Improved Tools for Accessing Pain Following Fracture and Enabling Standardized Pain Phenotyping

改进用于获取骨折后疼痛并实现标准化疼痛表型的工具

• 批准号: 10856944
• 负责人: Chelsea Shields Bahney
• 金额: $ 51.64万
• 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/10856944
• 关键词: Abate; Acceleration; Acute; Address; Afferent Neurons; Affinity; Age; Alzheimer' s Disease; Applications Grants; Area; Behavioral; Binding; Biocompatible Materials; Biological; Biological Assay; Biological Factors; Biological Products; Black race; Bolus Infusion; Bone Regeneration; Bone Transplantation; Bone callus; Breeding; Chondrocytes; Chronic; Clinical; Clinical Trials; Collaborations; Coupled; Data; Diabetes Mellitus; Dose; Encapsulated; Fracture; Future; Gait; Gene Deletion; Goals; Grant; Growth; High Prevalence; Hindlimb; Hour; Hyperalgesia; Imaging technology; Immune; Impaired healing; Implant; Inflammation; Injectable; Injections; Injury; Laboratories; Lead; Limb structure; LoxP-flanked allele; Machine Learning; Measures; Mechanics; Modeling; Molecular; Monitor; Mus; NGFR Protein; Nerve Growth Factor Pathway; Nerve Growth Factor Receptors; Nerve Growth Factors; Neurons; Neuropathy; Neurotrophic Tyrosine Kinase Receptor Type 1; Nociception; Obesity; Operative Surgical Procedures; Opioid; Pain; Pain Measurement; Pain Research; Painless; Pathological fracture; Pathway interactions; Patients; Peripheral; Phenotype; Physiologic Ossification; Point Mutation; Posture; Progress Reports; Protein Isoforms; Protocols documentation; Publishing; Receptor Signaling; Reporting; Research; Resolution; Role; Signal Transduction; Site; Standardization; System; Technology; Testing; Therapeutic; Therapeutic Uses; Thermal Hyperalgesias; Translating; Translations; Validation; Weight-Bearing state; Wild Type Mouse; base; bone; bone fracture repair; bone repair; burden of illness; cholinergic neuron; chronic pain; clinical diagnosis; clinically significant; comorbidity; falls; healing; hospital readmission; improved; innovation; limb fracture; mouse model; mutant; nanowire; new technology; non-opioid analgesic; novel; novel imaging technology; opioid use; pain sensation; pain symptom; parent grant; pharmacologic; pre-clinical; prevent; programs; receptor; regenerative; repaired; response; spontaneous pain; standard of care; success; tool; transcriptional coactivator p75

ABSTRACT Fractures are one of the most common injuries worldwide with The Lancet Global Burden of Diseases reporting 178 million new fractures and 445 million prevalent fractures in 2019.1 Delayed healing and non-union are qualitative clinical diagnoses based on the persistence of a fracture line in longitudinal radiographs and pain/ instability with weight bearing. While robust global estimates of delayed/non-union are not available, the best current data finds that 8-14% of fractures were readmitted for healing complications within 2 years post-injury.2 Delayed healing rates increase significantly if the fracture occurs in patients with high co-morbidity burdens such as increased age, diabetes, or obesity.3,4 Current standard-of-care for these fractures is surgery to alter hardware or implant bone grafts. There are currently no pharmacological agents approved to accelerate fracture healing. As such, there exists an unmet clinical need for biologics that could stimulate bone regeneration in a non-surgical delivery platform. The long-term goal of the Parent Grant is to develop and validate an injectable, biodegradable nanowire delivery platform for local and sustained release of a “painless” nerve growth factor (NGF) isoform to accelerate fracture healing in clinical scenarios of delayed healing. In support of the Parent Grant, we have published that NGF acts on chondrocytes to promote molecular programs associated with endochondral ossification5 and that NGF can be encapsulated into biomaterial platforms for controlled and localized delivery6. Opioids are the standard of care for addressing post-fracture pain.7-11 The goal of this Pain Supplement is to validate a novel technology with machine learning for measuring induced and spontaneous pain following fractures. An innovative and central premise of the Parent Grant is the therapeutic use of a “painless” isoform of NGF to promote fracture healing in murine models of delayed repair. Painless NGF results from a naturally occurring point mutation in the wild type NGFβ sequence (NGFR100W) that enables binding to the TrkA receptor, responsible for the trophic activity of NGF, but not to the p75 receptor responsible for pain.12 In our progress report for the Parent Grant, we shared new data demonstrating that NGFR100W does not induce pain sensitization at a dose 10-fold higher than NGFβ in the hindpaw of an unfractured limb. However, standard reflexive avoidance assays were not reliable for induced pain when translated to a fractured limb. In this grant, we present the first data using a novel technology, the BlackBox, coupled with DeepLabCutTM machine learning to monitor how quantifiable behavioral endpoints of pain shift after bone fracture. We then utilize this technology to understand perturbations to fracture pain by evaluating (Aim 1) induced pain in response to the injected NGF therapy, (Aim 2) changes in spontaneous pain in models of delayed fracture healing, and (Aim 3) the role of the NGF receptors in modulating pain response. We accomplish these three Aims by establishing a new collaboration outside of our current research base that has expertise in pain research (NOSI Goal B: Allan Basbaum Laboratory).

