新型可注射疗法支持长期喉返神经及部分周围神经修复

文献信息

中文摘要

背景： 由喉返神经（RLN）损伤引起的单侧声带麻痹（VFP）目前尚无促进靶向神经再支配的可注射治疗方案。在此前的一项初步研究中，Agrin、神经调节蛋白-1（NRG1）和乙酰胆碱（ACh）增强了RLN损伤后早期（1个月）的神经再支配。本研究的目的是（1）评估这些效应在3个月RLN损伤模型中是否持续存在，以及（2）检验Agrin/ACh/NRG1是否促进坐骨神经（SN）横断后的再生，从而探讨其与喉部以外神经修复的相关性。
方法： 成年C57BL/6小鼠接受单侧RLN或SN横断，并分别注射入甲杓肌或腓肠肌。独立的RLN和SN队列包括生理盐水组（N=5）、生物分子组（Agrin、NRG1、ACh）（N=5）和未损伤对照组（N=5）。RLN损伤采用视频喉镜检查和肌电图（EMG）评估功能恢复，SN模型采用步态分析和EMG评估。组织学结果包括免疫组织化学以及甲杓肌或腓肠肌的肌纤维直径。
结果： 生物分子治疗改善了RLN模型中的声带运动并恢复了EMG对称性，与功能性神经再支配一致。组织学显示神经肌肉接头形成增加，肌纤维完整性得以保留。在SN模型中，基于EMG和步态缺陷，治疗未产生有意义的功能恢复。然而，神经大体连续性、神经丝染色增加以及肌纤维结构保留表明存在部分结构性再生。
结论： 生物分子疗法支持RLN损伤后的功能性和结构性再生，并在SN模型中表现出结构性恢复，但未表现出持续的功能性恢复。可能需要进一步研究持续递送或重复给药，以支持较大周围神经的再生。
证据等级： 不适用。

英文摘要

BACKGROUND: Unilateral vocal fold paralysis (VFP) from recurrent laryngeal nerve (RLN) injury currently has no injectable treatment options that promote targeted reinnervation. In a prior pilot study, Agrin, neuregulin-1 (NRG1), and acetylcholine (ACh) enhanced early (1-month) reinnervation after RLN injury. The aims of the current study were to (1) assess if these effects persist in a 3-month RLN injury model and (2) test whether Agrin/ACh/NRG1 promotes regeneration after sciatic nerve (SN) transection, with relevance to nerve repair beyond the larynx.
METHODS: Adult C57BL/6 mice underwent unilateral RLN or SN transection with injections into the thyroarytenoid or gastrocnemius, respectively. Separate RLN and SN cohorts included saline (N = 5), biomolecule (Agrin, NRG1, ACh) (N = 5), and uninjured controls (N = 5). Functional recovery was evaluated using videolaryngoscopy and electromyography (EMG) for RLN injury, and gait analysis with EMG for the SN model. Histologic outcomes included immunohistochemistry and myofiber diameter of the thyroarytenoid or gastrocnemius muscles.
RESULTS: Biomolecule treatment improved vocal fold movement and restored EMG symmetry in the RLN model, consistent with functional reinnervation. Histology demonstrated increased NMJ formation and preserved myofiber integrity. In the SN model, treatment did not produce meaningful functional recovery based on EMG and gait deficits. However, gross nerve continuity, increased neurofilament staining, and preserved myofiber architecture indicated partial structural regeneration.
CONCLUSIONS: Biomolecule therapy supports functional and structural regeneration following RLN injury and demonstrates structural, but not sustained functional, recovery in the SN model. Further investigation into sustained delivery or repeat dosing may be necessary to support regeneration in larger peripheral nerves.
LEVEL OF EVIDENCE: N/A.