Localization of adenosine to promote fracture healing

腺苷定位促进骨折愈合

• 批准号: 10461465
• 负责人: Shyni Varghese
• 金额: $ 50.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461465
• 关键词: ADORA2A gene; Acids; Address; Adenosine; Adjuvant; Age; Aging; Animals; BMP2 gene; Behavior; Biocompatible Materials; Blood Circulation; Bone Diseases; Bone Injury; Bone Regeneration; Bone Tissue; Bone Transplantation; Bone callus; CD8-Positive T-Lymphocytes; Cells; Clinical; Cyclic AMP; Defect; Development; Dose; Economic Burden; Elderly; Environment; Flow Cytometry; Fracture; Functional disorder; Gait; Gene Expression; Half-Life; Histologic; Hyaluronic Acid; Immune; Immune response; Impaired healing; Implant; In Situ; Injectable; Injury; Knock-out; Literature; Matrix Metalloproteinases; Mechanics; Modeling; Mus; Natural regeneration; Nature; Operative Surgical Procedures; Osteogenesis; Osteoporosis; Patients; Plasma; Play; Population; Prevalence; Proteins; Public Health; Purinergic P1 Receptors; Quality of life; Receptor Signaling; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; Site; T-Lymphocyte; Testing; Therapeutic; Tibial Fractures; Tissues; Trauma; Vascularization; Wild Type Mouse; active lifestyle; age related; aged; angiogenesis; base; bone; bone aging; bone fracture repair; bone healing; bone health; bone quality; cost; cost effective; crosslink; cytokine; extracellular; fragility fracture; healing; immunoregulation; improved; juvenile animal; laser capture microdissection; longitudinal analysis; macrophage; neutrophil; novel therapeutic intervention; older patient; peripheral blood; regenerative; repaired; scaffold; sex; single-cell RNA sequencing; spatiotemporal; success; tissue regeneration; tissue repair

ABSTRACT Bone fracture is a very common injury, and there has been a dramatic increase in trauma-induced fractures with the increase in active lifestyle. Despite the regenerative ability of bone, bone injuries often suffer from delayed healing or non-unions. The prevalence of bone fracture and the cost of repair is on the rise primarily due to aging of the population. The profound negative impact on the patient’s quality of life and the economic burden of fracture treatment following trauma or age-related fragility fractures warrants the development of efficient and cost-effective fracture-healing adjuvants to accelerate the healing rate and improve the quality of healing. The proposed research focuses on biomaterial-assisted local delivery of adenosine to promote bone healing of aged bone tissues by rejuvenating the endogenous tissue environment and reparative cells. We hypothesize that local delivery of adenosine at the injury site will induce a pro-regenerative immune environment and promote regeneration of aging bone tissues through enhanced osteoblastogenesis and angiogenesis. These hypotheses will be tested through the following aims. Aim 1 will determine the effect of local delivery of adenosine to promote bone regeneration in aged mice by using two injury models: transverse tibial fracture and critical-sized segmental femoral defect. Aim 2 will determine the role of adenosine delivery on immunomodulation leading to enhanced bone regeneration. Successful completion of the proposed studies will have a significant impact in public health by establishing a new therapeutic intervention for promoting bone regeneration.

摘要 骨折是一种非常常见的损伤，并且随着年龄的增长， 积极生活方式的增加。尽管骨的再生能力，骨损伤往往遭受延迟 愈合或不愈合。骨折的患病率和修复费用正在上升，主要是由于老龄化 的人口。对患者的生活质量和经济负担的深刻负面影响， 创伤或与年龄相关的脆性骨折后的骨折治疗需要开发有效且 具有成本效益的创伤愈合佐剂，以加快愈合速度并提高愈合质量。的 拟议的研究集中在生物材料辅助的腺苷局部递送，以促进老年人的骨愈合。 通过再生内源性组织环境和修复细胞来修复骨组织。我们假设当地 腺苷在损伤部位的递送将诱导促再生免疫环境并促进细胞的再生。 通过增强成骨细胞生成和血管生成使老化骨组织再生。这些假设 将通过以下目标进行测试。目的1将确定腺苷的局部递送的效果，以促进 老年小鼠胫骨横断骨折和临界节段性骨折骨再生的实验研究 股骨缺损目的2将确定腺苷递送在免疫调节中的作用，从而增强 骨再生成功完成拟议的研究将对公共卫生产生重大影响 通过建立一种新的治疗干预来促进骨再生。