Publication Date

2011-04-29

Availability

Embargoed

Embargo Period

2012-04-28

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biomedical Engineering (Engineering)

Date of Defense

2011-04-08

First Committee Member

Cherie L. Stabler

Second Committee Member

Antonello Pileggi

Third Committee Member

Weiyong Gu

Fourth Committee Member

Herman Cheung

Fifth Committee Member

Fotios Andreopoulos

Abstract

Clinical islet transplantation is a promising treatment for type 1 diabetes. It involves the transplantation of pancreatic islets, isolated from a donor, into the portal vein of a recipient in order to replace his/her dysfunctional islets. Though promising, islet implantation into the liver is greatly hindered by numerous problems, including mechanical stresses, inflammatory responses, exposure to high drug and toxin loads, as well as irretrievability. In order to address these concerns, investigation into alternative implant sites, such as the subcutaneous site, has intensified. Transplantation of islets within these extrahepatic sites is commonly met with three primary obstacles: 1) inadequate spatial distribution of the cells; 2) oxygen deficiency in the local environment; and 3) insufficient vascularization within and around the implant. Thus, the objective of this proposal is to engineer a superior bioartificial pancreas, a device combining novel biomaterials and insulin-secreting cells, by focusing on these critical issues, specifically how to best reduce islet aggregation, as well as increase oxygen delivery, both in the short term and long term. A highly macroporous silicone scaffold will be engineered to distribute the islets three-dimensionally, while not imparting diffusion resistances commonly encountered in microporous materials. Macroporous scaffolds will also permit vascular in-growth. In order to sustain oxygen levels at the moment of device implantation, a novel, oxygen generating disk, which relies on the decomposition of calcium peroxide, will be developed and incorporated alongside the scaffold to deliver short-term supplemental oxygen. Therefore, it is postulated that these bioactive scaffolds, which interact with islets on a spatial, chemical, and biological level, will improve the viability as well as the function of islets, both in vitro and in vivo, as compared to naked islets under extrahepatic conditions.

Keywords

diabetes; islets; scaffold; PDMS; oxygen; calcium peroxide

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