Engineering novel, nanofibrous scaffolds to promote neural regeneration in parkinson's disease

Abstract

The debilitating symptoms that arise from damage to the central nervous system (CNS) have received significant attention due to the limited capacity for self-repair of both the brain and spinal cord. Cell replacement therapy (CRT) has emerged as a potential treatment alternative for CNS damage where by stem cells are implanted at the site of injury in order to replace damaged neural tissue. Clinical trials have demonstrated proof-of-concept that CRT could provide an effective alternative treatment for CNS damage. Significant issues, however, including the survival of transplanted cells and reinnervation of host tissue, must still be overcome for successful translation to the clinic. Biomaterials have been identified as potential tools that could help improve cell survival by providing a supportive environment in an otherwise hostile milieu. Furthermore, engineered biomaterials can direct cell behaviour including adhesion, migration and differentiation. Through the rational design of materials that appropriately mimic the native extracellular environment, we seek to present structural and biochemical cues to cells in an effort to enhance current CRT strategies and enhance neural tissue repair. In this thesis, the development of a novel, nanofibrous biomaterial is described. Bioactive peptide sequences were incorporated in minimalist fluorenylmethyloxycarbonyl-based self-assembling peptides (Fmoc-SAPs) to form nanofibrous hydrogel networks via non-covalent interactions known as pi-beta self-assembly. The research reported here demonstrates a materials development approach to the tissue specific biofunctionalisation of these Fmoc-SAPs inspired by extracellular matrix (ECM) proteins. Following materials development and characterisation, we assessed the biocompatibility of these Fmoc-SAP hydrogels in vivo. Initial evaluation was carried out in the intact brain of mice, showing no negative effect on the survival and fibre innervation of injected SAPs carrying primary neural progenitor cells as well as a limited inflammatory response after 28 days. This work was expanded on by investigation of the support afforded by Fmoc-SAPs to ventral mesencephalon (VM) donor cells in a Parkinson's disease model. Finally, we enhanced the biomimetic capacity of Fmoc-SAPs through investigation of these injectable hydrogels as neurotrophic growth factor delivery vehicles. As well as demonstrating the ability of Fmoc-SAPs to stabilise soluble proteins for long-term growth factor delivery, we developed a modified Fmoc-SAP with the capacity for localised delivery of genetic material via non-covalent immobilisation of viral vectors. The described evolution in this thesis of a biologically inert biomaterial to a sophisticated biomimetic highlights the research and development process required for optimisation of an adjuvant scaffold to improve CRT. Through this progression in bioactive Fmoc-SAP development, we provide a platform for further expansion in the design of enhanced biomaterials for tissue engineering, not only for CRT in the CNS, but for applications in regenerative medicine globally. Show more