Creation of a rich vascular subcutaneous space for cell transplantation via injectable biological hydrogels

The subcutaneous space offers an attractive and accessible site for cell transplantation. However, its clinical utility is often hindered by insufficient vascularization. This study evaluated the vascularization potential of three hydrogels; human collagen type I, human fibrin, and alginate implanted subcutaneously in Sprague-Dawley rats. Polylactide-co-glycolide (PLG) scaffolds used as positive controls for foreign body response. Sequential injections were performed at 1, 2, and 4 weeks, and tissues were retrieved for histopathological examination. Human collagen type I and fibrin induced robust neovascularization compared to controls, with peak vessel density at week 1 (2.79-fold and 3.18-fold; P < 0.001) and sustained increases through week 4 (1.94-fold and 2.3-fold, respectively). No significant differences were observed between human collagen type I and fibrin at any time point. Both biomaterials were well tolerated without evident of fibrosis or foreign body reaction. Alginate produced the strongest early angiogenic effect (3.96-fold at week 1; P < 0.001) but was associated with marked inflammation and fibrosis by week 4. PLG scaffolds induced modest vascularization but consistently provoked inflammatory reactions and fibrosis. Human-derived hydrogels thus combine rapid and durable vascularization with excellent biocompatibility, providing a minimally invasive strategy to enhance subcutaneous cell transplantation outcomes.