Three dimensional glycosaminoglycan mimetic peptide amphiphile hydrogels for regenerative medicine applications

Abstract

Defects and impairments of tissues or organs affect millions of people, resulting in considerable losses in workforce and life quality. The treatment of major tissue injuries requires the development of advanced medical techniques that enhance the natural repair processes of the human body. Novel biomaterials can modulate the repair of organs and tissues by providing a suitable environment for the recruitment, proliferation and differentiation of stem and progenitor cells, allowing the recovery of degenerated or otherwise nonfunctional tissues. Peptide amphiphiles (PAs) serve as model biomaterials due to their capacity for self-assembly, which allows peptide monomers to form complex networks that approximate the structure and function of the natural extracellular matrix. Peptide networks can be further modified by the attachment of various epitopes and functional groups, allowing these materials to present bioactive signals to surrounding cells. Glycosaminoglycans (GAGs) are negatively charged, unbranched polysaccharides that constitute a substantial part of the ECM in various tissues and play an important role in maintaining tissue integrity. Therefore, mimicking GAGs presents a suitable means for modulating cell behavior and especially lineage commitment in stem cells. In this work, I describe the design and synthesis of several bioactive, three dimensional (3D) GAG-mimetic peptide amphiphile hydrogels for in vitro stem cell differentiation and in vivo pancreatic islet transplantation. In Chapter 1, I detail the extracellular environment of tissues and the importance of GAGs in maintaining cell and tissue function. In Chapter 2, I describe the in vitro experiments involving the effects of sulfonation and the presence of glucose units on the differentiation of mesenchymal stem cells. In Chapter 3, I utilize a heparin-mimetic PA to increase the survival of pancreatic islets transplanted into the rat omentum, and demonstrate that increased angiogenesis results in enhanced survival. Lastly, in Chapter 4, I summarize my results and describe the course of future experiments for the artificial regeneration of tissues through peptide amphiphile networks.