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（应用程序提供）：毁灭性的语音损失（吞咽困难或厌食症）每年会影响美国成千上万的人接受创伤性或肿瘤学部分喉切除术，或者由于声带瘫痪而遭受肌肉量的损失。这些患者的语音恢复选择是次优的，因此，大多数患者将遭受永久性的语音丧失和沟通障碍。该应用程序引入了一种新颖的方法，用于恢复直接声带损伤和/或神经保护后的声带肌肉量和功能。结果可能会导致患有声带瘫痪和/或患有半乳腺切除术，脐带切除术或创伤性撕脱的患者的语音恢复手术选择。该应用的第一个目标是开发肌肉祖细胞衍生的植入物（MI），该植入物在动物模型中植入后会受到强大的神经。具体而言，将确定肌纤维运动端机表达对MIS植入后神经支配的影响。为此，我们将与体外因素进行制造和预处理，以诱导MI肌肉表达运动终结物。将根据喉肌电图和具有神经接触的运动终结量的数量来确定MIS将用于替代合成大鼠模型中的部分喉切除术缺陷，并替代植入后的神经支配状态。使用该动物植入物模型，将进行研究的结果将与在有或没有复发性喉神经完整性的环境中的控制MIS进行比较。该应用程序的下一个目标是在定制的胶原蛋白基质中开发MI，并确定这种方法是否有助于改善肌肉纤维的比对，并在用于修复喉部肌肉缺陷时增强肌肉体积。为了实现这些目标，将使用胶原蛋白聚合物来创建MIS，以表现出自组装和分层工程设计的胶原纤维材料材料，以指导细胞命运，从而支持形成肌肉纤维的尺寸，肌化纤维密度和对齐，并模仿本机vocal suscle肌肉的特征。同样，使用动物模型，将基于胶原蛋白的MIS的结果与具有和没有复发性喉神经完整性的环境中的控制MIS进行比较。拟议的研究的发现应克服当前的主要障碍，以开发功能性组织工程的MCC，用于半叶脊髓重建的障碍，即肌肉的神经支配不足，肌纤维的次优组织，以及与天然肌肉发射肌肉的肌肉发射。此外，这些最初实验的结果应导致具有里程碑意义的临床创新，这将与语音恢复应用和全球肌肉修复概念相关。