Islet transplantation is a therapy in which insulin-producing beta (β) islet cells are infusedinto the liver via the portal vein to restore glycemic control. This therapy is beneficial for patients suffering from chronic pancreatitis or type I diabetes. However, islet transplantation is not widely implemented due to the instant blood-mediated inflammatory reaction which kills about half of all transplanted cells and, in allogeneic cases, the need for lifelong immunosuppressive therapy, which is associated with a slew of side effects. Poly(ethylene glycol) (PEG) is an immune stealth polymer. PEG-based biocompatible materials known as “biomaterials” can be used to mitigate inflammatory immune responses. PEG-based biomaterials of focus include poly(poly ethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) and poly(ethylene glycol)-b-poly(propylene sulfide)(PEG-b-PPS). PPCN is a thermoresponsive, antioxidative hydrogel. PPCN can be used to transplant islets to the omentum (fat pad), instead of the hepatic vasculature. Omentum transplant prevents immediate islet contact with blood, thus avoiding complement activation and coagulation, mitigating oxidative stress, and enhancing islet viability and function. PPCN was found to be biocompatible when implanted in the omentum of nonhuman primates. PEG-based biomaterials can also be used to improve the properties of transplant immunotherapies. PEG-b-PPS self-assembles into polymersome (PS) nanostructures and readily loads the mTOR inhibitor rapamycin. Loading rapamycin in PS overcomes issues associated with standard oral rapamycin (i.e. Rapamune®), such as poor bioavailability, broad biodistribution, hydrophobicity (preventing parenteral administration), and off-target side effects. While oral 4 rapamycin inhibits T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes (rPS) modulate antigen-presenting cells instead of T cells significantly improving maintenance of normoglycemia in a murine allogeneic islet transplantation model. These results demonstrate the ability of a rationally designed nanocarrier to re-engineer the immunosuppressive mechanism of a drug for tolerance by controlling cellular biodistribution. While generally PEG-based biomaterials are useful for a diverse array of applications. In patient populations with anti-PEG (αPEG) antibodies, PEG can have unintended effects. Enzymelinked immunoassay (ELISA)-based methods are developed to assay for the presence of these abs. Two mouse models with αPEG ab are developed to provide a platform to screen PEG-based drugs for adverse effects in patients that possess these abs.

Creator

• Burke, Jacqueline Alexis

DOI

• https://doi.org/10.21985/n2-cstn-dz67

Subject

• Biomedical engineering

Language

• en

Alternate Identifier

• http://dissertations.umi.com/northwestern:15918
• etdadmin_upload_878166

Date created

• 2022-01-01

Resource type

• Dissertation

Rights statement

• In Copyright