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  • Review Article
  • Published:

Therapeutic applications of polymeric artificial cells

Nature Reviews Drug Discovery volume 4, pages 221–235 (2005)Cite this article

Key Points

  • The concept of using 'artificial cells' — ultrathin polymer membrane microcapsules — to encapsulate materials such as transplanted cells, enzymes and absorbents was first put forward 40 years ago.

  • Encapsulation was proposed to protect the enclosed materials from the external environment, thereby helping to prevent rejection by the immune system.

  • The permeability, composition and configuration of the membrane can be varied using different types of materials, which allows for extensive variations in the properties and functions of the artificial cells. The artificial cells can also range in size from macro-dimensions of up to 2-mm diameter, through micron- and nano-dimensions to molecular dimensions.

  • This review considers potential therapeutic applications of artificial cells, from cell encapsulation to treat disorders such as diabetes and neurological disorders, to enzyme replacement therapies and red-blood-cell substitutes. The key challenges for the future clinical development of such approaches are discussed.

Abstract

Polymeric artificial cells have the potential to be used for a wide variety of therapeutic applications, such as the encapsulation of transplanted islet cells to treat diabetic patients. Recent advances in biotechnology, molecular biology, nanotechnology and polymer chemistry are now opening up further exciting possibilities in this field. However, it is also recognized that there are several key obstacles to overcome in bringing such approaches into routine clinical use. This review describes the historical development and principles behind polymeric artificial cells, the present state of the art in their therapeutic application, and the promises and challenges for the future.

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Figure 1: Polymeric artificial cells.
Figure 2: Potential therapeutic applications for polymeric artificial cells that encapsulate biological cells.
Figure 3: Development of artificial cells for cell encapsulation.
Figure 4: Applications of artificial cells containing enzymes.
Figure 5: Artificial cells in the molecular dimensions.
Figure 6: Artificial cells with nano-dimensions.

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References

  1. Chang, T. M. S. Semipermeable microcapsules. Science 146, 524–525 (1964). The first scientific publication describing the principle of artificial cells, including methods of preparation, in vitro and in vivo studies and potential areas of biotechnological and medical applications.

    CAS  PubMed  Google Scholar 

  2. Chang, T. M. S. Semipermeable Aqueous Microcapsules Ph.D. Thesis. McGill Univ. Montreal (1965).

    Google Scholar 

  3. Chang, T. M. S., MacIntosh, F. C. & Mason, S. G. Semipermeable aqueous microcapsules: I. Preparation and properties. Can. J. Physiol. Pharmacol. 44, 115–128 (1966).

    CAS  PubMed  Google Scholar 

  4. Soon-Shiong, P. et al. Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation. Lancet 343, 950–951 (1994). The first published report on a Phase I clinical trial using artificial cells containing islets in a patient. The result shows the safety and feasibility of this approach. Efficacy may require further development to increase the amount of islets encapsulated.

    CAS  PubMed  Google Scholar 

  5. Kulitreibez, W. M., Lauza, P. P. & Cuicks, W. L. (eds) Cell Encapsulation Technology and Therapy 1–450 (Burkhauser, Boston, 1999).

    Google Scholar 

  6. Orive, G. et al. Cell encapsulation: promise and progress. Nature Med. 9, 104–107 (2003). A consensus review written by major groups around the world working on the use of artificial cells, with emphasis on bio-encapsulation of cells, including genetically engineered cells. Present status, potential areas of application and problems to be solved are covered.

    CAS  PubMed  Google Scholar 

  7. Chang, T. M. S. Removal of endogenous and exogenous toxins by a microencapsulated absorbent. Can. J. Physiol. Pharmacol. 47, 1043–1045 (1969).

    CAS  PubMed  Google Scholar 

  8. Chang, T. M. S. & Malave, N. The development and first clinical use of semipermeable microcapsules (artificial cells) as a compact artificial kidney. Trans Am. Soc. Artif. Intern. Organs 16, 141–148 (1970).

    CAS  PubMed  Google Scholar 

  9. Chang, T. M.S. Microencapsulated adsorbent hemoperfusion for uremia, intoxication and hepatic failure. Kidney Int. Suppl. 7, S387–S392 (1975). Overview of the first clinical use of artificial cells containing adsorbents in patients with medication overdose, kidney failure and liver failure.

    Google Scholar 

  10. Winchester, J.F. in Replacement of Renal Function by Dialysis (ed. Maher, J. F.) 439–592 (Kluwer Academic, Boston, 1988).

    Google Scholar 

  11. Chang, T. M. S. Hemoglobin Corpuscles Report of a research project for Honours Physiology (Medical Library, McGill University, 1957).

    Google Scholar 

  12. Chang, T. M. & Poznansky, M. J. Semipermeable microcapsules containing catalase for enzyme replacement in acatalsaemic mice. Nature 218, 243–245 (1968). The first scientific report of the implantation of polymeric artificial cells containing an enzyme for replacement of the deficient gene in a mouse model of an inborn error of metabolism.

