Muscle progenitor cell-based implants for dynamic laryngeal muscle reconstruction

项目摘要 毁灭性的失声(发音困难或失声)影响着美国成千上万的人。 每年接受创伤性或肿瘤性喉部分切除术或肌肉受苦的国家 由于声带麻痹导致的音量损失。这些患者的语音恢复选项包括 不理想，因此，大多数患者都会永久失声和交流 减损。这项应用介绍了一种恢复声带肌肉容量的新方法 并在直接声带损伤和/或去神经后恢复功能。结果可能会带来改善 声带麻痹患者和/或已接受手术的患者的发音重建手术选择 半喉切除、全喉切除或创伤性撕脱。此应用程序的第一个目标是 设计一种自体肌肉-软骨植入祖细胞来源的植入物(MI)，在 在动物模型中植入，接受强大的神经支配，并在使用时变得有功能 来修复一个巨大的喉部缺陷。为了做到这一点，我们将在定制的胶原蛋白中制造MI 体外诱导心肌梗死肌肉运动表达因子的基质和预处理 端板。MIS将被用来替代猪模型中的部分喉切除缺损区，以及 术后神经支配状态的喉肌电信号和量化的研究 将确定有神经接触的运动终板。使用这个动物植入模型， 研究管理信息系统的结果将与具有和控制管理信息系统的环境中的结果进行比较 没有喉返神经的完整性。拟议研究的结果应该会克服 目前研制功能性组织工程半喉微通道的主要障碍 重建-这些障碍是软骨支持不足，神经支配不良 肌肉，肌纤维的次优组织，以及肌肉与 天然内收肌。此外，因为这些研究现在正在大规模地进行 动物(猪)模型，喉部大小和功能与人类非常相似，发现 将具有很强的翻译性。这些实验的结果应该会导致里程碑式的临床 与语音恢复应用和肌肉修复相关的创新 全球概念。

Project Summary Devastating voice loss (dysphonia or aphonia) impacts thousands of individuals in the United States each year undergoing traumatic or oncologic partial laryngectomies, or suffering muscle volume loss due to vocal fold paralysis. Voice restoration options for these patients are suboptimal, and, as a result, most patients are left with permanent voice loss and communication impairment. This application introduces a novel approach for restoring vocal fold muscle volume and function after direct vocal fold injury and/or denervation. Results may lead to improved surgical options for voice restoration in patients who have vocal paralysis and/or have undergone hemilaryngectomies, cordectomies, or traumatic avulsions. The first goal of this application is to engineer an autologous muscle-cartilage implant progenitor cell-derived implant (MI) that, after implantation in an animal model, receives strong innervation and becomes functional when used to repair a large laryngeal defect. To do this, we will fabricate MIs within a customized collagen matrix and pre-treat MIs with factors in vitro that induce the MI muscle to express motor endplates. The MIs will be used to replace a partial laryngectomy defect in a porcine model, and post-implantation innervation status, based on laryngeal electromyography and quantification of motor endplates with nerve contact, will be determined. Using this animal implant model, outcomes with the study MIs will be compared to those of control MIs in environments with and without recurrent laryngeal nerve integrity. Findings from the proposed studies should overcome current major hurdles to developing a functional tissue engineered MCC for hemilaryngeal reconstruction—those hurdles being inadequate cartilaginous support, poor innervation of the muscle, suboptimal organization of myofibers, and asynchronous firing of the muscle with the native adductor muscle. Furthermore, because these studies are being done now in a large animal (porcine) model, with laryngeal size and function very similar to that of humans, findings will be highly translational. Results from these experiments should lead to landmark clinical innovations that will be relevant to both voice restoration applications, and muscle repair concepts globally.