Date of Award

Spring 1-1-2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemical & Biochemical Engineering

First Advisor

Kristi S. Anseth

Second Advisor

Christopher N. Bowman

Third Advisor

Stephanie J. Bryant

Abstract

Cell-based therapies are a promising approach for the treatment of diseases such as Type I diabetes mellitus (TIDM), where endogenous insulin production is restored via delivery of insulin-producing beta-cells or islet of Langerhans clusters. Tissue rejection by the host's immune system, however, is a major hurdle limiting the broad use of transplanted tissues, so beta-cell-based therapies require systemic immunosuppression. To reduce this requirement, tissues have been encapsulated within natural and synthetic barrier materials in a process known as immunoisolation. Immunoisolation materials, including poly (ethylene glycol) (PEG) hydrogels, create physical barriers between host immune cells and donor tissue while enabling the diffusion of small molecules like nutrients and oxygen. Unmodified immunoisolation barriers, however, are unable to prevent the diffusion of small cytotoxic molecules, including reactive oxygen species (ROS) (e.g., superoxide) and cytokines. This research investigated strategies to introduce immunoactive modifications to PEG hydrogels for the purpose of improving their immunoisolation capacity. Towards this, a polymerizable superoxide dismutase mimetic (SODm) was covalently tethered within beta-cell-laden hydrogels to significantly increase cell survival following challenges with superoxide, a major inflammatory mediator of the immune response. Next, photoiniferter chemistry was employed to polymerize PEG chains co-functionalized with an apoptosis inducing factor (anti-fas) and a T cell adhesion ligand (ICAM-1) to locally reduce, through apoptosis, the population of T cells, the adaptive immune responder cells implicated in islet transplant rejection. Further, conformal, immunoactive coatings were formed directly on the surfaces of cell-laden PEG hydrogels using a versatile, reactive dip-coating strategy to present a high density of immunoactive signal while maintaining encapsulated cell cytocompatibility. Finally, towards preventing the development of deleterious adaptive immunity altogether, immunosuppressive hydrogels modified with TGF-beta1 and IL-10 were introduced, and their capacity to reduce dendritic cell maturation was highlighted. The immunoactive materials developed within this thesis suggest innovative strategies for the engineering of future immunoisolation barriers to provide localized and targeted protection of transplanted cells.

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