    CAS  PubMed  Google Scholar 

  13. Chang, T. M. S. The in vivo effects of semipermeable microcapsules containing L-asparaginase on 6C3HED lymphosarcoma. Nature 229, 117–118 (1971).

    CAS  PubMed  Google Scholar 

  14. Chang, T. M. S. Artificial Cells (Thomas, Springfield, 1972). This monograph provides a detailed description of all areas of artificial-cell research up to 1972, including the underlying principles of artificial cells, methods of preparation and experimental demonstrations of areas of application. Most of the basic principles and methods and potential areas of application are now being developed. Although this book is now out of print, it is freely available to download at http://www.artcell.mcgill.ca .

    Google Scholar 

  15. Chang, T. M. S. Semipermeable aqueous microcapsules ['artificial cells']: with emphasis on experiments in an extracorporeal shunt system. Trans. Am. Soc. Artif. Intern. Organs 12, 13–19 (1966).

    CAS  PubMed  Google Scholar 

  16. Chang, T. M. S. Biodegradable semipermeable microcapsules containing enzymes, hormones, vaccines, and other biologicals. J. Bioengineering. 1, 25–32 (1976). The first report on the use of biodegradable membrane microcapsules and microparticles as delivery systems for drugs and biotechnology products. It now forms the basis of many of the present approaches using biodegradable microcapsules, microparticles, nanocapsules, nanoparticles and others.

    CAS  Google Scholar 

  17. Chang, T. M. S. Stabilization of enzyme by microencapsulation with a concentrated protein solution or by crosslinking with glutaraldehyde. Biochem. Biophys. Res Comm. 44, 1531–1533 (1971). The first report on the use of glutaraldehyde for intermolecular crosslinking of proteins, which showed that this increases the stability of the proteins. This forms the basic principle for the present polyhaemoglobin that is being used as a blood substitute in the final stages of Phase III clinical trials in the United States and in routine use in patients in South Africa and Russia.

    CAS  PubMed  Google Scholar 

  18. Emerich, D. F. et al. Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington's disease. Nature 386, 395–399 (1997).

    CAS  PubMed  Google Scholar 

  19. Read, T. A. et al. Local endostatin treatment of gliomas administered by microencapsulated producer cells. Nature Biotechnol. 19, 29–34 (2001).

    CAS  Google Scholar 

  20. Joki, T. et al. Continuous release of endostatin from microencapsulated engineered cells for tumor therapy. Nature Biotechnol. 19, 35–39 (2001).

    CAS  Google Scholar 

  21. LaVan, D. A., Lynn, D. M. & Langer, R. Moving smaller in drug discovery and delivery. Nature Rev. Drug Discov. 1, 77–84 (2002).

    CAS  Google Scholar 

  22. Pardridge, W. M. Drug and gene targeting to the brain with molecular Trojan horses. Nature Rev. Drug Discov. 1, 131–139 (2002).

    CAS  Google Scholar 

  23. Duncan, R. The dawning era of polymer therapeutics. Nature Rev. Drug Discov. 2, 347–360 (2003).

    CAS  Google Scholar 

  24. Singh, S. M., McCormick, B. B., Mustata, S., Thompson, M. & Prasad, G. V. Extracorporeal management of valproic acid overdose: a large regional experience. J. Nephrol. 17, 43–49 (2004).

    PubMed  Google Scholar 

  25. Lin, C. C., Chan, T. Y. & Deng, J. F. Clinical features and management of herb-induced aconitine poisoning. Ann. Emerg. Med. 43, 574–579 (2004).

    PubMed  Google Scholar 

  26. Peng, A., Meng, F. Q., Sun, L. F., Ji, Z. S. & Li, Y. H. Therapeutic efficacy of charcoal hemoperfusion in patients with acute severe dichlorvos poisoning. Acta Pharmacol. Sin. 25, 15–21 (2004).

    CAS  PubMed  Google Scholar 

  27. Lopez Lago, A. M. et al. Paraquat poisoning and hemoperfusion with activated charcoal. An. Med. Interna. 19, 310–312 (2002).

    CAS  PubMed  Google Scholar 

  28. Kawasaki, C., Nishi, R., Uekihara, S., Hayano, S. & Otagiri, M. Charcoal hemoperfusion in the treatment of phenytoin overdose. Am. J. Kidney Dis. 35, 323–326 (2000).

    CAS  PubMed  Google Scholar 

  29. Lin, C. C., Chou, H. L. & Lin, J. L. Acute aconitine poisoned patients with ventricular arrhythmias successfully reversed by charcoal hemoperfusion. Am. J. Emerg. Med. 20, 66–67 (2002).

    PubMed  Google Scholar 

  30. Tominaga, M. et al. Pharmacological evaluation of portal venous isolation and charcoal haemoperfusion for high-dose intra–arterial chemotherapy of the pancreas. Br. J. Surg. 84, 1072–1076 (1997).

    CAS  PubMed  Google Scholar 

  31. Chang, T. M. Haemoperfusions over microencapsulated adsorbent in a patient with hepatic coma. Lancet. 23, 1371–1372 (1972).

