Muscle progenitor cell-based implants for dynamic laryngeal muscle reconstruction

用于动态喉肌重建的肌肉祖细胞植入物

• 批准号: 9305034
• 负责人: Stacey L. Halum
• 金额: $ 43.09万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305034
• 关键词: 3-Dimensional; Adipose tissue; Adult; Animal Model; Animals; Aphonia; Autologous; Cells; Characteristics; Clinical; Collagen; Collagen Fibril; Communication impairment; Cordectomy; Custom; Data; Defect; Denervation; Dysphonia; Electromyography; Engineering; Environment; Exhibits; Expressed Emotion; Fiber; Goals; Human; Implant; In Vitro; Individual; Injury; Laryngeal Injury; Laryngeal muscle structure; Laryngectomy; Larynx; Lead; Left; Literature; Malignant Neoplasms; Medial; Methods; Modeling; Motion; Motor; Motor Endplate; Muscle; Muscle Fibers; Muscle satellite cell; Nerve; Neuromuscular research; Operative Surgical Procedures; Organ; Outcome; Paralysed; Patients; Pattern; Personality; Polymers; Positioning Attribute; Rattus; Recurrent Laryngeal Nerve; Reporting; Stem cells; Surface; Tissue Engineering; Trauma; United States; Voice; base; density; design; engineering design; experience; experimental study; functional restoration; implantation; improved; in vivo; innovation; instrument; muscle engineering; nerve injury; nerve supply; novel; novel strategies; public health relevance; reconstruction; repaired; restoration; scaffold; self assembly; vocal cord

 DESCRIPTION (provided by applicant): 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 develop a muscle progenitor cell-derived implant (MI) that, after implantation in an animal model, receives strong innervation. Specifically, the effect of myofiber motor endplate expression on post-implantation innervation of MIs will be determined. To do this, we will fabricate 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 syngeneic rat 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. The next goal of this application is to develop a MI within a customized collagen matrix, and determine if this approach will facilitate improved alignment of muscle fibers and enhanced muscle volume when used to repair laryngeal muscle defects. To reach these goals, MIs will be created with collagen polymers exhibiting self-assembly and hierarchical engineering design of collagen fibril matrices to guide cell fate, and thereby facilitating formation of muscle fibers wih size, myofiber density, and alignment that mimics the characteristics of the native vocal fold muscle. Again, using an animal model, outcomes with the collagen based 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 innervation of the muscle, suboptimal organization of myofibers, and asynchronous firing of the muscle with the native adductor muscle. Furthermore, results from these initial experiments should lead to landmark clinical innovations that will be relevant to both voice restoration applications, and muscle repair concepts globally.

 描述（由申请人提供）：毁灭性的失声（发声困难或失音）每年影响着美国成千上万的人，他们接受创伤性或肿瘤性部分喉切除术，或因声带麻痹而遭受肌肉体积损失。这些患者的声音恢复方案并不理想，因此，大多数患者都会出现永久性的失声和沟通障碍。本申请介绍了一种在直接声带损伤和/或去神经支配后恢复声带肌肉体积和功能的新方法。结果可能会改善患有声带麻痹和/或接受过半喉切除术、脊髓切除术或创伤性撕脱伤的患者的声音恢复手术选择。该应用的第一个目标是开发一种肌肉祖细胞衍生的植入物（MI），在植入动物模型后，该植入物会受到强烈的神经支配。具体来说，将确定肌纤维运动终板表达对 MI 植入后神经支配的影响。为此，我们将用体外因子制备和预处理 MI，诱导 MI 肌肉表达运动终板。 MI 将用于替代同基因大鼠模型中的部分喉切除术缺陷，并将根据喉肌电图和神经接触运动终板的量化来确定植入后神经支配状态。使用这种动物植入模型，研究 MI 的结果将与在有或没有喉返神经完整性的环境中对照 MI 的结果进行比较。该应用的下一个目标是在定制的胶原蛋白基质内开发 MI，并确定这种方法在用于修复喉部肌肉缺陷时是否有助于改善肌纤维的排列并增强肌肉体积。为了实现这些目标，将使用胶原蛋白聚合物来创建 MI，该聚合物表现出胶原纤维基质的自组装和分层工程设计，以指导细胞命运，从而促进具有模仿天然声带肌肉特征的尺寸、肌纤维密度和排列的肌纤维的形成。同样，使用动物模型，将基于胶原蛋白的 MI 的结果与在有或没有喉返神经完整性的环境中对照 MI 的结果进行比较。拟议研究的结果应该克服目前开发用于半喉重建的功能性组织工程 MCC 的主要障碍，这些障碍包括肌肉神经支配不足、肌纤维组织不理想以及肌肉与天然内收肌的异步发射。此外，这些初步实验的结果应该会带来具有里程碑意义的临床创新，这些创新将与全球语音恢复应用和肌肉修复概念相关。