The self-assembly of molecules in nature relies on non-covalent intermolecular associations to build the complex nanoscale architectures that compose cells and tissues. Peptide amphiphiles (PAs) are synthetic molecules that utilize self-assembly to form one-dimensional nanofibers that mimic native extracellular matrix. These PA nanofibers can present bioactive peptides capable of cell signaling, and nanofibers can be organized by ions to form biodegradable gels capable of cell encapsulation. In this work, PA nanofibers have been engineered with specific biological functionality applicable to the treatment of diabetes, chronic inflammation, and transplant rejection. To improve the efficacy of transplanted pancreatic islets as a permanent cure for type 1 diabetes mellitus, a PA molecule that mimics the activity of glucagon-ike peptide 1 (GLP-1) has been developed. This GLP-1-mimetic PA self-assembles into nanofibers that are used to encapsulate β-cells and are shown to stimulate insulin secretion, prevent inflammatory cytokine-induced cell death, and enhance proliferation of these cells via cyclic AMP signaling. To enhance localized therapy for chronic inflammation, a PA molecule that mimics the activity of interleukin-1 receptor antagonist (IL-1ra) has been engineered. This IL-1raPA self-assembles into nanofibers that are shown to inhibit lymphocyte proliferation and prostaglandin release from fibroblasts via blockade of the IL-1 receptor on these cells, and IL-1raPA nanofiber gels are used to protect encapsulated β-cells from monocyte-induced inflammatory cell death. To increase the clinical applicability of induced transplant tolerance based on activation of recipient regulatory T-cells with donor B-cells, PA nanofiber-coated alginate microparticles have been utilized to replace genetically engineered cancer cells in the activation of the donor B-cells. These PA-coated microparticles are shown to upregulate surface markers of activation on B-cells observed on flow cytometry, and the resulting PA-activated B-cells are further shown to upregulate surface markers of activation on T-cells. Finally, a novel method for functionalizing the PA nanofiber with bioactive epitopes post-assembly has been developed based on native chemical ligation (NCL). This method is used to incorporate the cell-adhesive biological functionality of the RGDS peptide into the PA nanofiber post-assembly while maintaining its architecture and biodegradability, and the NCL method is further utilized to conjugate fluorescent proteins to the nanofiber surface. The possibility of engineering the PA nanofiber with these diverse biological functionalities demonstrates the broad applicability of this platform technology to the treatment of multiple clinical disorders.
|Advisor:||Stupp, Samuel I.|
|Commitee:||Ho, Dean, Messersmith, Phillip B., Shea, Lonnie D.|
|School Location:||United States -- Illinois|
|Source:||DAI-B 74/05(E), Dissertation Abstracts International|
|Subjects:||Biomedical engineering, Nanotechnology, Materials science|
|Keywords:||Biomimetic materials, Diabetes, Inflammation, Peptide amphiphiles, Self assembly, Supramolecular chemistry|
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