Title:

The Effect of Phase-separated Microstructures on Cell Migration in 3D Dextran Hydrogels

Chronic wounds impact 6.5 million Americans, and are classified as injuries that take more than three months to heal. There are four main stages of wound healing: hemostasis, inflammation, proliferation, and remodeling. Chronic wounds perpetually are stuck in a cycle of inflammation, leading to necrosis and decreased cell migration. As of now many of the clinical treatments are therapeutic and aim to convert chronic wounds into acute wounds. With in-vivo mouse models lacking to mimic human wound healing process, in-vitro modeling of a chronic wound is becoming increasingly popular. Specifically, matrix-based hydrogels which mimic the extracellular matrix (ECM) are used due to their easily tunable nature. Microstructural heterogeneity and compositional diversity of native ECM are essential to promote cell migration and tissue regeneration. Thermoresponsive polysaccharide-based biomaterials with phase-separated microstructures offer significant opportunities to regulate cellular response. We employed dextran (Mw: 86kDa) which is already FDA approved and chemically modified its backbone with methacrylate groups to undergo phase separation in aqueous solution. Photo-initiated radical polymerization of the polymer solution enabled the formation of dextran methacrylate (Dex-MA) hydrogels with defined microdomains. The objective of this study was an attempt to model in vitro vascular assembly in Dex-MA hydrogels. Phase separated Dex-MA hydrogels at 50 mg/mL concentration (blended with 250kDa dextran) exhibited enhanced interfacial-driven fibroblasts cell migration in 3D. While the same condition produced no migration in endothelial cells. Therefore it was predicted co-culture of fibroblast and endothelial cells supplemented with vascular endothelial growth factor (VGEF) and basic fibroblast growth factor (BFGF) will promote vascular network formation.

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