Biomaterials strategies for neural regeneration: The impact of surface topography and biofunctional cues.

摘要

Cells in vivo exist in a very specific microenvironment that defines their functions, of which the extracellular matrix comprises an essential structural component. Gaining insight into some of the interactions between cells and their extracellular matrix is a crucial first step towards solving some of the challenges of tissue regeneration and repair. The overall objective of the thesis was to design biomimetic platforms using biomaterials engineering strategies, and apply them towards investigating differentiation, migration, repair and regeneration in the nervous system.;In the first section of this dissertation, we showed that cell behavior and response can be modulated by the topographical features of their underlying substrate. Using electrospinning technique, polymeric fibrous scaffolds were fabricated that were amenable to further functionalization via a variety of different chemical conjugation techniques. We then applied this platform to investigate the influence of morphological restriction of adult neural stem cells and its subsequent impact on differentiation fate, and found that substrate-induced cell elongation and alignment yielded better neuronal differentiation. This was attributed to a combination of substrate selectivity for neurons, as well as shape-induced upregulation of canonical Wnt signaling.;In addition to enhancing neuronal differentiation, topographical cues from electrospun fibers were found to promote directional spreading and migration of primary neural cell populations. Schwann cell migration into and repopulation of the peripheral nerve injury site appears to be a limiting factor in the success of nerve regeneration. In the second section of the dissertation, we integrated both alignment and biochemical signaling cues into the design and testing of a clinically-relevant solution for the treatment of peripheral nerve transaction. Delivery of bioactive neurotrophic factors from the conduits resulted in enhanced functional and histological recovery. Introduction of extracellular matrix proteins in the form of a thermoset hydrogel also enhanced regeneration, especially when combined with a porous electrospun conduit wall.;In summary, we have demonstrated that salient features of the extracellular milieu can be recapitulated using engineered biomaterials platforms, provided some mechanistic insight into how substrate topography influences cell behavior, and integrated these concepts into designing a new generation of devices for facilitating tissue regeneration and repair.