Islet transplantation into subcutaneous polymer scaffolds has shown to successfully induce normoglycemia in type 1 diabetes models. Vascularization of these scaffolds is imperative for optimal control of glucose levels. We studied the effect of the vascular stimulator hydrogen sulfide (H2S) on the degree of vascularization of a scaffold and the role of the immune system in this process. Scaffolds were subcutaneously implanted in immunocompetent C57BL/6 and immunocompromised nude mice. Mice received twice-daily intraperitoneal injections of the fast-releasing H2S donor sodium hydrosulfide (NaHS, 25 or 50 μmol/kg) or saline for 28 days. After 63 days the vascular network was analyzed by histology and gene expression. Here we showed that the vascularization of a subcutaneous scaffold in nude mice was significantly impaired by H2S treatment. Both the CD31 gene and protein expression were reduced in these scaffolds compared to the saline-treated controls. In C57BL/6 mice, the opposite was found, the vascularization of the scaffold was significantly increased by H2S. The mRNA expression of the angiogenesis marker CD105 was significantly increased compared to the controls as well as the number of CD31 positive blood vessels. In conclusion, the immune system plays an important role in the H2S mediated effect on vascularization of subcutaneous scaffolds.

The liver as transplantation site for pancreatic islets is associated with significant loss of islets, which can be prevented by grafting in a prevascularized, subcutaneous scaffold. Supporting vascularization of a scaffold to limit the period of ischemia is challenging and was developed here by applying liposomes for controlled release of angiogenic factors. The angiogenic capacity of platelet-derived growth factor, vascular endothelial growth factor, acidic fibroblast growth factor (aFGF), and basic FGF were compared in a tube formation assay. Furthermore, the release kinetics of different liposome compositions were tested. aFGF and L-α-phosphatidylcholine/cholesterol liposomes were selected to support vascularization. Two dosages of aFGF-liposomes (0.5 and 1.0 μg aFGF per injection) were administered weekly for a month after which islets were transplanted. We observed enhanced efficacy in the immediate post-transplant period compared to the untreated scaffolds. However, on the long-term, glucose levels of the aFGF treated animals started to increase to diabetic levels. These results suggest that injections with aFGF liposomes do improve vascularization and the immediate restoration of blood glucose levels but does not facilitate the long-term survival of islets. Our data emphasize the need for long-term studies to evaluate potential beneficial and adverse effects of vascularization protocols of scaffolds. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2533-2542, 2017.