Dual-Delivery of Bioactive and Anti-Microbial Nanowires for Accelerated Bone Repair

双重递送生物活性和抗菌纳米线以加速骨修复

• 批准号: 10630656
• 负责人: Chelsea Shields Bahney
• 金额: $ 4.34万
• 依托单位: STEADMAN PHILIPPON RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630656
• 关键词: Alzheimer' s Disease; Biocompatible Materials; Blood Vessels; Bone Regeneration; Bone Transplantation; Cells; Chondrocytes; Clinical; Clinical Trials; Coupled; Fracture; Goals; Grant; Heparin; Hyperalgesia; Impaired healing; Injectable; Injections; Injury; Mediating; NGFR Protein; Nerve Growth Factors; Neurons; Neuropathy; Neurotrophic Tyrosine Kinase Receptor Type 1; Nociception; Operative Surgical Procedures; Osteoblasts; Pain; Painless; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral Nervous System; Pharmacology; Phase; Physiologic Ossification; Point Mutation; Population; Positioning Attribute; Protein Isoforms; Proteins; Publishing; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Effect; Translating; Treatment Factor; United States; Work; antimicrobial; base; bone fracture repair; bone healing; bone repair; cartilaginous; clinically relevant; comorbidity; efficacy testing; healing; improved; long bone; multidisciplinary; nanowire; neuron regeneration; novel; polycaprolactone; regenerative; standard of care; translational potential

ABSTRACT Fractures are one of the most common injuries worldwide with an estimated 15 million fractures each year in the United States alone. Complications in bone healing, such as delayed and non-unions, are estimated to occur in approximately 10-15% of fractures. Delayed healing rates increase to ~50% when the fracture involves vascular damage or are coupled with high co-morbidity burdens. Current standard of care for impaired healing is surgical intervention to increase stability or promote healing through application of bone grafts. There are currently no pharmacological agents approved to accelerate fracture healing or treat malunions. As such there exists an unmet clinical need for osteoinductive therapeutics that could stimulate bone regeneration through a non-surgical delivery platform. This proposal builds on recently published work from our group demonstrating that Nerve Growth Factor (NGF) given therapeutically during the cartilaginous phase of fracture repair promoted endochondral ossification and accelerated fracture healing. While NGF has not been rigorously studied in long bone fractures, NGF is well established as a potent regenerative factor within the central and peripheral nervous system. Multiple clinical trials suggested a therapeutic potential for NGF in treating Alzheimer’s disease and neuropathies, but the therapy failed to translate due to pain (hyperalgesia) noted upon injection. Recently, our team has isolated a novel NGF isoform identified from patients that lack nociception due to a point mutation in the protein (NGFR100W) that fails to transduce pain through an inability to activate the p75NTR signaling pathway. Since NGFR100W retains TrkA mediated trophic activity, this “painless” NGF presents an exciting opportunity to revisit the translational potential of NGF. The long-term goal of this grant is to develop and validate a translationally relevant, non-surgical, therapeutic platform to accelerate fracture repair based on the use of biodegradable nanowires to provide local and sustained release of “painless” NGF. We accomplish this through three specific aims. In Aim 1 we tune heparin-coated polycaprolactone-nanowires for the delivery of NGFR100W and validate this platform can achieve functional activation of the TrkA pathway to promote neuronal regeneration, while decreasing nociception relative to wild type NGF (NGFWT). We then rigorously test efficacy of the NGFR100W-nanowires in our clinical target of fracture repair (Aim 2). In parallel we also probe the mechanism by which NGF/TrkA signaling stimulates fracture repair. This is done in Aim 3 by genetically deleting the TrkA receptor from specific cell populations to determine whether this pathway is essential for endochondral fracture repair and if it can be rescued by NGF treatment. These aims allow us to test the central hypothesis that NGFR100W nanowires will accelerate fracture repair by acting through TrkA signaling to stimulate chondrocyte-to-osteoblast transformation. Our multidisciplinary team of experts in fracture healing, biomaterials, and NGF/TrkA signaling uniquely positions us to successfully accomplish the proposed study with the ultimate goal of significantly improving patient outcomes following a fracture.

抽象的 骨折是全世界最常见的伤害之一，估计每年有 1500 万例骨折 仅在美国，估计就会出现骨愈合并发症，例如延迟愈合和不愈合。 当骨折涉及血管时，约 10-15% 的骨折延迟愈合率增加至约 50%。 损伤或伴有高并发症负担的目前治疗受损的标准是手术。 通过应用骨移植来增加稳定性或促进愈合的干预措施 目前尚无。 因此，存在一种被批准用于加速骨折愈合或治疗畸形愈合的药物。 对骨诱导疗法的未满足的临床需求可以通过刺激骨再生 该提案建立在我们小组最近发表的展示工作的基础上。 在骨折修复的软骨阶段给予神经生长因子（NGF）促进治疗 软骨内骨化和加速骨折愈合长期以来尚未得到严格研究。 NGF 被认为是中枢和周围神经内的有效再生因子 多项临床试验表明 NGF 在治疗阿尔茨海默病和 神经病，但由于注射时出现疼痛（痛觉过敏），治疗未能发挥作用。 研究小组从由于点突变而缺乏伤害感受的患者中分离出一种新的 NGF 同工型 该蛋白质 (NGFR100W) 由于无法激活 p75NTR 信号通路而无法传导疼痛。 由于 NGFR100W 保留了 TrkA 介导的营养活性，这种“无痛”NGF 提供了一个令人兴奋的机会 重新审视 NGF 的转化潜力 这笔赠款的长期目标是开发和验证 转化相关的非手术治疗平台，可根据用途加速骨折修复 我们实现了可生物降解的纳米线，以提供“无痛”NGF 的局部持续释放。 在目标 1 中，我们通过调整肝素涂层聚己内酯纳米线来实现这一目标。 NGFR100W并验证该平台可以实现TrkA通路的功能激活，促进神经元 再生，同时相对于野生型 NGF (NGFWT) 减少伤害感受，然后我们严格测试功效。 同时，我们还探讨了 NGFR100W 纳米线在骨折修复临床目标中的应用（目标 2）。 NGF/TrkA 信号刺激骨折修复的机制 这是通过基因删除实现的。 来自特定细胞群的 TrkA 受体，以确定该途径是否对于软骨内细胞至关重要 骨折修复以及是否可以通过 NGF 治疗来挽救这些目标使我们能够检验中心假设。 NGFR100W 纳米线将通过 TrkA 信号传导刺激加速骨折修复 我们的骨折愈合多学科专家团队， 生物材料和 NGF/TrkA 信号传导使我们能够成功完成拟议的研究 最终目标是显着改善骨折后患者的预后。