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VEGF Gradients in Porous Hydrogels for Therapeutic Angiogenesis

用于治疗性血管生成的多孔水凝胶中的 VEGF 梯度

基本信息

批准号：
8992266
负责人：
Donald Richieri Griffin
金额：
$ 6万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8992266
关键词：
Address Affinity Anastomosis - action Behavior Binding Biochemical Biochemical Reaction Biocompatible Materials Blood Vessels Cells Chemicals Chemistry Chemotaxis Chronic Clinical Treatment Communities Complex Development Diabetic mouse Diabetic wound Diffuse Diffusion Embryo Endothelial Cells Endothelial Growth Factors Receptor Engineering Environment Experimental Models Extracellular Matrix Flow Cytometry Generations Goals Growth Growth Factor Gene Healed Heterogeneity Homeostasis Hyaluronic Acid Hybrids Hydrogels Immobilization Immunohistochemistry Implant In Vitro Individual Infiltration Knowledge Lung MAPK14 gene Modeling Mus Nature Neonatal Patients Phenotype Photochemistry Population Protein Isoforms Publishing RNA Splicing Radial Recruitment Activity Research Route Scanning Series Signal Transduction Site Skin Speed Staging Testing Tissues Training Translations VEGF165 VEGF189 Vascular Endothelial Growth Factors Vascular System Work Wound Healing X-Ray Computed Tomography angiogenesis base cell behavior diabetic healing improved in vitro Assay in vitro Model in vivo porous hydrogel public health relevance response scaffold therapeutic angiogenesis wound

项目摘要

DESCRIPTION (provided by applicant): Our immediate goal of this proposal is to investigate the relationship between vascular endothelial growth factor (VEGF) gradient strength and activation of the tip cell phenotype in endothelial cells (the primary cell of the vascular network. Our ultimate goal of understanding this relationship is to maximize in vivo vascular infiltration and anastomosis within a biomaterial implant. The natural extracellular matrix (ECM) contains a heterogeneous composition of biomolecules (not a homogeneous concentration or distribution). This heterogeneity is of particular importance during development of the vascular system in embryos. Engineered ECMs (eECMs) that attempt to recapitulate the natural ECM generally lack this heterogeneity. We believe that this lack is a significant oversight. In particular, we ar excited to focus on instructional chemical gradients to control cell behavior. We believe that the lack of heterogeneity in hydrogels is the reason hydrogel-based in vivo therapies have failed to treat complex maladies, such as chronic and ischemic skin wounds. In this proposal we intend to focus on the activation of the tip cell phenotype, which is the phenotype presented by the leading endothelial cell of an angiogenic sprout. We hypothesize that by activating this phenotype we will subsequently enhance angiogenic sprout infiltration speed and directionality (e.g. into the center of a hydrogel implant). Specifically, in this proposal we will use a hybrid platform of photochemistry and enzymatic chemistry (Hybrid Photopatterned Enzymatic Reaction or HyPER) that we have published to spatially control the covalent immobilization of VEGF within a hyaluronic acid (HA) hydrogel scaffold. In our previous work, we have shown that HyPER allows for both the creation of gradients and immobilization of large growth factors within hydrogels. For this proposal, we will combine these abilities to produce controlled gradients of VEGF. The proposed training plan is a comprehensive study that includes material synthesis, in vitro biochemical and cell behavior analysis, and in vivo studies. We will also include a diabetic mouse colony in our in vivo studies to analyze our approach as a potential therapy. Beyond expanding the knowledge of the trainee and the scientific community-at-large, we believe that this project will provide a route to treating patients with diminished wound healing ability.