    Google Scholar 

  32. Gazzard, B. G et al. Charcoal haemoperfusion in the treatment of fulminant hepatic failure. Lancet 1, 1301–1307 (1974).

    CAS  PubMed  Google Scholar 

  33. Liu, J. P., Gluud, L. L., Als-Nielsen, B. & Gluud, C. Artificial and bioartificial support systems for liver failure. Cochrane Database Syst. Rev. (1):CD003628 (2004).

  34. Lesney, M. S. Going cellular. Modern Drug. Disc. 4, 45–46 (2001).

    Google Scholar 

  35. US Pharmacopeia and National Formulary 1046, 2762–2790 (2002)

  36. Lim, F. & Sun, A. M. Microencapsulated islets as bioartificial endocrine pancreas. Science 210, 908–909 (1980). The first report on the laboratory demonstration of encapsulation of islets and the ability of this to maintain a normal blood glucose level when implanted.

    CAS  PubMed  Google Scholar 

  37. Sun, Y. L., Ma, X. J., Zhou, D. B., Vacek, I. & Sun, A. M. Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. J. Clin. Invest. 98, 1417–1422 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Calafiore, R. et al. Transplantation of minimal volume microcapsules in diabetic high mammalians. Ann. N. Y. Acad. Sci. 875, 219–232 (1999).

    CAS  PubMed  Google Scholar 

  39. De Vos, P., Hamel, A. F. & Tatarkiewicz, K. Considerations for successful transplantation of encapsulated pancreatic islets. Diabetologia 45, 159–173 (2002).

    CAS  PubMed  Google Scholar 

  40. Duvivier-Kali, V. F., Omer, A., Parent, R. J., O'Neil, J. J. & Weir, G. C. Complete protection of islets against allorejection and autoimmunity by a simple barium–alginate membrane. Diabetes 50, 1698–1705 (2001).

    CAS  PubMed  Google Scholar 

  41. Sakai, S., Ono, T., Ijima, H. & Kawakami, K. Synthesis and transport characterization of alginate/aminopropyl– silicate/alginate microcapsule: application to bioartificial pancreas. Biomaterials 22, 2827–2834 (2001).

    CAS  PubMed  Google Scholar 

  42. Cruise, G. M. et al. In vitro and in vivo performance of porcine islets encapsulated in interfacially photopolymerized poly(ethylene glycol) diacrylate membranes. Cell Transplant. 8, 293–306 (1999).

    CAS  PubMed  Google Scholar 

  43. De Vos, P. & Marchetti, P. Encapsulation of pancreatic islets for transplantation in diabetes: the untouchable islets. Trends Mol. Med. 8, 363–366 (2002).

    CAS  PubMed  Google Scholar 

  44. Chang, T. M. S. Bioencapsulated hepatocytes for experimental liver support. J. Hepatol. 34, 148–149 (2001).

    CAS  PubMed  Google Scholar 

  45. Wong, H. & Chang, T. M. S. Bioartificial liver: implanted artificial cells microencapsulated living hepatocytes increases survival of liver failure rats. Int. J. Artif. Organs 9, 335–336 (1986).

    CAS  PubMed  Google Scholar 

  46. Wong, H. & Chang, T. M. S. The viability and regeneration of artificial cell microencapsulated rat hepatocyte xenograft transplants in mice. J. Biomat. Artif. Cells Artif. Organs 16, 731–740 (1988).

    CAS  Google Scholar 

  47. Kashani, S. & Chang, T. M. S. Effects of hepatic stimulatory factor released from free or microencapsulated hepatocytes on galactosamine induced fulminant hepatic failure animal model. Biomat. Artif. Cells Immob. Biotech. 19, 579–598 (1991).

    CAS  Google Scholar 

  48. Bruni, S. & Chang, T. M. S. Hepatocytes immobilized by microencapsulation in artificial cells: effects on hyperbilirubinemia in Gunn Rats. J. Biomat. Artif. Cells Artif. Organs 17, 403–412 (1989).

    CAS  Google Scholar 

  49. Bruni, S. & Chang, T. M. S. Encapsulated hepatocytes for controlling hyperbilirubinemia in Gunn Rats. Int. J. Artif. Organs 14, 239–241 (1991).

    CAS  PubMed  Google Scholar 

  50. Bruni, S. & Chang, T. M. S. Kinetics of UDP-glucuronosyl–transferase in bilirubin conjugation by encapsulated hepatocytes for transplantation into Gunn rats J. Artif. Organs 19, 449–457 (1995).

    CAS  Google Scholar 

  51. Legallais, C., David, B. & Doré, E. Bioartificial livers (BAL): current technological aspects and future developments. J. Membrane Sci. 181, 81–95 (2001).

    CAS  Google Scholar 

  52. Allen, J. W., Hassanein, T. & Bhatia, S. N. Advances in bioartificial liver devices. Hepatology 34, 447–455 (2001).

    CAS  PubMed  Google Scholar 

  53. Koo, J. & Chang, T. M. S. Secretion of erythropoietin from microencapsulated rat kidney cells: Preliminary results. Intl J. Artific. Organs 16, 557–560 (1993).

