Innovative medical device to treat nonunion fracture for older adults

治疗老年人骨折不愈合的创新医疗设备

• 批准号: 10766444
• 负责人: Mo Chen
• 金额: $ 29.94万
• 依托单位: WNT SCIENTIFIC, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10766444
• 关键词: Affect; Aging; Agreement; Area; BMP2 gene; Benchmarking; Biological; Biomechanics; Biotechnology; Blood Vessels; Bone Transplantation; Bone callus; Businesses; Cell Separation; Cells; Chronic; Clinic; Clinical; Clinical Research; Defect; Devices; Disease; Down-Regulation; Elderly; Endothelial Cells; FDA approved; Failure; Fracture; Goals; Growth Factor; Health; Healthcare Systems; Impairment; In Vitro; Inflammaging; Inflammation; Inflammatory; Intellectual Property; Laboratory Research; Legal patent; Licensing; Life; Ligands; Mediating; Mediation; Medical Device; Methods; Mus; Musculoskeletal Diseases; New York City; Nutrient; Open Fractures; Operative Surgical Procedures; Oxygen; Pattern; Periosteum; Population; Process; Property; Psyche structure; Signal Transduction; Small Business Technology Transfer Research; Stromal Cell-Derived Factor 1; Structure; Technology; Technology Transfer; Therapeutic; Tissues; Universities; Vascular blood supply; Washington; aged; aging population; angiogenesis; biodegradable scaffold; bone; bone fracture repair; bone healing; chemokine; clinical research site; commercialization; cost; design; dosage; effectiveness evaluation; experimental study; improved; in vivo; innovation; musculoskeletal injury; novel strategies; older patient; pre-clinical; rapid growth; reconstruction; response; restoration; scaffold; side effect; stem cells; systemic inflammatory response

Abstract Bony fracture is one of the most challenging musculoskeletal injuries in the elderly population. In clinic, a significant decline in bone healing potential, accompanying with mental and life- threatening complications, is commonly observed in elderly who are 65 years or older. With the rapid growth of elderly population in the US, it imposes a substantial cost burden on the health care system to treat fracture. Although significant advances have been made in developing therapeutic approaches (bone graft materials, growth factors and stem cells) for fracture repair, there is still unmet clinical need for new approaches to treat delayed fracture healing or fracture non-union, especially for elderly patients. To fulfill this effort, we have focused on angiogenesis, which has long been considered as a key initial step during fracture healing to re-establish blood supply for delivery of oxygen, nutrients, and cells. Particularly, recent studies have illustrated that due to the inflammaging in elderly patients, chronic inflammation adversely affects angiogenesis, and in turn results in the failure of bony callus formation and develops delayed union or non-union. In this regard, we provide evidence that systemic inflammation results in impaired angiogenesis and fracture non-union in mice. Mechanistically, angiogenesis defect mediated by inflammation is at least partially due to down-regulation of CXCL12 (C-X-C Motif Chemokine Ligand 12) and exogenous CXCL12 can restore angiogenesis capacity in vitro. In order to apply CXCL12 to local fracture treatment while avoiding excessive angiogenesis or other side effects in other tissues, we design to deliver CXCL12 locally by FDA approved PCL material. The PCL/CXCL12 material display similar biomechanical properties compared to periosteum and a controlled slow-release pattern of CXCL12. More importantly, local delivery of CXCL12 shows a robust angiogenesis process and a restoration of fracture union in mice under systemic inflammation conditions. The overarching goal of this STTR proposal is to pursue the commercialization of this biodegradable and release controllable PCL/CXCL12 material as a potential therapeutic treatment to promote fracture healing, especially in elderly patients.

抽象的 骨骨折是老年人中最具挑战性的肌肉骨骼损伤之一。 在临床上，骨愈合潜力显着下降，伴随着精神和生活- 威胁性并发症，常见于 65 岁或以上的老年人。随着 美国老年人口快速增长，给健康带来巨大的成本负担 治疗骨折的护理系统。尽管在开发方面已经取得了重大进展 骨折修复的治疗方法（骨移植材料、生长因子和干细胞）， 对于治疗骨折延迟愈合或骨折的新方法的临床需求仍未得到满足 不愈合，特别是对于老年患者。 为了实现这一目标，我们将重点放在血管生成上，这长期以来一直被认为是关键 骨折愈合过程中的第一步是重新建立血液供应以输送氧气、营养物质、 和细胞。特别是最近的研究表明，由于老年人的炎症 对于患者来说，慢性炎症会对血管生成产生不利影响，进而导致血管生成失败。 骨痂形成并发展为延迟愈合或不愈合。对此，我们提供 有证据表明全身炎症会导致血管生成受损和骨折不愈合 老鼠。从机制上讲，炎症介导的血管生成缺陷至少部分是由于 CXCL12（C-X-C基序趋化因子配体12）和外源性CXCL12的下调可以 恢复体外血管生成能力。为将CXCL12应用于局部骨折治疗 在避免其他组织中过度血管生成或其他副作用的同时，我们设计 使用 FDA 批准的 PCL 材料在本地输送 CXCL12。 PCL/CXCL12材质展示 与骨膜相比具有相似的生物力学特性和受控的缓释模式 CXCL12。更重要的是，CXCL12 的局部递送显示出强大的血管生成过程 以及全身炎症条件下小鼠骨折愈合的恢复。这 该 STTR 提案的总体目标是追求这种可生物降解的商业化 并释放可控的 PCL/CXCL12 材料作为潜在的治疗方法，以促进 骨折愈合，尤其是老年患者。