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Artificial Pancreas to Treat Type 1 Diabetes Mellitus

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Tissue Engineering

Part of the book series: Methods in Molecular Medicine™ ((MIMM,volume 140))

Summary

Substitution of diseased organ/tissues with totally artificial machines or transplantable biohybrid devices where functionally competent cells are enveloped within immunoprotective artificial membranes could represent one of the future goals in medicine. In particular, artificial or, closer to feasibility, biohybrid artificial pancreas (BHAP) could replace the function of pancreatic islet β-cells that have been destroyed by autoimmunity, thereby obviating the need to treat patients with type 1 diabetes mellitus (T1DM) with multiple daily insulin injections. State-of-the-art diabetes therapy and perspectives in the use of BHAP, with special regard to islet-cell-containing microcapsules fabricated with alginate-based polymers, including applications to experimental animal models according to different chemical procedures, are reviewed. Special emphasis has been given to preparation methods, immunoprotection strategies, and biocompatibility of the islet-cell-containing microbarriers, as well as to approaches to ameliorate these features. Currently available BHAP prototypes have been critically reviewed to define expectations about the next generation devices targeting the final cure of T1DM.

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References

  1. Colton, C. K. (1995) Implantable biohybrid artificial organ. Cell Transplant. 4, 415–436.

    Article  CAS  Google Scholar 

  2. Williams, R. (1998) The burden of diabetes in the next millennium. Diabetes Rev. Int. 7(3), 21–27.

    Google Scholar 

  3. American Diabetes Association (position statement) (2005) Standard of medical care in diabetes, Diabetes Care 28(Suppl. 1), S4–S36.

    Article  Google Scholar 

  4. Calafiore, R. (1997) Perspectives in pancreatic and islet cell transplantation for the therapy of IDDM, Diabetes Care 20, 889–896.

    Article  CAS  Google Scholar 

  5. Ryan, E. A., Bigam, D., and Shapiro, A. M. (2006) Current indications for pancreas or islet transplant. Diabetes Obes. Metab. 8, 1–7.

    Article  Google Scholar 

  6. International Islet Transplant Registry (1999) Newsletter 8, 1.

    Google Scholar 

  7. Shapiro, A. M., Lakey, J. R., Paty, B. W., Senior, P. A., Bigam, D. L., and Ryan, E. A. (2005) Strategic opportunities in clinical islet transplantation. Transplantation 79, 1304–1307.

    Article  Google Scholar 

  8. Korbutt, G. S., Elliott, J. F., Ao, Z., Smith, D. K., Warnock, G. L., and Rajotte, R. V. (1996) Large scale isolation, growth, and function of porcine neonatal islet cells. J. Clin. Invest. 97, 2119–2129.

    Article  CAS  Google Scholar 

  9. Hunkeler, D., Sun, A. M., Rajotte, R., Gill, R., Calafiore, R., and Morel, P. (1999) Bioartificial organs and acceptable risk. Nat. Biotechnol. 17, 1045.

    Article  CAS  Google Scholar 

  10. Toso, C., Mathe, Z., Morel, P., Oberholzer, J., Bosco, D., Sainz-Vidal, D., Hunkeler, D., Buhler, L. H., Wandrey, C., and Berney, T. (2005) Effect of microcapsule composition and short-term immunosuppression on intraportal biocompatibility. Cell Transplant. 14, 159–167.

    Article  Google Scholar 

  11. Orive, G., Hernandez, R. M., Gascon, A. R., Calafiore, R., Chang, T. M., de Vos, P., Hortelano, G., Hunkeler, D., Lacik, I., Shapiro, A. M., and Pedraz, J. L. (2003) Cell encapsulation: promise and progress. Nat. Med. 9, 104–107.

    Article  CAS  Google Scholar 

  12. Petruzzo, P., Pibiri, L., De Giudici, M. A., Basta, G., Calafiore, R., Falorni, A., Brunetti, P., and Brotzu, G. (1991) Xenotransplantation of microencapsulated pancreatic islets contained in a vascular prosthesis: preliminary results. Transpl. Int. 4, 200–204.