摘要 骨折是全球最常见的伤害之一，《柳叶刀》全球疾病负担报告称， 2019年新增骨折1.78亿例，现有骨折4.45亿例。1延迟愈合和骨不连 基于纵向X线片中骨折线的持续存在和疼痛的定性临床诊断/ 不稳定性与承重。虽然延迟愈合/骨不连的可靠全球估计值不可用，但最好的 目前的数据发现，8-14%的骨折在伤后2年内因愈合并发症而再次入院。 如果骨折发生在有高并发症负担的患者中， 随着年龄的增长，糖尿病或肥胖。3，4目前对这些骨折的标准治疗是手术改变硬件 或植入骨移植物。目前还没有批准用于加速骨折愈合的药物。 因此，存在对可以在非手术治疗中刺激骨再生的生物制剂的未满足的临床需求。 交付平台。父母补助金的长期目标是开发和验证一种可注射的，可生物降解的 用于局部和持续释放“无痛”神经生长因子（NGF）同种型的纳米线递送平台 在延迟愈合的临床情况下加速骨折愈合。为了支持父母补助金，我们有 发表了NGF作用于软骨细胞以促进与软骨内分泌相关的分子程序， 并且NGF可以被封装到生物材料平台中用于受控和局部递送6。 阿片类药物是治疗骨折后疼痛的标准治疗。7 -11本疼痛补充剂的目标是 验证一种新的机器学习技术，用于测量以下诱发性和自发性疼痛： 骨折父母补助金的一个创新和中心前提是治疗性使用一种“无痛”的同种型， 神经生长因子促进延迟修复小鼠模型骨折愈合。无痛神经生长因子的结果，从自然 在野生型NGFβ序列（NGFR 100 W）中发生点突变，能够与TrkA受体结合， 负责神经生长因子的营养活性，但不是负责疼痛的p75受体。 在Parent Grant的报告中，我们分享了新的数据，证明NGFR 100 W不会诱导疼痛致敏 在未骨折肢体的后爪中的剂量比NGFβ高10倍。然而，标准的反身回避 当转移到骨折肢体时，测定对于诱发的疼痛不可靠。在这份补助金中，我们提出了第一个 数据使用一种新的技术，黑盒，再加上DeepLabCutTM机器学习，以监测如何 骨折后疼痛转移的可量化行为终点。我们利用这项技术来了解 通过评估（目的1）对注射NGF治疗的反应引起的疼痛，（目的 2)骨折延迟愈合模型中自发性疼痛的变化，以及（目的3）NGF受体的作用 在调节疼痛反应方面。我们通过在外部建立新的合作来实现这三个目标。 我们目前的研究基地在疼痛研究方面具有专业知识（NOSI目标B：Allan Basbaum实验室）。