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Presenter: Norma, Kenyon, Miami, United States
Authors: Norma S. Kenyon1,2,3,5, Eileen Pedraza1,3, Dora M. Berman1,2, Melissa A. Willman1, Norman M. Kenyon1, Emilio Margolles-Clark1, Peter Buchwald1,6, Paul Latta7, Camillo Ricordi1,2,3,4, Cherie L. Stabler1,2,3
Long term survival of allogeneic, nonhuman primate islets in non-biodegradable scaffolds within an omental pouch
Norma S. Kenyon1,2,3,5, Eileen Pedraza1,3, Dora M. Berman1,2, Melissa A. Willman1, Norman M. Kenyon1, Emilio Margolles-Clark1, Peter Buchwald1,6, Paul Latta7, Camillo Ricordi1,2,3,4, Cherie L. Stabler1,2,3
1Diabetes Research Institute; 2Department of Surgery; 3Biomedical Engineering; 4Department of Medicine; 5Department of Microbiology and Immunology; 6Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL, United States; 7Converge Biotech, Inc., Miami, FL, United States
Previously, we have demonstrated that the omental pouch (OP) site supports survival of islets loaded onto biodegradable scaffolds in a nonhuman primate model. In this study, we tested whether a macroporous non-biodegradable scaffold can support function of islets alone (n=1) or together with immunomodulatory mesenchymal stem cells (MSC) (n=2) in an OP site. Recipient MSC (4.5 million/scaffold) were seeded onto 5-7 scaffolds (30 mm diameter-2 mm thick), and cultured 5 days before loading 15-25K allogeneic islet equivalents (IEQ)/kg on post-operative day (POD 0). Baboons were treated with 20 mg/kg anti-CD154 (5c8) on POD -1, 0, 3, 10, 18, 28 (induction) and every ‚Ä®10-28 days for maintenance. Insulin, administered to achieve normoglycemia, was tapered beginning on POD 40-60. Occurrence of nontherapeutic anti-CD154 levels between monthly maintenance doses resulted in rejection episodes and partial loss of function, whereby maintenance dosing was switched to every 10 days. A recipient of islets alone (25K IEQ/kg) was insulin independent from POD 130-374, minor graft destabilization occurred and daily treatment with the GLP-1 analogue Liraglutide started on POD 403. Removal of scaffolds on POD 445 was followed by a return to full diabetes. The first recipient of islets+MSC (15K IEQ/kg+MSC) was insulin independent from POD 96-200. Minor graft destabilization occurred and the implants were removed for analysis on POD 222, followed by a return to full diabetes (c-peptide negative, increased exogenous insulin requirements, EIR). Immunofluorescence revealed viable, vascularized, insulin-positive islets within the scaffolds. The second recipient of islet+MSC (25K IEQ/kg+MSC) experienced significant reduction of EIR, but rejection episodes precluded insulin independence. Removal of scaffolds at POD 188 resulted in full loss of c-peptide; insulin positive islets were observed. This non-biodegradable scaffold provides a novel means to locally deliver MSC and islets in a 3-D configuration, with the potential for local immunomodulation and growth factor delivery.
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