    CAS  Google Scholar 

  13. acy, P. E., Hegre, O. D., Gerasimidi-Vazeou, A., Gentile, F. T., and Dionne, K. E. (1991) Subcutaneous xenografts of rat islets in acrylic copolymer capsules maintain normoglycemia in diabetic mice. Science 254, 1782–1784.

    Article  CAS  Google Scholar 

  14. Lanza, R. P., Beyer, A. M., Staruk, J. E., and Chick, W. L. (1993) Biohybrid artificial pancreas: long-term function of discordant islet xenografts in streptozotocin-diabetic rats. Transplantation 56, 1067–1072.

    Article  CAS  Google Scholar 

  15. Lanza, R. P., Borland, K. M., Staruk, J. E., Appel, M. C., Solomon, B. A., and Chick, W. L. (1992) Transplantation of encapsulated canine islets into spontaneously diabetic BB/Wor rats without immunosuppression. Endocrinology 131, 637–642.

    Article  CAS  Google Scholar 

  16. de Vos, P., Hillebrands, J. L., De Haan, B. J., Strubbe, J. H., and Van Schilfgaarde, R. (1997) Efficacy of a prevascularized expanded polytetrafluoroethylene solid support system as a transplantation site for pancreatic islets. Transplantation 63, 824–830.

    Article  Google Scholar 

  17. Maki, T., Otsu, I., O’Neil, J. J., Dunleavy, K., Mullon, C. J., Solomon, B. A., and Monaco, A. P. (1996) Treatment of diabetes by xenogeneic islets without immunosuppression: use of a vascularized bioartificial pancreas. Diabetes 45, 342–347.

    Article  CAS  Google Scholar 

  18. Calafiore, R. (1992) Transplantation of microencapsulated pancreatic human islets for the therapy of diabetes mellitus: a preliminary report. ASAIO J. 38, 34–37.

    Article  CAS  Google Scholar 

  19. Kizilel, S., Garfinkel, M., and Opara, E. (2005) The bioartificial pancreas: progress and challenges. Diabetes Technol. Ther. 7, 968–985.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Iwata, H., Amemiya, H., Matsuda, T., Takano, H., Hayashi, R., and Akutsu, T. (1989) Evaluation of microencapsulated islets in agarose gel as bioartificial pancreas by studies of hormone secretion in culture and by xenotransplantation. Diabetes 38(Suppl. 1), 224–225.

    Google Scholar 

  22. Cruise, G. N., Hegre, O. D., Lamberti, F. V., Hager, S. R., Hill, R., Scharp, D. S., and Hubbell, J. A. (1999) In vitro and in vivo performance of porcine islets encapsulated in interfacially photopolymerized poly(ethylene glycol) diacrylate membranes. Cell Transplant. 8, 293–306.

    CAS  Google Scholar 

  23. Zielinski, B. A. and Aebischer, P. (1994) Chitosan as a matrix for mammalian cell encapsulation. Biomaterials 15, 1049–1056.

    Article  CAS  Google Scholar 

  24. Dawson, R. M., Broughton, R. L., Stevenson, W. T., and Sefton, M. V. (1987) Microencapsulation of CHO cells in a hydroxyethyl-methacrylate methyl methacrylate copolymer. Biomaterials 8, 360–366.

    Article  CAS  Google Scholar 

  25. Kessler, L., Pinget, M., Aprahaim, M., Dejardin, P., and Damge, C. (1991) In vitro and in vivo studies of the properties of an artificial membrane for pancreatic islet encapsulation. Horm. Metab. Res. 23, 312–317.

    Article  CAS  Google Scholar 

  26. Calafiore, R., Basta, G., Luca, G., Lemmi, A., Montanucci, M. P., Calabrese, G., Racanicchi, L., Mancuso, F., and Brunetti, P. (2006) Microencapsulated pancreatic islet allografts into nonimmunosuppressed patients with type 1 diabetes: first two cases. Diabetes Care 29, 137–138.

    Article  Google Scholar 

  27. Lim, F. and Sun, A. M. (1980) Microencapsulated islets as bioartificial endocrine pancreas. Science 210, 908–910.

    Article  CAS  Google Scholar 

  28. Hunkeler, D., Prokop, A., Powers, A., Haralson, M., DiMari, S., and Wang, T. (1997) A screening of polymers as biomaterials for cell encapsulation. Polymer News 22, 232.

