Reversal of Hyperglycemia by Subcutaneous Islet Engraftment Using an Atelocollagen Sponge as a Scaffold

Abstract

Type 1 diabetes mellitus (T1DM) affects 8.4 million people worldwide, with patients primarily relying on exogenous insulin injections to maintain blood glucose levels. Islet transplantation via the portal vein has allowed for the direct internal release of insulin by glucose-sensitive islets. However, this method might not be desirable for future cell therapy transplanting pluripotent stem cell-derived β cells, facing challenges including difficulties in cell retrieval and graft loss due to the instant blood-mediated inflammatory reaction (IBMIR). Here, we established a subcutaneous transplantation protocol using an atelocollagen sponge as a scaffold. While the subcutaneous site has many advantages, the lack of a vascular bed limits its application. To address this issue, we performed angiogenesis stimulation at the transplantation site using bFGF absorbed in a gelatin sponge (Spongel), significantly improving the microvascular area. Our in vivo experiments also revealed angiogenesis stimulation is crucial for reversing hyperglycemia in streptozotocin (STZ)-induced diabetic mice. In addition to the angiogenic treatment, an atelocollagen sponge is used to carry the islets and helps avoid graft leakage. With 800 mouse islets delivered by the atelocollagen sponge, the STZ-induced diabetic mice showed a reversal of hyperglycemia and normalized glucose intolerance. Their normoglycemia was maintained until the graft was removed. Analysis of the harvested islet grafts exhibited a high vascularization and preserved morphologies, suggesting that using an atelocollagen sponge as a scaffold helps maintain the viability of the islet grafts.