Reversal of diabetes in mice by xenotransplantation of a bioartificial pancreas in a prevascularized subcutaneous site.

Abstract

The subcutaneous site has been regarded as a potential site for a bioartificial pancreas. Transplantation of islets, encapsulated by the development of diverse biocompatible materials and structural designs, can reverse hyperglycemia in diabetic recipients. Approximately 750 Sprague-Dawley rat islets macroencapsulated in an agarose/poly (styrene sulfonic acid) mixed gel were implanted into a prevascularized subcutaneous site. The site was constructed by subcutaneous injection of basic fibroblast growth factor (bFGF)-impregnated gelatin microspheres in streptozotocin-induced C57BL/6 diabetic mice. Diabetic mice treated with bFGF-free gelatin microspheres and diabetic mice without any treatment undergoing the same subcutaneous transplantation were used as controls. After transplantation, non-fasting blood glucose, body weight, intraperitoneal glucose tolerance test, and histologic evaluations were processed. All the recipients undergoing the subcutaneous xenograft returned to normoglycemia within 1 week after transplantation. Eight of 10 recipients in the bFGF+ group maintained normoglycemia for a period of 38-101 days and gradually gained increase of body weight. Two of 10 recipients became hyperglycemic again when the grafts were respectively retrieved at days 31 and 63. Intraperitoneal glucose tolerance tests at month 1 and 2 revealed significant ameliorated glucose tolerance but a tendency to reduced glucose tolerance when compared respectively with those of the streptozotocin-induced diabetic mice and normal mice. Histologic examination revealed that islets within the retrieved grafts at days 31 and 63 were viable and intact; no fibrotic overgrowth was present around the surface of grafts. A successfully prevascularized subcutaneous site could be constructed by a tissue bioengineering approach. Xenotransplantation of the agarose/poly (styrene sulfonic acid) mixed gel-based bioartificial pancreas in the prevascularized subcutaneous site could reverse diabetes in mice.