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Sustained function of syngeneic and allogeneic islets in a macroporous scaffold implanted in the rat omentum

Maria M. Coronel^1,2, Ann-Christine Brady³, Eileen Pedraza^1,2, R. Damaris Molano¹, Mikael M. Martio⁶, Jessica A Weaver^1,2, Jeffery A. Hubbell^1,6, Camillo Ricordi^1,2,3,4,5, Antonello Pileggi^1,2,3,4, Peter Buchwald^1,5, Cherie L. Stabler^1,2,3

¹Diabetes Research Institute; ²Department of Biomedical Engineering; ³Department of Surgery; ⁴Department of Microbiology & Immunology; ⁵Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL, United States; ⁶Institute of Bioengineering and Chemical Sciences and Technology, Swiss Federal Institute of Technology, Switzerland

Currently, islet transplantation consists of intrahepatic embolization into the porto-venous system, which makes islets irretrievable and prone to mechanical, chemical, and inflammatory stress. We designed a macroporous polydimethylsiloxane (PDMS)-based scaffold, co-delivered with a polymer-bound angiogenic factor, to serve as a support structure for transplanted islets and competent vascular network development. PDMS scaffolds (10mm diameter/2mm height) were fabricated via solvent casting and particulate leaching. Fibrin matrix was functionalized with a fibronectin fragment to promote cell adhesion and cell-demanded platelet-derived growth factor BB (PDGF-BB) release. Lewis (1800 IEQ, syngeneic) or Wistar-Furth (3000 IEQ, allogeneic) rats islets were transplanted into streptozotocin-induced diabetic Lewis rats. Islets were loaded onto scaffolds, sealed with PDGF-fibrin matrix, and wrapped in an omental pouch. Control islets were implanted under the kidney capsule.

Syngeneic implants corrected diabetes with a median time to normoglycemia (MTN) of 2.5 days (range 1-6; n=6) in the omental scaffolds, compared to 3 days (range 1-6; n=3) for kidney capsule controls. Removal of the scaffolds-bearing grafts (>100 days) invariably resulted in prompt return to hyperglycemia. Histological assessment showed high material compatibility, viable islets, and strong vascular infiltration. Immunosuppression of allograft recipients consisted of anti-lymphocyte serum (day -3), 3-week course mycophenolic acid (MPA, 10mg/ml), and chronic fingolimod treatment (FTY720, 1mg/kg starting on day 0). Allografts implants corrected diabetes with a MTN of 2 days for omental scaffolds (n=4) and kidney capsule grafts (n=2). All grafts maintained long-term (>60 days) function under systemic immunosuppression.

Our data indicates that the three-dimensional bioengineered scaffold is highly biocompatible and efficacious in supporting islet engraftment and function in both syngeneic and immunosuppressed, allogeneic diabetic rat models. These characteristics, along with its ease of retrieval, make the platform an excellent support structure permitting implantation of insulin-producing cells in alternate sites for the treatment of type 1 diabetes. Supported by JDRF and DRIF.