? Spatial concentration gradients of endogenous soluble growth factors play critical roles directing cell migration, proliferation, and differentiation during development, homeostasis, and wound healing. This grant application addresses the question: Could an exogenous solid-phase growth factor immobilized in specified directional gradients within an engineered biomimetic extracellular matrix (bECM) be an effective approach to recruit and guide surrounding host cells into a bECM and promote a desired biological outcome? The goal is to determine if this growth factor delivery paradigm would be relevant for future therapy development in tissue engineering applications. The paradigm in vitro models will include human microvascular endothelial cell, MG-63 human preosteoblastic cell, and human adult mesenchymal stem cell responses to solid-phase human fibroblast growth factor-2 (FGF-2) in fibrin bECMs. The in vivo model will be a chicken embryo chorioallantoic membrane (CAM) assay to assess directed angiogenic response within fibrin bECM/FGF-2 structures placed on the CAM. The research will systematically progress from two-dimensional patterns of FGF-2 on fibrin films to three-dimensional (3D) patterns of FGF-2 within fibrin bECMs, and from isolated cell responses in vitro to angiogenic responses in vivo. The overall hypotheses are spatial gradients of solid phase FGF-2 in a fibrin bECM will direct cell migration in vitro in register with gradient directionality, and cell migrational flux will be greater in response to gradient patterns than patterns with uniform distributions. And in vivo, a directed angiogenic response will be greater in designs with gradients in comparison with uniform distributions. The bECM/FGF-2 structures will be fabricated with a solid freeform fabrication printing process that produces specified 3D spatial patterns of growth factors within 3D fibrin bECMs. Fluorescent based quantum dot imaging technology and fluorescence optical sectioning microscopy will be used to validate printed structures and assess cell and CAM responses. The research will be carried out by multidisciplinary bioengineering with expertise in endocrinology, advanced manufacturing, and biophysical imaging. ? ?
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