    CAS  Google Scholar 

  54. Hasse, C., Klöck, G., Schlosser, A., Zimmermann, U. & Rothmund, M. Parathyroid allotransplantation without immunosuppression. Lancet 350, 1296–1297 (1997).

    CAS  PubMed  Google Scholar 

  55. Lacy, P. E., Hegre, O. D, Gerasimidi-Vazeou, A., Gentile, F. T. & Dionne, K. E. Maintenance of normoglycemia in diabetic mice by subcutaneous xenografts of encapsulated islets. Science 254, 1782–1784 (1991).

    CAS  PubMed  Google Scholar 

  56. de Vos, P. et al. Association between macrophage activation and function of micro-encapsulated rat islets. Diabetologia 46, 666–673 (2003).

    CAS  PubMed  Google Scholar 

  57. Wong, H. & Chang, T. M. S. Microencapsulation of cells within alginate poly-L-lysine microcapsules prepared with standard single step drop technique: histologically identified membrane imperfections and the associated graft rejection. Biomat. Artific.Cells Immobil. Biotechnol. 19, 675–686 (1991)

    CAS  Google Scholar 

  58. Wong, H. & Chang, T. M. S. A novel two-step procedure for immobilizing living cells in microcapsule for improving xenograft survival. Biomat. Artific. Cells Immobil. Biotechnol. 19, 687–698 (1991).

    CAS  Google Scholar 

  59. Liu, Z. & Chang, T. M. S. Effects of bone marrow cells on hepatocytes: when co-cultured or co-encapsulated together. Artif. Cells Blood Substit. Immobil. Biotechnol. 28, 365–374 (2000).

    CAS  PubMed  Google Scholar 

  60. Liu, Z. C. & Chang, T. M. S. Transplantation of co-encapsulated hepatocytes and marrow stem cells into rats. Artif. Cells Blood Substit. Immobil. Biotechnol. 30, 99–112 (2002).

    CAS  PubMed  Google Scholar 

  61. Liu, Z. C. & Chang, T. M. S. Coencapsulation of stem cells and hepatocytes: in vitro conversion of ammonia and in vivo studies on the lowering of bilirubin in Gunn rats after transplantation. Intl J. Artific. Organs 26, 491–497 (2003).

    CAS  Google Scholar 

  62. Hunkeler, D. in Bioartificial Organs III: Tissue Sourcing, Immunoisolation and Clinical Trials vol. 944 Ann. NY Acad. Sci. (eds Hunkeler, D., Cherrington, A., Prokop, A. and Rajotte, R.) 1–6 (NY Acad. Sci., New York, 2001).

    Google Scholar 

  63. Schuldt, U. & Hunkeler, D. Characterization methods for microcapsules. Minerva Biotec. 12, 249–264 (2000).

    Google Scholar 

  64. Uludag, H., De Vos, P. & Tresco, P. A. Technology of mammalian cell encapsulation. Adv. Drug Delivery Rev. 42, 29–64 (2000).

    CAS  Google Scholar 

  65. Dionne, K. E. et al. Transport characterization of membranes for immunoisolation. Biomaterials 17, 257–266 (1996).

    CAS  PubMed  Google Scholar 

  66. Coromili, V. & Chang, T. M. S. Polydisperse dextran as a diffusing test solute to study the membrane permeability of alginate polylysine microcapsules. Biomat Art. Cells Imm. Biotech. 21, 427–444 (1993).

    CAS  Google Scholar 

  67. Omer, A. et al. Survival and maturation of microencapsulated porcine neonatal pancreatic cell clusters transplanted into immunocompetent diabetic mice. Diabetes 52, 69–75 (2003).

    CAS  PubMed  Google Scholar 

  68. Binette, T. M., Dufour, J. M. & Korbutt, G. S. In vitro maturation of neonatal porcine islets: a novel model for the study of islet development and xenotransplantation. Ann. NY Acad. Sci. 944, 47–61 (2001).

    CAS  PubMed  Google Scholar 

  69. Chang, T. M. S. & Prakash, S. Therapeutic uses of microencapsulated genetically engineered cells. Mol. Med. Today 4, 221–227 (1998).

    CAS  PubMed  Google Scholar 

  70. Basic, D., Vacek, I. & Sun, A. M. Microencapsulation and transplantation of genetically engineered cells: a new approach to somatic gene therapy. Artif. Cells Blood Substit. Immobil. Biotechnol. 24, 219–255 (1996).

    CAS  PubMed  Google Scholar 

  71. Tan, S. A. et al. Rescue of motoneurons from axotomy-induced cell death by polymer encapsulated cells genetically engineered to release CNTF. Cell Transplant. 5, 577–587 (1996).

    CAS  PubMed  Google Scholar 

  72. Al-Hendy, A., Hortelano, G., Tannenbaum, G. S. & Chang, P. L. Growth retardation — an unexpected outcome from growth hormone gene therapy in normal mice with microencapsulated myoblasts. Hum. Gene Ther. 7, 61–70 (1996).

