Characterizing the effects of PEG-based hydrogels on neural precursor cell function and their suitability for in vivo brain applications .

摘要

There is a pressing need to develop more advanced strategies for the treatment and reversal of neurodegenerative diseases. Even though cellular transplants have been used to achieve some reversal of physical symptoms of Parkinson's disease, improvements are needed in order to ensure greater control over donor cell survival, function, and neurite extension. Cell scaffolds may be used to provide positive cues that improve transplant survival, elicit and guide neurite extension, and promote regeneration within the central nervous system (CNS). However, more information about these novel tissue engineering and drug delivery devices is needed regarding the influence of these scaffolds on the growth of donor cells and the influence of these scaffolds on the host tissue reaction. This thesis studied the effect of different formulations of PEG-based hydrogels on donor neural cells and hydrogel suitability for in vivo applications. The chemical and mechanical properties of these hydrogels can be varied by altering degradable content and the weight percent of macromer present during polymerization. Chemical and mechanical properties were both shown to influence neural function, proliferation, and differentiation. Lactic acid, a product of hydrogel degradation, was shown to improve the function and proliferation of neural cells and prevent oxidative damage. Additional studies showed that the mechanical properties impacted differentiation, glial activation and that a hydrogel with stiffness similar to native tissue promoted the greatest degree of neural survival and proliferation. Building on that work, greater degradable content of a gel was shown to improve neural metabolic activity, oxidative health, and proliferation.;The biocompatibility of a degradable PEG-based hydrogel approach was demonstrated in host tissue using animal models, with hydrogel degradation rate having a significant impact on the glial response. Additionally, the incorporation of microparticles delivering neurotrophic factors modulated the glial response. The release of the neurotrophic factors to surrounding tissue over time was shown to be scaled appropriately for tissue transplant survival and tissue formation. Overall this thesis provides fundamental studies showing that PEG-based hydrogels are a versatile in vitro culture system that can be used to culture and expand a variety of neural and glial cell types by altering their degradable content and material properties. Furthermore, evidence is provided that PEG-based hydrogels are biocompatible within the brain and can be used effectively as precise delivery devices of bioactive factors to the brain.