 51, Raven Press, New York.Google Scholar
  44. May, S. W., and Li, N. N., 1972, The immobilization of urease using liquid-surfactant membranes, Biochem. Biophys. Res. Commun. 47:1179.CrossRefGoogle Scholar
  45. Mori, T., Sato, T., Matuo, Y., Tosa, T., and Chibata, I., 1972, Preparation and characteristics of microcapsules containing asparaginase, Biotechnol. Bioeng. 14:663.CrossRefGoogle Scholar
  46. Mori, T., Tosa, T., and Chibata, I., 1973, Enzymatic properties of microcapsules containing asparagi-nase, Biochem. Biophys. Acta 321:653.Google Scholar
  47. Nadler, H. L., and Updike, S. J., 1974, Gel-entrapment of enzyme: strategy for enzyme correction, Enzyme 18:150.Google Scholar
  48. Ohnuma, T., O’Driscoll, K. F., Korus, R., and Walczak, I. A., 1974, Pharmacological studies and antitumor activity of E. coli asparaginase immobilized in 2-hydroxyethylmethacrylate, Abstr. Papers Amer. Chem. Soc. 174:81.Google Scholar
  49. Poznansky, M. J., and Chang, T. M. S., 1974, Comparison of the enzyme kinetics and immunological properties of catalase immobilized by microencapsulation and catalase in free solution for enzyme replacement, Biochim. Biophys. Acta 334:103.Google Scholar
  50. Salmona, M., Saronio, C., Bartosek, I., Vecchi, A., and Mussini, E., 1974, Fibre-entrapped enzymes, in: Insolubilized Enzymes (M. Salmona, C. Saronia, and S. Garattini, eds.), p. 189, Raven Press, New York.Google Scholar
  51. Sampson, D., Hersh, L. S., Cooney, D., and Murphy, G. P., 1972, A new technique employing extracorporeal chemotherapy, Trans. Amer. Soc. Artificial Internal Organs 18:54.CrossRefGoogle Scholar
  52. Sekiguchi, W., and Kondo, A., 1966, Studies on microencapsulated hemoglobin, J. Japan. Soc. Blood Transfusion 13:153.CrossRefGoogle Scholar
  53. Siuchong, E. D., and Chang, T. M. S., 1974, In-vivo effects of intraperitoneally injected L-asparaginase solution and L-asparaginase immobilized within semipermeable nylon microcapsules with emphasis on blood L-asparaginase, “body” L-asparaginase, and plasma L-asparagine levels, Enzyme 18:218.Google Scholar
  54. Sparks, E. R., Mason, N. S., Meier, P. M., Litt, M. H., and Lindan, O., 1971, Removal of uremic waste metabolites from the intestinal tract by encapsulated carbon and oxidized starch, Trans. Amer. Soc. Artificial Internal Organs 17:229.Google Scholar
  55. Thorne, S. R., Fiddler, M. B., and Desnick, R. J., 1975, Enzyme therapy V: in-vivo fate of /3glucuronidase deficient mice, Pediat. Res. 9:918.Google Scholar
  56. Updike, S. J., Shults, M. C. N., and Magnuson, J., 1973a, Catalase for oxygenator membranes, J. Apps. Physiol. 34:271.Google Scholar
  57. Updike, S. J., Prieve, C., and Magnuson, J., 1973b, Immobilization in hypoallergenic gel, a method of protecting enzymes from proteolysis and antibody complexing, in: Enzyme Therapy in Genetic Diseases, Birth Defects (Original Article Series, Vol. 9), p. 77, The Williams & Wilkins Company, Baltimore.Google Scholar
  58. Venkatasubramanian, K., Vieth, W. R., and Bernath, F. R., 1974, Use of collagen immobilized enzymes in blood treatment, in: Enzyme Engineering, Vol. 2 (E. K. Pye and L. B. Wingard, Jr., eds), p. 439, Plenum Press, New York.Google Scholar
  59. Venter, J. C., Venter, B. R., Dixon, J. E., and Kaplan, N. O., 1975, Extracorporeal immobilized enzyme reactors, Biochem. Med. 12:79.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1977

Authors and Affiliations

  • T. M. S. Chang
    • 1
  1. 1.Departments of Physiology and MedicineMcGill UniversityMontrealCanada

Personalised recommendations