Muscle progenitor cell-based implants for dynamic laryngeal muscle reconstruction

项目摘要 毁灭性的声音丧失（发音困难或失声）影响了美国成千上万的人。 国家每年接受创伤或肿瘤部分喉切除术，或遭受肌肉 声带麻痹导致的音量损失这些患者的声音恢复选择是 次优，因此，大多数患者留下永久性的声音损失和沟通 损伤这个应用程序介绍了一种新的方法来恢复声带肌肉体积 和/或去神经支配后的功能。结果可能导致改善 声带麻痹和/或经历过声带麻痹的患者的声音恢复手术选择 半喉切除术、声带切除术或创伤性撕脱。此应用程序的第一个目标是 工程化自体肌肉-软骨植入物祖细胞衍生的植入物（MI）， 植入动物模型中，接受强神经支配并在使用时变得有功能 修复一个巨大的喉部缺损为此，我们将在定制的胶原蛋白中制造MI 基质和用体外诱导MI肌肉表达运动的因子预处理MI 终板MI将用于置换猪模型中的部分喉切除术缺损， 植入后神经支配状态，基于喉肌电图和定量 运动终板与神经接触，将被确定。使用这种动物植入模型， 研究MI的结果将与环境中的对照MI进行比较， 没有喉返神经的完整性。拟议研究的结果应克服 目前主要的障碍是开发一种功能性组织工程MCC用于半喉 重建-这些障碍是软骨支持不足， 肌肉，肌纤维的次优组织，以及肌肉与 天然内收肌此外，由于这些研究目前正在大规模进行， 动物（猪）模型，喉的大小和功能与人类非常相似，结果 将是高度可转换的。这些实验的结果将导致具有里程碑意义的临床研究。 创新，将相关的声音恢复应用，和肌肉修复， 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.