Introduction: The subcutaneous space is currently being pursued as an alternative transplant site for human pancreatic islets, stem cell and xenogeneic derived-islets, due to its retrievability, minimally invasiveness, accommodation of large transplant volumes, and potential for monitoring graft function. However, transplantation of islets into an unmodified subcutaneous niche fails to reverse diabetes due to a lack of adequate blood supply. Biomaterial nanofibrous scaffolds can be functionalized to enhance the host tissues integration, provide a platform for the delivery of pro-engraftment growth factors, and immunomodulatory agents. 
Method: Herein, we utilize poly (ε-caprolactone) (PCL) and poly (lactic-co-glycolic acid) (PLGA) polymers to make nanofibrous scaffolds and functionalized with bioactive peptides, to prime the subcutaneous space into a more suitable environment. We implanted the nylon catheter (2 cm length, 6 French diameter) (deviceless space, DL), and nanofibrous scaffolds (scaffold was wrapped around the nylon catheter) such as PCL, PCL+RGD+VEGF (PCL+R+V), PCL+RGD+Laminin (PCL+R+L), PLGA and PLGA+Gelatin (PLGA+G) into the subcutaneous space of immunodeficient B6.129S7-Rag1tm1Mom/J mice for four weeks to create a prevascularized space. After 4 weeks, DL and scaffolds implanted mice and those intended for kidney capsule (KC) implantation were rendered diabetic by intraperitoneal injection of 180 mg/kg streptozotocin. Subsequently, neonatal porcine islets (3000 NPI) were transplanted under the KC or within the subcutaneous DL and scaffolds. Graft function was evaluated by monitoring non-fasting blood glucose, stimulated porcine insulin measurement, intraperitoneal glucose tolerance test, and histochemical analysis. 
Results: Our preliminary scaffolds implantation (no cells) study demonstrates that PCL, PCL+R+V and PCL+R+L scaffolds did not absorb and partially integrated with the host tissues (PCL based scaffolds remain intact at the implanted site) whereas PLGA and PLGA+G scaffolds were completely absorbed and integrated with the host tissues (no remnants of PLGA based scaffolds at the implanted site), and we also observed that there were numerous blood vessels innervated in and around these scaffolds. Compared with peptide functionalized PCL scaffolds, PLGA and PLGA+G fibrous scaffolds with NPI resulted in 86% and 100% euglycemia (*p< 0.05, **p<0.01 respectively), superior glucose clearance (*p<0.05) and greater stimulated porcine insulin secretion (*p<0.05). Moreover, PLGA and PLGA+G scaffolds exhibited comparable graft functions with the positive controls (DL and KC)(p>0.05). 
Conclusion: Our study demonstrates that PLGA based fibrous scaffolds facilitates the engraftment and function of NPIs in the subcutaneous space of diabetic mice. These collective data emphasize the support of biomaterial implants on cellular graft function in the subcutaneous space for clinical islet xenotransplant applications in a near future.