    CAS  PubMed  Google Scholar 

  73. Okada, N. et al. Cytomedical therapy for IgG1 plasmacytosis in human interleukin-6 transgenic mice using hybridoma cells microencapsulated in alginate-poly(l)lysine–alginate membrane. Biochim. Biophys. Acta 1360, 53–63 (1997).

    CAS  PubMed  Google Scholar 

  74. Dalle, B. et al. Improvement of the mouse β-thalasemia upon erythropoietin delivery by encapsulated myoblasts. Gene Ther. 6, 157–161 (1999).

    CAS  PubMed  Google Scholar 

  75. Saitoh, Y., Taki, T., Arita, N., Ohnishi, T. & Hayakawa, T. Cell therapy with encapsulated xenogeneic tumor cells secreting β-endorphin for treatment of peripheral pain. Cell Transplant. S1, S13–S17 (1995).

    Google Scholar 

  76. Hagihara, Y. et al. Transplantation of xenogeneic cells secreting β-endorphin for pain treatment: analysis of the ability of components of complement to penetrate through polymer capsules. Cell Transplant. 6, 527–530 (1997).

    CAS  PubMed  Google Scholar 

  77. Winn, S. R. et al. Polymer-encapsulated cells genetically modified to secrete human nerve growth factor promote the survival of axotomized septal cholinergic neurons. Proc. Natl Acad. Sci. USA 91, 2324–2328 (1994).

    CAS  PubMed  Google Scholar 

  78. Aebischer, P. et al. Gene therapy for amyotrophic lateral sclerosis (ALS) using a polymer encapsulated xenogenic cell line engineered to secrete hCNTF. Hum. Gene Ther. 7, 851–860 (1996).

    CAS  PubMed  Google Scholar 

  79. Bloch, J. et al. Neuroprotective gene therapy for Huntington's disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a Phase I STUDY. Hum. Gene Therapy. 15, 968–975 (2004). A recent Phase I clinical trial in patients with Huntington's disease showing the safety of encapsulated genetically engineered cells for use in a neurological disease. It also discusses potential, results and areas for improvements.

    CAS  Google Scholar 

  80. Bachoud–Levi, A. C. et al. Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF. Hum. Gene Ther. 11, 1723–1729 (2000).

    PubMed  Google Scholar 

  81. Xu, W., Liu, L. & Charles, I. G. Microencapsulated iNOS-expressing cells cause tumor suppression in mice. FASEB J. 16, 213–215 (2002).

    CAS  PubMed  Google Scholar 

  82. Cirone, P., Bourgeois, M., Austin, R. C. & Chang, P. L. A novel approach to tumor suppression with microencapsulated recombinant cells. Hum. Gene Ther. 13, 1157–1166 (2002).

    CAS  PubMed  Google Scholar 

  83. Lörh, M. et al. Microencapsulated cell-mediated treatment of inoperable pancreatic carcinoma. Lancet 357, 1591–1592 (2001). This clinical trial shows the potential of encapsulated genetically engineered cells for the treatment of inoperable cancer.

    Google Scholar 

  84. Alison, M. R. et al. Cell differentiation: hepatocytes from non-hepatic adult stem cells. Nature 406, 257 (2000).

    CAS  PubMed  Google Scholar 

  85. McNeish, J. Embryonic stem cells in drug discovery. Nature Rev. Drug Discov. 3, 70–80 (2004).

    CAS  Google Scholar 

  86. Garofalo, F. & Chang, T. M. S. Effects of mass transfer and reaction kinetics on serum cholesterol depletion rates of free and immobilized Pseudomonas pictorum. Appl. Biochem. Biotech. 27, 75–91 (1991).

    CAS  Google Scholar 

  87. Lyold-George, I. & Chang, T. M. S. Characterization of free and alginate-polylysine-alginate microencapsulated Erwinia herbicola for the conversion of ammonia, pyruvate and phenol into L-tyrosine and L-DOPA. J. Bioeng. Biotech. 48, 706–714 (1995).

    Google Scholar 

  88. Prakash, S. & Chang, T. M. S. Microencapsulated genetically engineered live E coli DH5 cells administered orally to maintain normal plasma urea level in uremic rats. Nature Med. 2, 883–887 (1996).

    CAS  PubMed  Google Scholar 

  89. Chow, K. M., Liu, Z. C., Prakash, S. & Chang, T. M. S. Metabolic induction of Lactobacillus delbrueckii. Artif. Cells Blood Sub. Biotechnol. 34, 425–434 (2003).

    Google Scholar 

  90. Hunkeler, D. et al. Bioartificial organ grafts: a view at the beginning of the third millennium. Artif. Cells Blood Substit. Immobil. Biotechnol. 31, 365–382 (2003).

    CAS  PubMed  Google Scholar 

  91. Gill, I. & Ballesteros, A. Bioencapsulation within synthetic polymers (Part 2): non-sol-gel protein–polymer biocomposites. Trends Biotechnol. 18, 469–479 (2000).

