Angiogenic Peptide Scaffolds to Enhance Diabetic Wound Healing

血管生成肽支架促进糖尿病伤口愈合

• 批准号: 7531482
• 负责人: Daria A. Narmoneva
• 金额: $ 24.68万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531482
• 关键词: Amino Acids; Angiogenic Factor; Angiogenic Peptides; Animal Model; Apoptosis; Area; Beds; Bone Marrow; Bone Marrow Transplantation; Cardiac; Cell Proliferation; Cell Survival; Cells; Cellular biology; Chronic; Closure; Collagen; Communities; Complex; Data; Deposition; Development; Diabetes Mellitus; Diabetic mouse; Diabetic ulcer; Diabetic wound; Dorsal; Endopeptidases; Endothelial Cells; Environment; Epithelial; Extracellular Matrix; Fostering; Functional disorder; Gel; Goals; Granulation Tissue; Healed; Health Care Costs; Hyaluronic Acid; Hyperglycemia; Impaired wound healing; In Situ; In Vitro; Infiltration; Inflammation; Knowledge; Lead; Measures; Mediating; Modeling; Modification; Morphology; Mus; Operative Surgical Procedures; Patients; Peptide Hydrolases; Peptide Signal Sequences; Peptides; Phenotype; Platelet Factor 4; Procedures; Process; Property; Public Health; Recruitment Activity; Research; Research Personnel; Resistance; Role; Saline; Site; Skin; Specificity; Staging; Streptozocin; Technology; Testing; Thick; Time; Tissue Engineering; Tissues; Transgenic Organisms; Translational Research; Ulcer; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascularization; Week; Work; Wound Healing; angiogenesis; cell motility; day; density; diabetic; diabetic wound healing; extracellular; healing; immunogenicity; improved; innovation; interest; mouse model; nanobiotechnology; neovascularization; novel; novel strategies; pre-clinical; precursor cell; response; scaffold; type I and type II diabetes; vascular tissue engineering; vasculogenesis; wound

DESCRIPTION (provided by applicant): Chronic diabetic wounds are responsible for more than 27% of diabetic health care costs in the US annually, with total diabetic health costs annually exceeding $10.9 billion. Common treatment procedures are often inadequate and lead to complications and chronic non-healing ulcers. Insufficient vascularization is a major factor contributing to impaired wound healing of diabetic ulcers. The goal of our research is to develop a novel approach to treat chronic diabetic ulcers by applying a recent advancement in nano-biotechnology - a self- assembling peptide nanoscaffold - to modify the microenvironment of the ulcer. Our data for wound healing in genetically diabetic mice suggest that the peptide nanoscaffold provides a stable, protease-resistant environment which enables endothelial cell infiltration, promotes neovascularization and improves healing at 1 week after surgery. The objective of this R21 application is to determine the effects of the peptide treatment on early neovascularization (Aim 1) and on various components of the scaffold-mediated wound healing at the later healing stages (Aim 2), using excisional skin wound healing in murine models of type I and type II diabetes. We hypothesize that the RAD16-II peptide nanoscaffold will improve wound healing in mouse models of type I and type II diabetes by providing a granulation tissue substitute that promotes early angiogenesis and vasculogenesis and facilitates extracellular matrix deposition. Aim 1 will determine whether wound treatment with the peptide nanoscaffold promotes neovascularization through angiogenic, vasculogenic, or both mechanisms, using immunostaining for endothelial cell and endothelial precursor cell markers and cell proliferation, and Tie2/GFP bone marrow transplantation to identify precursor cells recruited from bone marrow. Aim 2 will demonstrate that wound treatment with the peptide nanoscaffold augments delayed wound healing at the final stages of healing process, and will determine which components of healing process (neovascularization, inflammation, cell proliferation, matrix remodeling) are influenced by this treatment. This will be achieved by assessment of wound morphology, neovascularization, inflammation, time of closure of epithelial gap, collagen deposition and wound breaking strength. This study will improve our understanding of the mechanisms for enhanced neovascularization in peptide nanoscaffold-treated wounds in the murine models of type I and type II diabetes. These results will enable purposeful modifications of the nanoscaffold, for example, via attaching signaling sequences to "fine tune" the microenvironment of the diabetic wounds and to facilitate the healing process, taking full advantage of the nanoscaffold technology. Significance of our approach is in application of a novel synthetic material with low immunogenicity to enhance neovascularization and modify extracellular environment of the diabetic wound. The impact of the proposed work is not limited to diabetic wound healing research; the results of this study will contribute to knowledge and will advance technology that will be of interest to a broad scientific community of researchers in vascular tissue engineering. Chronic diabetic wounds are responsible for more than 27% of diabetic health care costs in the US annually, with total health costs annually exceeding $10.9 billion. Common treatment procedures are often inadequate and lead to complications and chronic non- healing ulcers. PUBLIC HEALTH RELEVANCE:This study is focused on application of novel materials peptide nanoscaffolds- to restore angiogenic environment in the wound bed and enhance diabetic wound healing.

