2013 - CTS 2013 Congress


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Oral Communications 5

12.5 - Controlled local delivery of pro-angiogenic growth factors improve islet transplantation in the subcutaneous and the fat pad sites in mice

Presenter: Alice A., Tomei, Miami, United States
Authors: Alice A. Tomei1,2, Mejdi Najjar1,2, Vita Manzoli1,2, Chiara Villa1,2, Mikael M. Martino1,2, Ruth D. Molano1,2, Antonello Pileggi1,2, Luca Inverardi1,2, Camillo Ricordi1,2, Jeffrey A. Hubbell1,2

Controlled local delivery of pro-angiogenic growth factors improve islet transplantation in the subcutaneous and the fat pad sites in mice

Alice A. Tomei1,2, Mejdi Najjar1,2, Vita Manzoli1,2, Chiara Villa1,2, Mikael M. Martino1,2, Ruth D. Molano1,2, Antonello Pileggi1,2, Luca Inverardi1,2, Camillo Ricordi1,2, Jeffrey A. Hubbell1,2

1Diabetes Research Institute, University of Miami, Miller School of Medicine, Miami, FL, United States; 2Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

 

Islet transplantation in the liver through infusion into the portal vein is the current protocol for clinical trials. According to the CITR 2013 despite promising results, most patients lose insulin-independence and graft function in variable times after transplantation. Among the causes is early graft loss due to immunological, anatomical, physiological and metabolic limitations of the transplant site. Several alternative sites for islet transplantation have been proposed in order to minimize early inflammatory reactions, promote vascularization and easy-accessibility, mimic physiological insulin release and protect from immune responses. Among these is the subcutaneous (SC) site which has easy accessibility but trials in this site have been disappointing due to poor oxygen tension and blood supply and lack of neovascularization. Another alternative site is the omental pouch which can be well represented (being too small in mice) by the epididymal fat pad (EFP) that is well vascularized with good arterial supply, portal drainage and can accommodate large volumes including unpurified islets.

We have engineered the SC and the EFP sites for islet transplantation to promote angiogenesis with the goal of decreasing early graft loss and improving islet engraftment. We have utilized novel fibrin matrices as biodegradable scaffolds for local controlled release of pro-angiogenic growth factors through proteolitically cleavable recombinant fibronectin proteins that can bind both cells involved in tissue re-vascularization and growth factors. We chose to use degradable matrices to prevent fibrotic reactions that have been observed for permanent scaffolds. We show that in the SC site, 60% of mice transplanted with a marginal mass of 1,000 IEQ syngeneic islets within engineered matrices reverse diabetes at 40 days post-transplant (average reversal time 38 days, n=5) versus 20% of mice transplanted with islets alone after 100 days (undefined average reversal time, n=5). In the SC site, islet engraftment in engineered matrices is associated with neogenesis of blood vascular networks by day 7 and full vascularization by day 21. In the EFP site, 60% of mice transplanted with a marginal mass of 250 IEQ syngeneic islets within engineered matrices (average reversal time 24 days, n=10) and 10% of mice transplanted with islets alone reverse diabetes after 40 days (average reversal time: 85.5, n=8). In EFP grafts, islet density in grafts retrieved after 100 days and density of blood vessels is higher in the engineered matrices group (p<0.05). Also, proportion of beta and alpha cells in grafted islets is comparable to the one found in native pancreas. Our findings suggest that by promoting early re-vascularization of islet grafts we can promote engraftment and long-term function in the SC and EFP sites, which are clinically relevant sites. 


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