Intraoperative Nerve Damage Assessment Using Nerve-Specific Fluorescence Guided Surgery

项目摘要 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- 能量碰撞神经挤压、拉伸或横断可导致从麻木到 运动和感觉功能完全丧失，每年影响约160万创伤患者。学位评估 损伤的可能性和损伤后功能恢复仍然具有挑战性， 刺激是神经修复手术中辅助决策的唯一方法， 有用的信息因此，外科医生只能通过肉眼检查来评估神经损伤， 它不能捕捉轴突破坏的程度，使约50%的患者功能恢复不良 结果。外科医生和患者将受益于术中对神经损伤的快速评估， 做出明智的治疗决定。我们假设使用一种新的神经- 特定的荧光团可以提供一种客观的方法来确定程度和可回收性 神经损伤，实时指导手术干预，以改善患者的预后， 骨科创伤手术。我们已经开发了一个库的第一种，有针对性的，近红外（NIR） 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研究， 毒理学测试，以促进首次在人类（FIH）试验，以改善术中神经可视化。这些 荧光团在小鼠，大鼠， 初步研究表明，健康和受伤的神经组织之间的清晰识别， 局部或全身给药。在此，我们建议充分表征荧光摄取曲线， 使用我们的NIR神经特异性荧光团， 为术中神经损伤评估提供了一种客观的方法。这项研究是即时的 里程碑将包括（1）为开发的方法选择给药时间点，（2） 在健康、永久性损伤和 在小鼠坐骨神经损伤模型中恢复神经组织和（3）验证所发展的神经损伤 在盲法大鼠坐骨神经损伤研究中的评估方法用于未来的临床翻译。完成 提出的目标将导致创伤外科的第一个客观神经损伤评估方法 利用由固有靶向开发的新型NIR神经特异性荧光团。拟议的研究将 为我们的新型探头在未来临床翻译中的扩展实用性提供概念验证， 对患者进行可靠的诊断评估。这项工作将建立在正在进行的工作，以获得临床批准 为这些新的神经特异性探针，并提供了一个强大的基础，作为一个平台技术， 指导在该项目的第二阶段，将完成FIH试验，用于开发神经损伤评估 方法，以验证翻译创伤患者接受修复手术。

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.