    CAS  PubMed  Google Scholar 

  92. Halle, J. P. et al. Studies on small (<300 microns) microcapsules: II—Parameters governing the production of alginate beads by high voltage electrostatic pulses. Cell Transplant. 3, 365–372 (1994).

    CAS  PubMed  Google Scholar 

  93. Raymond, M. C., Neufeld, R. J. & Poncelet, D. Encapsulation of brewers yeast in chitosan coated carrageenan microspheres by emulsification/thermal gelation. Artif. Cells Blood Substit. Immobil. Biotechnol. 32, 275–291 (2004).

    CAS  PubMed  Google Scholar 

  94. Schwinger, C. et al. High throughput encapsulation of murine fibroblasts in alginate using the JetCutter technology. J. Microencapsul. 19, 273–280 (2002).

    CAS  PubMed  Google Scholar 

  95. Aebischer, P. et al. Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients. Nature Med. 2, 696–699 (1996).

    CAS  PubMed  Google Scholar 

  96. Zambrowicz, B. P. & Sands, A. T. Knockouts model the 100 best-selling drugs — will they model the next 100? Nature Rev. Drug Discov. 2, 38–51 (2003).

    CAS  Google Scholar 

  97. Setola, V. & Roth, B. L. Why mice are neither miniature humans nor small rats: a cautionary tale involving 5-hydroxytryptamine-6 serotonin receptor species variants. Mol. Pharmacol. 64, 1277–1278 (2003).

    CAS  PubMed  Google Scholar 

  98. Poznansky, M. J. & Chang, T. M. S. 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, 103–115 (1974).

    CAS  Google Scholar 

  99. Chang, T. M. S. Preparation and characterization of xanthine oxidase immobilized by microencapsulation in artificial cells for the removal of hypoxanthine. Biomat. Artif. Cells Artif. Org. 17, 611–616 (1989).

    CAS  Google Scholar 

  100. Palmour, R. M., Goodyer, P., Reade, T. & Chang, T. M. S. Microencapsulated xanthine oxidase as experimental therapy in Lesch–Nyhan disease. Lancet 2, 687–688 (1989). This is the first clinical use of polymeric artificial cells containing an enzyme for gene therapy in an infant with an inborn error of metabolism, Lesch–Nyhan disease, with congenital enzyme deficiency. The simplicity, safety and efficacy of this approach in this rare disease has been demonstrated.

    CAS  PubMed  Google Scholar 

  101. Chang, T. M. S., Bourget, L. & Lister, C. New theory of enterorecirculation of amino acids and its use for depleting unwanted amino acids using oral enzyme-artificial cells, as in removing phenylalanine in phenylketonuria. Artif. Cells Blood Substit. Immobil. Biotechnol. 23, 1–21 (1995).

    CAS  PubMed  Google Scholar 

  102. Bourget, L. & Chang, T. M. S. Phenylalanine ammonia lyase immobilized in microcapsules for the depleture of phenylalanine in plasma in phenylketonuric rat model. Biochim. Biophys. Acta. 883, 432–438 (1986). The first report of the use of oral polymeric artificial cells containing an enzyme for use as gene therapy in an inborn error of metabolism: an animal model of phenylketonuria. This oral approach has solved many of the problems related to the need for implantation or injection.

    CAS  PubMed  Google Scholar 

  103. Sarkissian, C. N. et al. A different approach to treatment of phenylketonuria: phenylalanine degradation with recombinant phenylalanine ammonia lyase. Proc. Natl Acad. Sci. USA 96, 2339–2344 (1999).

    CAS  PubMed  Google Scholar 

  104. Liu, J. et al. Study on a novel strategy to treatment of phenylketonuria. Artif. Cells Blood Substit. Immobil. Biotechnol. 30, 243–258 (2002).

    CAS  PubMed  Google Scholar 

  105. Yu, B. L. & Chang, T. M. S. Effects of long term oral administration of microencapsulated tyrosinase on maintaining decreased systemic tyrosine levels in rats. J. Pharm. Sci. 93, 831–837 (2004).

    CAS  PubMed  Google Scholar 

  106. Uhlenkott, C. E., Huijzer, J. C., Cardeiro, D. J., Elstad, C. A. & Meadows, G. G. Attachment, invasion, chemotaxis, and proteinase expression of B16–BL6 melanoma cells exhibiting a low metastatic phenotype after exposure to dietary restriction of tyrosine and phenylalanine. Clin. Exp. Metastasis 14, 125–137 (1996).

    CAS  PubMed  Google Scholar 

  107. Yu, W. P, Wong, J. & Chang, T. M. S. Preparation and characterization of polylactic acid microcapsules containing ciprofloxacin for controlled release. J. Microencapsul. 15, 515–523 (1998).

    CAS  PubMed  Google Scholar 

  108. Zhou, M. X. & Chang, T. M. S. Control release of prostaglandin E2 from polylactic acid microcapsules, microparticles and modified microparticles. J. Microencapsul. 5, 27–36 (1988).

