Innovative medical device to treat nonunion fracture for older adults

摘要 骨折是老年人群中最具挑战性的肌肉骨骼损伤之一。 在临床上，骨愈合潜能显著下降，伴随着精神和生活的改变， 威胁性并发症，通常在65岁或以上的老年人中观察到。与 随着美国老年人口的快速增长，它对健康造成了巨大的成本负担。 治疗骨折的护理系统。尽管在发展中取得了重大进展， 用于骨折修复的治疗方法（骨移植材料、生长因子和干细胞）， 对于治疗延迟骨折愈合或骨折的新方法的临床需求仍然没有得到满足 骨不连，尤其是老年患者。 为了实现这一目标，我们一直专注于血管生成，这一直被认为是关键 骨折愈合过程中重建血液供应以输送氧气、营养物 和细胞。特别是，最近的研究表明，由于老年人的炎症， 在患者中，慢性炎症对血管生成产生不利影响，进而导致血管生成失败。 骨痂形成并出现延迟愈合或不愈合。为此，我们提供 有证据表明，全身性炎症导致血管生成受损和骨折不愈合， 小鼠从机制上讲，炎症介导的血管生成缺陷至少部分是由于 CXCL 12（C-X-C基序趋化因子配体12）的下调和外源性CXCL 12可以 恢复体外血管生成能力。为了将CXCL 12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， 通过FDA批准的PCL材料在当地交付CXCL 12。PCL/CXCL 12材料显示 与骨膜相似的生物力学特性和受控的缓释模式 关于CXCL 12更重要的是，CXCL 12的局部递送显示出稳健的血管生成过程。 以及在全身炎症条件下恢复小鼠的骨折愈合。的 这个STTR提案的首要目标是追求这种可生物降解的商业化， 和释放可控的PCL/CXCL 12材料作为潜在的治疗性治疗，以促进 骨折愈合，尤其是老年患者。

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.