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

基本信息

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
项目类别：
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&apos 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

项目摘要

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).

抽象的根据《柳叶刀全球疾病负担》报告，骨折是全球最常见的伤害之一 2019 年新增骨折 1.78 亿例，常见骨折 4.45 亿例。1 延迟愈合和骨不连基于纵向X光片中骨折线的持续性和疼痛的定性临床诊断/ 虽然无法获得延迟/不愈合的可靠全球估计，但最好的估计是。目前的数据发现，8-14% 的骨折在受伤后 2 年内因愈合并发症而再次入院。2 如果骨折发生在合并症负担较高的患者中，延迟愈合率会显着增加，例如随着年龄的增长、糖尿病或肥胖。3,4 目前这些骨折的治疗标准是通过手术改变硬件目前尚无批准用于加速骨折愈合的药物。因此，对于能够刺激非手术骨再生的生物制剂存在未满足的临床需求。家长补助金的长期目标是开发和验证可注射、可生物降解的药物。用于局部持续释放“无痛”神经生长因子 (NGF) 同工型的纳米线递送平台为了在延迟愈合的临床情况下加速骨折愈合，我们有家长补助金的支持。发表 NGF 作用于软骨细胞以促进与软骨内相关的分子程序骨化5，并且 NGF 可以封装到生物材料平台中以进行受控和局部输送6。阿片类药物是解决骨折后疼痛的标准治疗方法。7-11 该疼痛补充剂的目标是验证一种利用机器学习测量诱发性和自发性疼痛的新技术父母资助的一个创新和核心前提是“无痛”亚型的治疗用途。 NGF 在延迟修复的小鼠模型中促进骨折愈合，无痛 NGF 是自然产生的。野生型 NGFβ 序列 (NGFR100W) 中发生点突变，能够与 TrkA 受体结合，负责 NGF 的营养活性，但不负责负责疼痛的 p75 受体。12 在我们的进展中在家长资助报告中，我们分享了新数据，证明 NGFR100W 不会引起疼痛敏化未骨折肢体后爪的剂量比 NGFβ 高 10 倍，但标准反射性回避。当转化为骨折肢体时，检测方法对于诱发疼痛并不可靠。在这项资助中，我们提出了第一个。使用 BlackBox 新技术结合 DeepLabCutTM 机器学习来监控数据然后我们利用这项技术来了解骨折后疼痛转移的可量化行为终点。通过评估（目标 1）注射 NGF 治疗引起的疼痛来扰动骨折疼痛，（目标 2) 骨折延迟愈合模型中自发性疼痛的变化，以及（目标 3）NGF 受体的作用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拥有疼痛研究方面的专业知识（NOSI 目标 B：艾伦巴斯鲍姆实验室）。