    CAS  PubMed  Google Scholar 

  109. Zhou, M. X. & Chang, T. M. S. Effects of polylactic acid microcapsules containing prostaglandin E2 on the survival rates of Grade II coma galactosamine–induced fulminant hepatic failure rats. J. Biomat. Art. Cells Art. Org. 15, 549–558 (1987).

    CAS  Google Scholar 

  110. Chang, T. M. S. Blood Substitutes: Principles, Methods, Products and Clinical Trials Vol. 1 1–138 (Karger, Basel, 1997). This monograph describes the principles, the method of preparation, and the experimental and clinical results of different types of red blood cell substitutes. The methods of preparation and research methodologies are described in sufficient detail for those interested in carrying out studies in this area. This monograph can be accessed freely on our public service website: www.artcell.mcgill.ca

    Google Scholar 

  111. Chang, T. M. S. Oxygen carriers. Curr. Opin. Investig. Drugs 3, 1187–1190 (2002).

    CAS  PubMed  Google Scholar 

  112. Winslow, R. Current status of blood substitute research: towards a new paradigm. J. Int. Med. 253, 508–517 (2003).

    CAS  Google Scholar 

  113. Chang, T. M. S. New generations of red blood cell substitutes. J. Int. Med. 253, 527–535 (2003).

    CAS  Google Scholar 

  114. Gould, S. A. et al. The life-sustaining capacity of human polymerized hemoglobin when red cells might be unavailable. J. Am. Coll. Surg. 195, 445–452 (2002). This contains a detailed description of the use of polyhaemoglobins as red blood cell substitutes in trauma patients undergoing surgery. Up to 20 units (10 litres) have been infused into individual patients whose original haemoglobin level can be less than 3 g/dl.

    PubMed  Google Scholar 

  115. Gould, S. A. et al. in Blood Substitutes: Principles, Methods, Products and Clinical Trials Vol. 2 (ed. Chang, T. M. S.) 12–28 (Karger, Basel, 1998).

    Google Scholar 

  116. Sprung, J. et al. The use of bovine hemoglobin glutamer-250 (Hemopure) in surgical patients: results of a multicenter, randomized, single-blinded trial. Anesth. Analg. 94, 799–808 (2002).

    CAS  PubMed  Google Scholar 

  117. Pearce, L. B. & Gawryl, M. S. in Blood Substitutes: Principles, Methods, Products and Clinical Trials Vol. 2 (ed. Chang, T. M. S.) 82–98 (Karger, Basel, 1998).

    Google Scholar 

  118. Alayash, A. I. Oxygen therapeutics: can we tame hemoglobin. Nature Rev. Drug Discov. 3, 152–159 (2004).

    CAS  Google Scholar 

  119. D'Agnillo, F & Chang, T. M. S. Polyhemoglobin–superoxide dismutase, catalase as a blood substitute with antioxidant properties. Nature Biotechnol. 16, 667–671 (1998).

    CAS  Google Scholar 

  120. D'Agnillo, F & Chang, T. M. S. Absence of hemoprotein-associated free radical events following oxidant challenge of crosslinked hemoglobin-superoxide dismutase–catalase. Free Radical Biol. Med. 24, 906–912 (1998).

    CAS  Google Scholar 

  121. Razack, S., D'Agnillo, F & Chang, T. M. S. Effects of polyhemoglobin-catalase-superoxide dismutase on oxygen radicals in an ischemia–reperfusion rat intestinal model. Artif. Cells Blood Substit. Immobil. Biotechnol. 25, 181–192 (1997).

    CAS  PubMed  Google Scholar 

  122. Powanda, D. & Chang, T. M. S. Crosslinked polyhemoglobin-superoxide dismutase-catalase supplies oxygen without causing blood brain barrier disruption or brain edema in a rat model of transient global brain ischemia–reperfusion. Artif. Cells Blood Substit. Immobil. Biotechnol. 30, 23–37 (2002).

    CAS  PubMed  Google Scholar 

  123. Shorr, R. G., Viau, A. T. & Abuchowski, A. Phase 1B safety evaluation of PEG hemoglobin as an adjuvant to radiation therapy in human cancer patients. Artif. Cells Blood Substit. Immobil. Biotechnol. 24, 407 (1996).

    Google Scholar 

  124. Yu, B. L. & Chang, T. M. S. In vitro and In vivo enzyme studies of polyhemoglobin–tyrosinase. J. Biotechnol. Bioeng. 32, 311–320 (2004).

    Google Scholar 

  125. Yu, B. L. & Chang, T. M. S. In vitro and in vivo effects of polyhemoglobin–tyrosinase on murine B16F10 melanoma. Melanoma Res. 14, 197–202 (2004).

    CAS  PubMed  Google Scholar 

  126. Yu, B. L. & Chang, T. M. S. Effects of combined oral administration and intravenous injection on maintaining decreased systemic tyrosine levels in rats. Artif. Cells Blood Substit. Immobil. Biotechnol. 32, 129–148 (2004).

