Intraoperative Nerve Damage Assessment Using Nerve-Specific Fluorescence Guided Surgery

使用神经特异性荧光引导手术进行术中神经损伤评估

• 批准号: 10482087
• 负责人: Connor William Barth
• 金额: $ 37.51万
• 依托单位: INHERENT TARGETING, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10482087
• 关键词: Acute; Affect; Affinity; Animals; Atrophic; Autopsy; Axon; Blinded; Clinical; Closed Fractures; Complex; Contrast Media; Decision Making; Development; Diagnosis; Diagnostic; Electromyography; Family suidae; Fast Blue; Fluorescence; Foundations; Future; Gastrocnemius Muscle; Gold; Histologic; Image; Injury; Joint Dislocation; Label; Lead; Left; Libraries; Linear Regressions; Measurement; Measures; Methodology; Modeling; Monitor; Motor; Mus; Muscular Atrophy; Myelin; Nerve; Nerve Crush; Nerve Tissue; Numbness; Open Fractures; Operative Surgical Procedures; Orthopedics; Outcome; Paint; Patient-Focused Outcomes; Patients; Peripheral nerve injury; Pharmacology; Pharmacology and Toxicology; Phase; Physiological; Prognosis; Rattus; Receiver Operating Characteristics; Recording of previous events; Recovery; Recovery of Function; Reproducibility; Resected; Rodent; Salvelinus; Sensitivity and Specificity; Sensory; Severities; Signal Transduction; Specificity; Stains; Stretching; Surgeon; Surgical Models; Technology; Testing; Time; Tissues; Training; Translations; Trauma; Trauma patient; Tweens; Validation; Visual; Visualization; Wallerian Degeneration; Work; base; clinical translation; cohort; density; design; first-in-human; fluorescence imaging; fluorescence-guided surgery; fluorophore; follow-up; improved; in vivo; injured; injury recovery; loss of function; millimeter; nerve damage; nerve injury; nerve repair; novel; pre-clinical; reconstruction; repaired; sciatic nerve; sciatic nerve injury; trauma surgery; uptake

PROJECT SUMMARY Acute peripheral nerve crush injuries frequently result from closed or open fractures, joint dislocations, and high- energy collisions. Nerve crush, stretch, or transection can lead to functional deficits ranging from numbness to complete motor and sensory function loss, affecting ~1.6M trauma patients annually. Assessment of the degree of injury and the possibility for functional recovery after injury remains challenging and intraoperative nerve stimulation, the only methodology to aid in decision-making during nerve repair surgery, often yields minimally useful information. Thus, surgeons are left to make nerve damage assessments via gross visual examination, which fails to capture the degree of axonal disruption, leaving ~50% of patients with poor functional recovery outcomes. Surgeons and patients would benefit from a rapid intraoperative assessment of nerve damage to make informed treatment decisions. We hypothesize that fluorescence imaging using a novel nerve- specific fluorophore could provide an objective methodology to determine the degree and recoverability of nerve injury, guiding surgical intervention in real-time to improve patient outcomes following orthopaedic trauma surgery. We have developed a library of first-in-kind, targeted, near-infrared (NIR) fluorophores that label nerve tissue with high affinity and are currently undergoing preclinical pharmacology and toxicology testing to facilitate first-in-human (FIH) trials for improved intraoperative nerve visualization. These fluorophores provide nerve visualization with high contrast at millimeter to centimeter tissue depths in mice, rats, and swine and preliminary studies show clear identification between healthy and injured nerve tissues following topical or systemic administration. Herein, we propose to fully characterize the fluorescent uptake profiles and intensity differences between healthy and damaged nerve tissue using our NIR nerve-specific fluorophores to provide an objective methodology for intraoperative nerve damage assessment. This study’s immediate milestones will include (1) selection of an administration time point for the developed methodology, (2) quantification of fluorescence intensity (FI) and uptake parameters in healthy, permanently damaged, and recovering nerve tissue in mouse sciatic nerve injury models and (3) validation of the developed nerve damage assessment methodology in a blinded rat sciatic nerve injury study for future clinical translation. Completion of the proposed aims will result in the first objective nerve damage assessment methodology for trauma surgery utilizing novel NIR nerve-specific fluorophores developed by Inherent Targeting. The proposed studies will provide proof-of-concept for the expanded utility of our novel probe for future clinical translation, enabling a robust diagnostic assessment for patients. This work will build upon work underway to obtain clinical approval for these novel nerve-specific probes and provide a strong foundation as a platform technology for intraoperative guidance. In Phase II of this project, FIH trials will be completed for the developed nerve damage assessment methodology to validate translation to trauma patients undergoing reparative surgery.

项目概要 急性周围神经挤压伤通常由闭合性或开放性骨折、关节脱位和高位骨折引起。 神经挤压、拉伸或横断可导致从麻木到功能障碍。 运动和感觉功能完全丧失，每年影响约 160 万创伤患者的程度评估。 损伤的发生以及损伤后功能恢复的可能性仍然具有挑战性，术中神经 刺激是神经修复手术期间帮助决策的唯一方法，但效果通常很小 因此，外科医生只能通过肉眼检查来评估神经损伤， 它无法捕捉轴突破坏的程度，导致约 50% 的患者功能恢复不佳 外科医生和患者将受益于术中神经损伤的快速评估。 我们使用一种新型神经成像技术来做出明智的治疗决策。 特定的荧光团可以提供客观的方法来确定程度和可恢复性 神经损伤后，实时指导手术干预以改善患者预后 我们开发了一个同类首创、有针对性的近红外 (NIR) 库。 以高亲和力标记神经组织的荧光团，目前正在进行临床前药理学和 毒理学测试，以促进首次人体 (FIH) 试验，以改善术中神经可视化。 荧光团为小鼠、大鼠、小鼠等提供毫米至厘米组织深度的高对比度神经可视化 和猪，初步研究表明健康和受伤的神经组织之间的清晰识别 在此，我们建议充分表征荧光摄取曲线和 使用我们的近红外神经特异性荧光团来观察健康和受损神经组织之间的强度差异 这项研究为术中神经损伤评估提供了客观的方法。 里程碑将包括（1）为所开发的方法选择管理时间点，（2） 健康、永久受损和健康的荧光强度（FI）和摄取参数的量化 在小鼠坐骨神经损伤模型中恢复神经组织以及（3）对所形成的神经损伤进行验证 盲法大鼠坐骨神经损伤研究的评估方法，用于未来的临床转化。 拟议的目标将为创伤手术带来第一个客观的神经损伤评估方法 拟议的研究将利用 Inherent Targeting 开发的近红外神经特异性荧光团。 为我们的新型探针在未来临床转化中的扩展实用性提供概念验证，从而实现 这项工作将以正在进行的工作为基础，以获得临床批准。 为这些新型神经特异性探针提供了作为术中平台技术的坚实基础 在该项目的第二阶段，将完成针对开发的神经损伤评估的 FIH 试验。 验证对接受修复手术的创伤患者的翻译的方法。