The disruption of vascular elastin matrices due to mechanical injury or acquired diseases (e.g., aneurysms), or their congenital absence or malformation can severely compromise vessel elasticity and elastin-mediated cell signaling important to morphogenesis, injury response, and inflammation. Regeneration of elastin within de-elasticized vessels and within tissue-engineered constructs is limited by the poor elastin output by adult vascular smooth muscle cells (VSMCs). Also, cell scaffold materials that can upregulate elastin synthesis and provide biologic cues necessary to regenerating faithful mimics of native elastin matrices are yet to be identified. Previously we determined that that highly biocompatible, crosslinked scaffolds (hylans) containing hyalruonan (HA), a glycosaminoglycan in the ECM, stimulates cultured VSMCs to synthesize close mimics of native elastin. Evidence suggests that HA fragments, not native long-chain HA elicit these elastogenic responses, although long-chain HA possibly facilitates matrix stabilization. The further fabrication of elastogenic scaffolds containing a mixture of long-chain HA and HA fragments, is however contingent on elucidating (i) the differential effects of surface tethered HA or/ and HA fragments on elastogenesis by adult VSMCs, important to optimizing scaffold composition, (ii) the potential benefits of cell culture within prealigned 3D HA scaffolds than on 2D surfaces, to mimicking vascular elastin ultrastructure, and (iii) the impact of concurrently provided mechanical and biochemical cues on the quality (amount, structure, durability, and mechanics) of the synthesized elastin matrix.
AIMS : The objective of this project is to clarify the impact of the above parameters on elastin synthesis in an adult rat VSMC culture model.
Aim 1 will optimize the HA-fragment size distribution within surface-tethered mixtures of HA based on their individual effects on elastin synthesis by adult RVSMCs.
Aim 2 will investigate the standalone and combined benefits of tubular, electrospun HA nanofiber scaffolds containing the optimized composition determined in Aim 1, cyclic mechanical strain, & growth factor (TGF-b, IGF-1) supplements to matrix quality. SIGNIFICANCE: The study outcomes will create a tool that can be integrated with existing vascular devices to fabricate faithful mimics of native elastin on demand. Such elastin mimics will be useful to augument and repair elastin in degenerated vessels, and also make available an in vitro model to study elastogenesis. ? ? ?
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