    CAS  PubMed  Google Scholar 

  127. Rudolph, A. S., Rabinovici, R. & Feuerstein, G. Z. (eds) Red Blood Cell Substitutes 1–485 (Dekker, New York, 1997).

    Google Scholar 

  128. Tsuchida, E. (ed) Blood Substitutes: Present and Future Perspectives 1–267 (Elsevier, Amsterdam, 1998).

    Google Scholar 

  129. Philips, W. T. et al. Polyethylene glycol-modified liposome–encapsulated hemoglobin: a long circulating red cell substitute. J. Pharm. Exp. Therap. 288, 665–670 (1999).

    Google Scholar 

  130. Yu, W. P. & Chang, T. M. S. Submicron biodegradable polymer membrane hemoglobin nanocapsules as potential blood substitutes: a preliminary report. Artif. Cells Blood Substit. Immobil. Biotechnol. 22, 889–894 (1994).

    CAS  PubMed  Google Scholar 

  131. Chang, T. M. S. & Yu, W. P. in Blood Substitutes: Principles, Methods, Products and Clinical Trials Vol. 2 (ed. Chang, T. M. S.) 216–231 (Karger, Basel, 1998).

    Google Scholar 

  132. Chang, T. M. S., Powanda, D. & Yu, W. P. Analysis of polyethylene-glycol-polylactide nano–dimension artificial red blood cells in maintaining systemic hemoglobin levels and prevention of methemoglobin formation. Artif. Cells Blood Substit. Immobil. Biotechnol. 31, 231–248 (2003).

    CAS  PubMed  Google Scholar 

  133. Yu, W. P., Wong, J. P. & Chang, T. M. S. Biodegradable polylactic acid nanocapsules containing ciprofloxacin: preparation and characterization. Artif. Cells Blood Substit. Immobil. Biotechnol. 27, 263–278 (1999).

    PubMed  Google Scholar 

  134. Rosental, A. M. & Chang, T. M. S. The incorporation of lipid and Na+-K+–ATPase into the membranes of semipermeable microcapsules. J. Membr. Sci. 6, 329–338 (1980).

    Google Scholar 

  135. Sipehia, R., Bannard, R. & Chang, T. M. S. Adsorption of large lipophilic molecules with exclusion of small hydrophilic molecules by microencapsulated activated charcoal formed by coating with polyethylene membrane. J. Membr. Sci. 29, 277–286 (1986).

    CAS  Google Scholar 

  136. Cousidneau, J. & Chang, T. M. S. Formation of amino acid from urea and ammonia by sequential enzyme reaction using a microencapsulated multi–enzyme system. Biochem. Biophys. Res. Commun. 79, 24–31 (1977).

    Google Scholar 

  137. Grunwald, J. & Chang, T. M. S. Nylon polyethyleneimine microcapsules for immobilizing multienzymes with soluble dextran-NAD+ for the continuous recycling of the microencapsulated dextran–NAD+. Biochem. Biophys. Res. Commun. 81, 565–570 (1978).

    CAS  PubMed  Google Scholar 

  138. Campbell, J. & Chang, T. M. S. Microencapsulated multi–enzyme systems as vehicles for the cyclic regeneration of free and immobilized coenzymes. Enzymes Engineer. 3, 371–377 (1978).

    Google Scholar 

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Acknowledgements

This author acknowledges the supports of the Canadian Institutes of Health Research, the 'Virage' Centre of Excellence in Biotechnology from the Quebec Ministry, the MSSS-FRSQ Research Group award on Blood Substitutes in Transfusion Medicine from the Quebec Ministry of Health's new Haemovigillance and Transfusion Medicine Programme and the Operating grant from the Research Fund of the Bayer/Canadian Blood Agency/Haema Quebec/Canadian Institutes of Health Research.

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  1. Departments of Physiology, Artificial Cells and Organs Research Center, Medicine and Biomedical Engineering, Faculty of Medicine, McGill University, 3655, Drummond Street, Montreal, H3G 1H6, Quebec, Canada

    Thomas Ming Swi Chang

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DATABASES

Entrez Gene

Catalase

CNTF

endostatin

ERBB2

Factor XI

hGH

IL-2

IL-6

nerve growth factor

Parathyroid hormone

propiomelanocortin

UDPGT

xanthine oxidase

OMIM

β-thalassaemia

Amyotrophic lateral sclerosis

Haemophilia B

Huntington's disease

Lesch–Nyhan disease

PKU

FURTHER INFORMATION

Artificial Cells and Organs Research Centre

International Society for Artificial Cells, Blood Substitutes and Immobilization Biotechnology

Glossary

AXOTOMIZE

Interruption of the axon of a neuron.

PRO-DRUG

A pharmacologically inactive compound that is converted to the active form of the drug by endogenous enzymes or metabolism.

ANGIOGENESIS

Growth of new blood vessels. For example, in pathology, the generation of a blood supply to a tumour.

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Chang, T. Therapeutic applications of polymeric artificial cells. Nat Rev Drug Discov 4, 221–235 (2005). https://doi.org/10.1038/nrd1659

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