Peripheral nerve grafts are known to support axonal regeneration across a lesion in the central nervous system or a lesioned nerve gap in the peripheral nervous system. Enhanced axon growth through these nerve segments is most likely caused by increased production of neurotrophins, adhesion molecules, and growth promoting extracellular matrix molecules such as laminin. These nerve segments also contain channels that act to Organize and direct axon growth. This proposal will test the hypothesis that an artificial matrix mimicking the features of peripheral nerve grafts will influence glial attachment, migration, and enhance axonal regeneration. To test this hypothesis, we constructed microfilaments from bioresorbable polymers that can be modified to promote axon growth and release neurotrophins. When bundled, these microfilaments provide channels that orient cell migration and axonal growth. To develop a more complete understanding of cellular-material interaction, microfilaments will be fabricated from two polymers with selective physical and biochemical properties and examined after implantation into either the sciatic nerve or spinal cord. To examine cell responses to changes in physical properties, porosity, protein-release rates, cross-sectional shape, and filament diameters will be altered. The primary polymers also have different biochemical properties that can be further modified by incorporating extracellular matrix molecules (matrigel Or laminin) or neurotrophins. These biochemical modifications should greatly influence microfilament interactions with glia and regenerating axons by providing necessary chemotactic and chemoaffinity signals. The most important aspect of this study is the consolidation and utilization of both the physical and biochemical properties to explore, influence, and organize the cellular- material interaction to enhance integration, wound healing, and regeneration. Cellular responses to microfilament implants will be examined using immunohistology, semi-thin plastic sections, and electron microscopy. These experiments will elicit a better understanding of how cells interact with bioresorbable materials and how these interactions can be manipulated by altering the physical and biochemical properties of the material. The ultimate goal of this research is to achieve a better understanding of the mechanisms that influence injury repair and to use these insights to improve the development and fabrication of biomaterials that can promote wound healing and regeneration of the nervous system.
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