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.

摘要 骨折是全世界最常见的损伤之一，在世界范围内每年估计有1500万例骨折。 只有美国。骨愈合并发症，如延迟愈合和骨不连，估计发生在 大约10-15%的骨折。当骨折累及血管时，延迟愈合率增加至约50%。 损害或伴随高并发症负担。目前治疗愈合受损的标准是手术 通过应用骨移植物进行干预以增加稳定性或促进愈合。目前没有 批准用于加速骨折愈合或治疗畸形愈合的药物。因此，存在一个 对骨诱导治疗的未满足的临床需求， 非手术输送平台。这个建议建立在我们小组最近发表的工作的基础上， 在骨折修复的软骨阶段给予神经生长因子（NGF）治疗， 软骨内骨化和加速骨折愈合。虽然神经生长因子还没有得到严格的研究， 在骨折中，NGF被公认为中枢和外周神经系统内的有效再生因子。 系统多项临床试验表明，神经生长因子在治疗阿尔茨海默病和阿尔茨海默病方面具有治疗潜力。 神经病，但由于注射时注意到的疼痛（痛觉过敏），治疗未能转化。最近我们 一个研究小组已经从缺乏伤害感受的患者中分离出一种新的NGF亚型， 蛋白质（NGFR 100 W），由于不能激活p75 NTR信号通路而不能抑制疼痛。 由于NGFR 100 W保留了TrkA介导的营养活性，这种“无痛”的NGF提供了一个令人兴奋的机会， 重新审视NGF的转化潜力。这项赠款的长期目标是开发和验证一个 根据使用情况，提供预防相关的非手术治疗平台，以加速骨折修复 可生物降解的纳米线，以提供局部和持续释放的“无痛”神经生长因子。我们完成 通过三个具体目标。在目标1中，我们调整肝素涂覆的聚己内酯纳米线，用于递送 NGFR 100 W，并验证此平台可以实现TrkA通路的功能性激活，促进神经元 再生，同时相对于野生型NGF（NGFWT）降低伤害感受。然后我们严格测试功效 NGFR 100 W-纳米线在我们的骨折修复临床目标中的应用（目标2）。同时，我们也探索 NGF/TrkA信号刺激骨折修复的机制。目标3通过基因删除 来自特定细胞群的TrkA受体，以确定该途径是否是软骨内分泌所必需的 骨折修复以及是否可以通过神经生长因子治疗来挽救。这些目标使我们能够检验中心假设 NGFR 100 W纳米线将通过TrkA信号刺激， 软骨细胞向成骨细胞的转化。我们的多学科骨折愈合专家团队， 生物材料和NGF/TrkA信号传导使我们能够成功地完成拟议的研究， 最终目标是显著改善骨折后患者的预后。