Introduction: Islets transplantation in the liver often results in limited islets survival presumably due to abnormal blood flow dynamics and acute inflammatory response. The objective of this study was to assess whether a biodegradable citrate-based thermoresponsive hydrogel would support the viability and function of transplanted islets in the epididymal fat pad.

Materials and Methods: Poly(polyethyleneglycol citrate-co-N-isopropylacrylamide) (PPCN) was synthesized from citric acid, poly(ethylene glycol), glycerol 1,3-diglycerolate diacrylate and poly-N-isopropylacrylamide. The resulting polymer was functionalized to entrap stromal cell derived factor-1α (SDF-1). The angiogenic capacity of SDF-1-releasing PPCN was evaluated in a diabetic mouse wound healing model. Islet viability was evaluated in vitro using a Live/Dead Assay and the islets function was assessed using syngeneic islet transplantation

Results: Cyclic-RGD (cRGD) was covalently linked to PPCN and the cRGD-PPCN retained its ability to reversibly change between liquid and gel phases at a lower critical solution temperature (LCST) of 25[deg]C and maintain micro- and macroporosity within the gel phase. In vitro, PPCN preserved the normal islet morphology while islets cultured in cell culture media began to lose this morphology due to cell spreading. SDF-1 was entrapped and slowly released from PPCN. Wounds treated with SDF-1-PPCN demonstrated enhanced vascularization. At 10 days after isolation, islets entrapped within PPCN maintained their original morphology and viability in vitro. Islets entrapped in cRGD-PPCN that was gelled on the epididymal fat pad restored euglycemia (glucose<200 mg/dl) within an average of 1.8 (±0.8) days following transplantation. The observed restoration of euglycemia is superior to what has been reported for other hydrogels when taking into account the number of islets required to achieve euglycemia and the time it took to reach the euglycemic state. Euglycemia was maintained in the cRGD-PPCN for the duration of the experiment (90 days).

Conclusion: The novel citrate-based thermoresponsive hydrogel PPCN can serve as a platform vehicle for extrahepatic islet transplantation. PPCN allows the modification of the islet microenvironment to achieve functional vascularization and display peptides such as cRGD if needed, thus enhancing long-term islet survival and function.

CITATION INFORMATION: Zhu Y, Zhang X, Guillermo A, Luo X. Citrate-Based Thermoresponsive Hydrogel as a Versatile Platform for Extrahepatic Islet Transplantation. Am J Transplant. 2016;16 (suppl 3).

« Back to 2016 American Transplant Congress