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Human islet isolation and autotransplantation [autologous islet transplant (AUTX)] is performed to prevent or ameliorate brittle diabetes after total pancreatectomy performed for benign disease. The success or failure of the transplant can be associated with a profound impact on the individual's quality of life and even survival. AUTX offers unique insights into the effects of pancreas quality, islet number, isolation technique and alternate site engraftment on transplant efficacy. Herein, we review islet isolation with a focus on potential pathways to further optimize the endocrine outcome of AUTX, and compare and contrast differences in islet processing for AUTX and allotransplantation (allogeneic islet transplant).New knowledge of human islet biology and issues surrounding the engraftment process offer opportunities for innovative approaches toward optimizing islet cell transplantation.Improving the rate and durability of insulin independence in the often-times marginal dose model of AUTX may provide new insight toward improving the efficiency and durability of single donor islet (allogeneic islet transplant).