All ETDs from UAB

Advisory Committee Chair

Ho-Wook Jun

Advisory Committee Members

Anath Shalev

Jeonga Kim

Shawn R Gilbert

Timothy M Wick

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) School of Engineering

Abstract

Pancreatic islet transplantation (PIT) has demonstrated consistent and sustained reversal of type 1 diabetes, generating optimism for its wider application as a potential cure for type 1 diabetes. However, the clinical efficacy is still lacking because of a substantial loss of islets during or shortly after transplant to the implantation site. The liver has been widely used as an implantation site for PIT, but it has serious risks for islet loss, such as massive islet destruction by instant blood-mediated inflammatory reaction, progressive attrition of islet cells due to exposure to the toxic environment. The omentum has gained significant attention as an islet transplantation site because it allows a large implantation volume, ease of surgical manipulation, and some immune privileges. However, many islets are still required to achieve euglycemia and technical problems related to islet leakage also exist in the omentum, which limit the potential to use omentum as a PIT site. Thus, the enhancement of islet engraftment in the omentum is crucial to overcome this limitation. Rapid islet revascularization for a sufficient supply of nutrients and oxygen to the implanted islets is a significant milestone to improve islet engraftment in the omentum. In addition, providing an islet nurturing and immune barrier microenvironment can help the implanted islets to better survive in the omentum. In order to increase the efficacy of PIT in the omentum, an innovative strategy was developed to embed islets with fibroblast growth factor-2 (FGF-2) within a bio-inspired hybrid nanosack. The hybrid nanosack was created by combination of two materials: 1) a self-assembled peptide amphiphile (PA) nanomatrix gel capable of encapsulating islets with an ECM-mimicking and immune barrier microenvironment, and 2) an electrospun Poly (ε-caprolactone) (ePCL) nanofiber sheet with porous crater-like structures for infiltration of blood vessels and mechanical stability. The hybrid nanosack also provided multi-stage release kinetics of FGF-2 to enhance vascularization, successfully recruited blood vessels within the sack, and promoted local blood vessel generation in the omentum of rats. Thus, it is expected to stimulate islet revascularization in the omentum. In addition, islet encapsulation with the PA nanomatrix gel demonstrated protection of islets from cellular inflammatory responses and maintenance of islet viability and insulin producing β-cell staining. Based on these results, the hybrid nanosack has great potential to enhance early islet survival and engraftment in the omentum, which may help to overcome the current limitations of PIT.

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