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STRATEGIES FOR REDUCING HYPOXIC INJURY TO THE BIOARTIFICAL PANCREAS

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abstract
Type-1 Diabetes is a devastating autoimmune disorder which results in the destruction of beta cells within the pancreas. A promising treatment for Type-1 Diabetes is the restoration of lost beta cell mass through the implantation of immune-isolated microencapsulated islets (bioartificial pancreas). The goal of this approach is to restore blood glucose regulation and prevent the long-term comorbidities of Type-1 Diabetes without the need for immunosuppressants. However, islets are highly metabolically active and require a significant amount of oxygen for normal function, and during the process of isolating and transplanting the islets’ oxygen supply is removed and a large amount of islets are therefore lost due to hypoxia. Islet loss due to hypoxia is a major barrier to achieving clinical success with this treatment. In this work we have investigated several approaches to preventing hypoxic injury to islets. First, we investigated the omental pouch as an alternative transplantation site for microencapsulated islets. Our studies demonstrated that the well-vascularized omental tissue supported long-term functionality of islets transplanted in immune competent diabetic animals. Next, we developed a system for providing a sustained release of the fibroblast growth factor FGF-1 from microencapsulated constructs. We demonstrated that this system significantly enhanced angiogenesis at the transplantation site; however, this approach was still an insufficient method to improve islet viability and functionality. Lastly we applied the oxygen generating materials sodium percarbonate and calcium peroxide as oxygen sources for islets during the period in which islets are most vulnerable to hypoxia, beginning at the start of isolation until engraftment in vivo. The work with O2-generating materials was divided into three studies, first sodium percarbonate particles were used as an oxygen source for islets during isolation. The second study utilized silicone films containing sodium percarbonate to provide additional oxygen to islets for up to 4 days in culture. Lastly, calcium peroxide was used as an oxygen source following encapsulation by co-encapsulating calcium peroxide particles with islets in alginate microspheres. These studies provide an important proof of concept for the feasibility of using these oxygen generating materials to prevent cell death caused by hypoxia induced from the start of islet isolation through the immediate post-transplant period.
subject
Islet Microencapsulation
Islet Transplantation
Omentum Pouch
Oxygen Generating Materials
contributor
McQuilling, John Patrick (author)
Opara, Emmanuel C. (committee chair)
Farney, Alan C (committee member)
Goldstein, Aaron S (committee member)
Harrison, Benjamin S (committee member)
Mohs, Aaron M (committee member)
Verbridge, Scott S (committee member)
date
2015-06-23T08:35:54Z (accessioned)
2017-06-22T08:30:08Z (available)
2015 (issued)
degree
Biomedical Engineering (discipline)
embargo
2017-06-22 (terms)
identifier
http://hdl.handle.net/10339/57154 (uri)
language
en (iso)
publisher
Wake Forest University
title
STRATEGIES FOR REDUCING HYPOXIC INJURY TO THE BIOARTIFICAL PANCREAS
type
Dissertation

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