Intraoperative Nerve Damage Assessment Using Nerve-Specific Fluorescence Guided Surgery

项目总结 急性周围神经挤压伤常由闭合性或开放性骨折、关节脱位和高位移位引起。 能量碰撞。神经挤压、拉伸或切断会导致功能障碍，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的可能性仍然具有挑战性和术中神经 刺激是在神经修复手术中帮助决策的唯一方法，通常产生的效果最小。 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， 未能捕捉到轴突破坏的程度，导致约50%的患者功能恢复较差 结果。外科医生和患者将受益于术中神经损伤的快速评估 做出知情的治疗决定。我们假设荧光成像使用一种新的神经- 特定的荧光团可以提供一种客观的方法学来确定程度和回收率 神经损伤，实时指导手术干预以改善患者的预后 整形外科创伤手术。我们已经开发了一个首创的、有针对性的近红外(NIR)资料库 荧光团以高亲和力标记神经组织，目前正在进行临床前药理学和 毒理学测试，以促进改善术中神经可视化的首例人类(FIH)试验。这些 荧光体在小鼠、大鼠、 和猪和初步研究表明，健康和受损的神经组织之间的明确识别 局部或全身性给药。在这里，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研究健康和受损神经组织之间的强度差异 为术中神经损伤评估提供客观方法学。这项研究是当务之急 里程碑将包括(1)为开发的方法选择管理时间点，(2) 定量荧光强度(FI)和摄取参数的健康，永久受损，和 小鼠坐骨神经损伤模型中神经组织的恢复及(3)神经损伤模型的验证 一项盲法大鼠坐骨神经损伤研究的评估方法学，用于未来的临床翻译。完成 拟议的目标将导致第一个创伤手术的客观神经损伤评估方法。 利用由Inherent靶向开发的新的近红外神经特异性荧光团。拟议的研究将 为我们的新型探头在未来的临床翻译中的扩展用途提供概念验证，使 为患者提供可靠的诊断评估。这项工作将在正在进行的获得临床批准的工作的基础上进行 为这些新颖的神经特异性探针提供了坚实的基础，为术中技术的应用提供了平台 指导。在这个项目的第二阶段，FIH将完成对开发的神经损伤评估的试验 对接受修复手术的创伤患者进行翻译验证的方法学。

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.