    CAS  Google Scholar 

  29. Draget, K. I., Skjak-Braek, G., and Smidsrod, O. (1997) Alginate based new materials. Int. J. Biol. Macromol. 21, 47–55.

    Article  CAS  Google Scholar 

  30. 30 Calafiore, R., Basta, G., Osticioli, L., Luca, G., Tortoioli, C., and Brunetti, P. (1996) Coherent microcapsules for pancreatic islet transplantation: a new approach for bioartificial pancreas. Transplant. Proc. 28, 812–813.

    CAS  Google Scholar 

  31. Duvivier-Kali, V. F., Omer, A., Lopez-Avalos, M. D., O’Neil, J. J., and Weir, G. C. (2004) Survival of microencapsulated adult pig islets in mice in spite of an antibody response. Am. J. Transplant. 4, 1991–2000.

    Article  CAS  Google Scholar 

  32. Strand, B. L., Gaserod, O., Kulseng, B., Espevik, T., and Skjak-Baek, G. (2002) Alginate-polylysine-alginate microcapsules: effect of size reduction on capsule properties. J. Microencapsul. 19, 615–630.

    Article  CAS  Google Scholar 

  33. Luca, G., Nastruzzi, C., Calvitti, M., Becchetti, E., Baroni, T., Neri, L. M., Capitani, S., Basta, G., Brunetti, P., and Calafiore, R. (2005) Accelerated functional maturation of isolated neonatal porcine cell clusters: in vitro and in vivo results in NOD mice. Cell Transplant. 14, 249–261.

    Article  Google Scholar 

  34. Calafiore, R., Basta, G., Falorni, A., Calcinaro, F., Pietropaolo, M., and Brunetti, P. (1992) A method for the large-scale production of microencapsulated islets: in vitro and in vivo results. Diabetes Nutr. Metab. 5, 23.

    Google Scholar 

  35. Lanza, R. P. (1995) Encapsulation technologies. Tissue Eng. 1, 18.

    Article  Google Scholar 

  36. de Vos, P., Wolters, G. H., and van Schilfgaarde, R. (1994) Possible relationship between fibrotic overgrowth of alginate-polylysine-alginate microencapsulated pancreatic islets and the microcapsule integrity. Transplant. Proc. 26, 782–783.

    Google Scholar 

  37. Sawhney, A., Pathak, C. P., and Hubbell, J. A. (1994) Modification of Langerhans islet surfaces with immunoprotective poly(ethylene glycol) coatings. Biotech. Bioeng. 44, 383.

    Article  CAS  Google Scholar 

  38. Calafiore, R., Basta, G., Osticioli, L., Luca, G., Tortoioli, C., and Brunetti, P. (1996) Coherent microcapsules for pancreatic islet transplantation: a new approach for bioartificial pancreas. Transplant. Proc. 28, 812–813.

    CAS  Google Scholar 

  39. Brunetti, P., Basta, G., Faloerni, A., Calcinaro, F., Pietropaolo, M., and Calafiore, R. (1991) Immunoprotection of pancreatic islet grafts within artificial microcapsules. Int. J. Artif. Organs 14, 789–791.

    CAS  Google Scholar 

  40. Soon-Shiong, P., Feldman, E., Nelson, R., Komtebedde, J., Smidsrod, O., Skjak-Braek, G., Espevik, T., Heintz, R., and Lee, M. (1992) Successful reversal of spontaneous diabetes in dogs by intraperitoneal microencapsulated islets. Transplantation 54, 769–774.

    Article  CAS  Google Scholar 

  41. Sun, X., Ma, X., Zhou, D., Vacek, I., and Sun, A. M. (1996) Normalization of diabetes in spontaneously diabetic cynomologous monkeys by xenografts of microencapsulated porcine islets without immunosuppression. J. Clin. Invest. 98,1417–1422.

    Article  CAS  Google Scholar 

  42. Elliott, R. B., Escobar, L., Tan, P. L., Garkavenko, O., Calafiore, R., Basta, P., Vasconcellos, A. V., Emerich, D. F., Thanos, C., and Bambra, C. (2005) Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates. Transplant. Proc. 37, 3505–3508.

