Matrices for optimal endogenous progenitor cell recruitment and function

最佳内源祖细胞招募和功能的基质

• 批准号: 9036122
• 负责人: WILLIAM L. MURPHY
• 金额: $ 22.42万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036122
• 关键词: Angiogenic Proteins; Animals; Biochemical; Biocompatible Materials; Biological; Biological Assay; Blood; Blood Circulation; Cardiovascular Diseases; Cell Adhesion; Cell physiology; Cells; Chemistry; Clinical; Coronary Arteriosclerosis; Cues; Defect; Diabetes Mellitus; Diabetic wound; Disease; Endothelial Cells; Extracellular Matrix; Fluorescence Microscopy; Formulation; Generic Drugs; Growth; Healed; Health; Hindlimb; Human; Hydrogels; Implant; In Vitro; Invaded; Ischemia; Low Prevalence; Mediating; Modeling; Mus; Myocardial Infarction; Myocardial Ischemia; Outcome; Peptides; Property; Recruitment Activity; Regenerative Medicine; Research; Scheme; Series; Site; Skin; Spottings; Stem cells; Stroke; Therapeutic; Time; Tissue Engineering; Tissues; Treatment Efficacy; Vascular blood supply; Wound Healing; angiogenesis; base; biophysical properties; bone; cell type; chemokine; clinical application; controlled release; design; diabetic wound healing; dosage; functional outcomes; healing; improved; in vivo; innovation; interest; mouse model; neovascularization; novel; peptidomimetics; programs; regenerative; tissue regeneration

DESCRIPTION: We propose an approach to use synthetic biomaterial arrays to recruit functional circulating angiogenic cells (CACs), and thereby enhance neovascularization. There is a critical need to: i) systematically explore the biomaterials-associated factors that may be critical to endogenous CAC recruitment, and ii) efficiently discover optimal biomaterials for CAC recruitment and function. We will use an enhanced throughput approach to discover optimal hydrogels for CAC recruitment and sustained function. We propose to use these biomaterials to leverage circulating CACs and enhance angiogenesis in vivo. Specific Aim 1 will characterize biomaterial parameters that control hCAC invasion and pro-angiogenic function. We hypothesize that the concentration of cell adhesion peptides, biomaterial stiffness, and the identity, dosage, and release rate of soluble chemokines will each significantly influence selective hCAC recruitment and pro-angiogenic function. Specific Aim 2 will use a novel in vivo hydrogel array to screen optimal biomaterial parameters for hCAC recruitment and hCAC- mediated angiogenesis in a mouse model. We hypothesize that hydrogel arrays implanted into a mouse skin- fold chamber will identify formulations that will improve functional outcome in a subsequent model of hindlimb ischemia. The proposed studies are Significant, as they will enable identification of biomaterials that enhance clinical use of endogenous CACs to improve angiogenesis. Tissue regeneration is limited by poor blood supply, and many disease states (e.g. diabetes) are characterized by a lack of sufficient vasculature. Therefore, a material approach to leverage endogenous CACs could have a substantial impact on tissue regeneration approaches. The proposed studies are Innovative, as they use chemically-defined hydrogel arrays to discover biomaterial cues for selective CAC recruitment and function, both in vitro and in vivo. The arrays are composed of biomaterials that are highly adaptable, such that the biochemical and biophysical properties of array spots can be broadly varied. These studies will provide a basis for a larger research program to elucidate the mechanisms of endogenous cell recruitment and CAC-mediated angiogenesis in vitro and in vivo.

产品说明：我们提出了一种方法，使用合成生物材料阵列招募功能循环血管生成细胞（CAC），从而增强新血管形成。迫切需要：i）系统地探索可能对内源性CAC募集至关重要的生物材料相关因素，以及ii）有效地发现CAC募集和功能的最佳生物材料。我们将使用增强的通量方法来发现用于CAC募集和持续功能的最佳水凝胶。我们建议使用这些生物材料来利用循环CAC并增强体内血管生成。具体目标1将表征控制hCAC侵袭和促血管生成功能的生物材料参数。我们假设细胞粘附肽的浓度、生物材料硬度以及可溶性趋化因子的特性、剂量和释放速率将各自显著影响选择性hCAC募集和促血管生成功能。Specific Aim 2将使用新型体内水凝胶阵列来筛选小鼠模型中hCAC募集和hCAC介导的血管生成的最佳生物材料参数。我们假设植入小鼠皮褶腔的水凝胶阵列将鉴定在随后的后肢缺血模型中改善功能结果的制剂。拟定的研究具有重要意义，因为它们将能够识别增强内源性CAC临床使用以改善血管生成的生物材料。组织再生受到血液供应不足的限制，并且许多疾病状态（例如糖尿病）的特征在于缺乏足够的脉管系统。因此，利用内源性CAC的材料方法可能对组织再生方法产生实质性影响。拟议的研究是创新的，因为它们使用化学定义的水凝胶阵列来发现体外和体内选择性CAC募集和功能的生物材料线索。阵列由高度适应性的生物材料组成，使得阵列点的生物化学和生物物理性质可以广泛变化。这些研究将为更大规模的研究计划提供基础，以阐明内源性细胞募集和CAC介导的血管生成在体外和体内的机制。