描述（由申请人提供）：慢性糖尿病伤口每年造成27％以上的糖尿病医疗保健费用，每年总糖尿病健康成本超过109亿美元。常见的治疗程序通常不足，导致并发症和慢性非治疗溃疡。血管形成不足是导致糖尿病性溃疡伤口愈合受损的主要因素。我们的研究的目的是通过应用纳米生物技术的最新进步（一种自组装肽纳米苏斯科托管）来修改溃疡的微环境，以开发一种新型方法来治疗慢性糖尿病性溃疡。我们在遗传性糖尿病小鼠中伤口愈合的数据表明，肽纳米尺度提供了一种稳定的抗蛋白酶耐药性环境，可实现内皮细胞浸润，促进新血管形成并在手术后1周改善愈合。该R21应用的目的是确定肽治疗对早期新血管形成的影响（AIM 1）以及在后期愈合阶段的支架介导的伤口愈合的各种成分（AIM 2），使用I类和II型糖尿病的鼠模型中的杂交皮肤伤口愈合。我们假设RAD16-II肽纳米尺度将通过提供促进早期血管生成和血管生成的肉芽组织替代品来改善I型和II型糖尿病模型中的伤口愈合，并促进细胞外基质沉积。 AIM 1将确定使用肽纳米苏卡夫的伤口是否通过血管生成，血管生成或两种机制促进新生血管化，并使用免疫染色来用于内皮细胞和内皮前体细胞标记物和细胞增殖，以及细胞增殖，以及TIE2/GFP骨髓骨髓的转移到识别前体细胞的骨骼细胞，可从骨头菌落菌群招募。 AIM 2将表明，用肽纳米施加剂的伤口治疗在愈合过程的最后阶段延迟了伤口愈合，并将确定愈合过程的哪些组成部分（新血管形成，炎症，细胞增殖，基质重塑）受此治疗的影响。这将通过评估伤口形态，新血管形成，炎症，上皮间隙闭合时间，胶原蛋白沉积和伤口断裂强度来实现。这项研究将提高我们对在I型和II型糖尿病的鼠模型中肽纳米施加治疗的伤口增强新血管形成机制的理解。这些结果将实现纳米镜的有目的修改，例如，通过将信号序列连接到“微调”糖尿病伤口的微环境中，并促进愈合过程，充分利用纳米镜技术。我们方法的重要性是应用具有低免疫原性的新型合成材料来增强糖尿病伤口的新血管形成和改变细胞外环境。拟议工作的影响不仅限于糖尿病伤口愈合研究。这项研究的结果将有助于知识，并将推进血管组织工程研究人员的广泛科学社区感兴趣的技术。在美国，慢性糖尿病伤口每年造成超过27％的糖尿病医疗保健费用，每年总的健康成本超过109亿美元。常见的治疗程序通常是不足的，并导致并发症和慢性非愈合溃疡。公共卫生相关性：这项研究的重点是应用新型材料肽纳米生成菌 - 以恢复伤口床中的血管生成环境并增强糖尿病伤口愈合。