Development of a Pre-vascularized Subcutaneous Site Using a Clinically Available Bioabsorbable Device for Islet Transplantation

Background and objective: Pancreatic islet transplantation is a minimally invasive therapy for type 1 diabetes, but current intrahepatic portal vein transplantation (IPTx) faces significant hurdles. These include the instant blood-mediated inflammatory reaction (IBMIR), which causes early islet loss, and the difficulty of graft removal. The subcutaneous space is an attractive alternative due to its accessibility and low-invasive nature, but its naturally poor blood flow requires pre-vascularization to ensure graft survival. This study evaluated a novel approach using a clinically available bioabsorbable collagen–gelatin sheet (CGS) impregnated with basic fibroblast growth factor (bFGF) to induce a vascularized transplant site in mice.
Materials and methods: C57BL/6 mice were used for all experiments, with diabetes induced by streptozotocin. To prepare the transplant site, bFGF-loaded CGS was implanted subcutaneously. The CGS contains acid gelatin that forms an ionic complex with bFGF, allowing for sustained release for over 10 days. Two weeks later, 200 islets (approximately one donor's worth) were transplanted into the pre-vascularized site. Control groups included CGS alone, bFGF-loaded agarose rods (a non-absorbable material), and standard IPTx. Functional success was monitored via blood glucose levels, Intraperitoneal Glucose Tolerance Tests (IPGTT), and SPECT/CT imaging using In-exendin-4.
Results: Two weeks post-implantation, the bFGF-loaded CGS group showed significant neovascularization and adipose accumulation compared to the CGS-alone and untreated groups. Histological analysis confirmed that the capillary area fraction was significantly higher in the bFGF-loaded CGS group (P < 0.01). The euglycemia rate at 100 days was 93.8% in the bFGF-loaded CGS group, which exceeded the rates for bFGF-loaded agarose rods (72.7%) and IPTx (71.2%). IPGTT results for the CGS group were comparable to naive mice, demonstrating excellent glucose responsiveness. SPECT/CT visualized viable -βcells at the subcutaneous site. By day 100, the CGS was completely absorbed, and histological staining (HE, CD31, Insulin) showed healthy islets surrounded by an abundant vascular network. Crucially, blood glucose levels rose immediately after graft removal, proving the graft's necessity for normoglycemia.
Discussion and conclusion: The high efficacy of bFGF-loaded CGS is attributed to its sustained release mechanism and the role of collagen as a scaffold. Unlike non-absorbable materials, CGS induces only the necessary stimulation for vascularization without causing persistent foreign body reactions or chronic inflammation. While differences between mouse and human skin must be considered, the clinical approval of CGS suggests high potential for translation. In conclusion, this bioabsorbable device method offers a simple, reliable, and minimally invasive platform for future clinical islet transplantation.