    Article  CAS  Google Scholar 

  43. Wu, H., Avgoustiniatos, E. S., Swette, L., Bonner-Weir, S., Weir, G. C., and Colton, C. K. (1999) In situ electrochemical oxygen generation with an immunoisolation device. Ann. N. Y. Acad. Sci. 875, 105–125.

    Article  CAS  Google Scholar 

  44. Desai, T. A., Chu, W. H., Rasi, G., Sinibaldi-Vallebona, P., Guarino, E., and Ferrari, M. (1999) Microfabricated biocapsules provide short-term immunoisolation of insulinoma xenografts. Biomed. Microdevices 1, 131–138.

    Article  CAS  Google Scholar 

  45. Basta, G., Sarchielli, P., Luca, G., Racanicchi, L., Nastruzzi, C., Guido, L., Mancuso, F., Macchiarulo, G., Calabrese, G., Brunetti, P., and Calafiore, R. (2004) Optimized parameters for microencapsulation of pancreatic islet cells: an in vitro study clueing on islet graft immunoprotection in type 1 diabetes mellitus. Transplant. Immunol. 13, 289–296.

    Article  CAS  Google Scholar 

  46. Hering, B. J., Wijkstrom, M., Graham, M. L., Hardstedt, M., Aasheim, T. C., Jie, T., Ansite, J. D., Nakano, M., Cheng, J., Li, W., Moran, K., Christians, U., Finnegan, C., Mills, C. D., Sutherland, D. E., Bansal-Pakala, P., Murtaugh, M. P., Kirchhof, N., and Schuurman, H. J. (2006) Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat. Med. 12, 301–303.

    Article  CAS  Google Scholar 

  47. Cardona, K., Korbutt, G. S., Milas, Z., Lyon, J., Cano, J., Jiang, W., Bello-Laborn, H., Hacquoil, B., Strobert, E., Gangappa, S., Weber, C. J., Pearson, T. C., Rajotte, R. V., and Larsen, C. P. (2006) Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat. Med. 12, 304–306.

    Article  CAS  Google Scholar 

  48. Patience, C., Takeuchi, Y., and Weiss, R. A. (1997) Infection of human cells by an endogenous retrovirus of pigs. Nat. Med. 3, 282–286.

    Article  CAS  Google Scholar 

  49. Fishman, J. A. and Patience, C. (2004) Xenotransplantation: infectious risk revisited. Am. J. Transplant. 4, 1383–1390.

    Article  Google Scholar 

  50. Lindeborg, E., Kumagai-Braesch, M., Tibell, A., Christensson, B., and Moller, E. (2004) Biological activity of pig islet-cell reactive IgG antibodies in xenotransplanted diabetic patients. Xenotransplantation 11, 457–470.

    Article  Google Scholar 

  51. Valdes-Gonzalez, R. A., Dorantes, L. M., Garibay, G. N., Bracho-Blanchet, E., Mendez, A. J., Davila-Perez, R., Elliott, R. B., Teran, L., and White, D. J. (2005) Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study. Eur. J. Endocrinol. 153, 419–427.

    Article  CAS  Google Scholar 

  52. Elliott, R. B., Escobar, L., Garkavenko, O., Croxson, M. C., Schroeder, B. A., McGregor, M., Ferguson, G., Beckman, N., and Ferguson, S. (2000) No evidence of infection with porcine endogenous retrovirus in recipients of encapsulated porcine islet xenografts. Cell Transplant. 9, 895–901.

    CAS  Google Scholar 

  53. Pakhomov, O., Martignat, L., Honiger, J., Clemenceau, B., Sai, P., and Darquy, S. (2005) AN69 hollow fiber membrane will reduce but not abolish the risk of transmission of porcine endogenous retroviruses. Cell Transplant. 14, 749–756.

    Google Scholar 

  54. Gill, R. G. and Wolf, L. (1995) Immunobiology of cellular transplantation. Cell Transplant. 4, 361–370.

    Article  CAS  Google Scholar 

  55. Grewal, I. S. and Flavell, R. A. (1998) CD40 and CD154 in cell-mediated immunity. Ann. Rev. Immunol. 16, 111–135.

    Google Scholar 

  56. Weber, C. J., Safley, S., Hagler, M., and Kapp, J. (1999) Evaluation of graft-host response for various tissue resources and animal models. Ann. N. Y. Acad. Sci. 875, 233–254.

    Article  CAS  Google Scholar 

  57. Rayat, G. R., Rajotte, R. V., and Korbutt, G. S. (1999) Potential application of neonatal porcine islets as treatment for type 1 diabetes: a review. Ann. N. Y. Acad. Sci. 875, 175–188.

    Article  CAS  Google Scholar 

  58. Gill, R. G. (1999) Antigen presentation pathways for immunity to islet transplants: relevance to immunoisolation. Ann. N. Y. Acad. Sci. 875, 255–260.

    Article  CAS  Google Scholar 

  59. Ricci, M., Blasi, P., Giovagnoli, S., Rossi, C., Macchiarulo, G., Luca, G., Basta, G., and Calafiore, R. (2005) Ketoprofen controlled release from composite microcapsules for cell encapsulation: effect on post-transplant acute inflammation. J. Control Release 107, 395–407.

    Article  CAS  Google Scholar 

  60. Luca, G., Nastruzzi, C., Basta, G., Brozzetti, A., Saturni, A., Mughetti, D., Ricci, M., Rossi, C., Brunetti, P., and Calafiore, R. (2000) Effects of anti-oxidizing vitamins on in vitro cultured porcine neonatal pancreatic islet cells. Diabetes Nutr. Metab. 13, 301–307.

    CAS  Google Scholar 

  61. Lanza, R. P., Ecker, D. M., Kuhtreiber, W. M., Marsh, J. P., Ringeling, J., and Chick, W. L. (1999) Transplantation of islets using microencapsulation: studies in diabetic rodents and dogs. J. Mol. Med. 77, 206–210.

    Article  CAS  Google Scholar 

  62. Fan, M. Y., Lum, Z. P., Fu, X. W., Levesque, L., Tai, I. T., and Sun, A. M. (1990) Reversal of diabetes in BB rats by transplantation of encapsulated pancreatic islets. Diabetes 39, 519–522.

    Article  CAS  Google Scholar 

  63. Lum, Z. P., Tai, I. T., Krestow, M., Norton, J., Vacek, I., Sun, A. M. (1991) Prolonged reversal of diabetic state in NOD mice by xenografts of microencapsulated rat islets. Diabetes 40, 1511–1516.

    Article  CAS  Google Scholar 

  64. Soon-Shiong, P., Heintz, R. E., Merideth, N., Yao, Q. X., Yao, Z., Zheng, T., Murphy, M., Moloney, M. K., Schmehl, M., and Harris, M. (1994) Insulin-independence in a type I diabetic patient after encapsulated islet transplantation. Lancet 343, 950–951.

    Article  CAS  Google Scholar 

  65. Dufour, J. M., Rajotte, R. V., Zimmerman, M., Rezania, A., Kin, T., Dixon, D. E., and Korbutt, G. (2005) Development of an ectopic site for islet transplantation, using biodegradable scaffolds. Tissue Eng. 11, 1323–1331.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, Section of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, Perugia, Italy

    Riccardo Calafiore

  2. Department of Internal Medicine, Section of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, Perugia, Italy

    Giuseppe Basta

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  1. Riccardo Calafiore
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  2. Giuseppe Basta
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Editors and Affiliations

  1. Department of Gene Regulation and Differentiation, National Research Center for Biotechnology GBF, Braunschweig, Germany

    Hansjörg Hauser

  2. Institute for Chemical and Bio-Engineering, ETH Zurich, Zurich, Switzerland

    Martin Fussenegger

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© 2007 Humana Press Inc.

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Calafiore, R., Basta, G. (2007). Artificial Pancreas to Treat Type 1 Diabetes Mellitus. In: Hauser, H., Fussenegger, M. (eds) Tissue Engineering. Methods in Molecular Medicine™, vol 140. Humana Press. https://doi.org/10.1007/978-1-59745-443-8_12

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  • DOI: https://doi.org/10.1007/978-1-59745-443-8_12

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-756-3

  • Online ISBN: 978-1-59745-443-8

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