Tissue engineering to regenerate functional vocal fold after scarring or tissue loss

摘要 因外伤或喉癌而丧失喉声带覆盖的患者 可能会有发音困难，治疗方案有限。可植入 振动替代组织将彻底改变喉部疾病的治疗。 在这个建议中所描述的工作优化了基于细胞的外声带 本实验室开发的替代（COVR），确定其在动物中的功能 模型，并确定其潜在的临床应用。分离的成人干细胞 在纤维蛋白水凝胶内培养， 适于声带植入的组织替代物。 初步工作已经开发出COVR并将其植入兔子体内， 振动函数这项工作计划系统地研究关键问题， 用于声褶替换。宿主与植入细胞和基质的相互作用将被 定义了将评估既存瘢痕环境和性别的影响。 将促进细胞外基质再生并量化机械行为。 成功完成拟议的研究将推进组织工程声乐 转向人工翻译。这项工作将定义合适的临床场景（现有 瘢痕与新鲜组织切除），最大化组织模仿正常声带， 确定COVR改善声带伤口愈合的机制， 对照本提案中的动物研究将提供必要的信息， 进行正式的临床前试验。

ABSTRACT Patients suffering loss of the larynx’s vocal fold cover due to trauma or laryngeal cancer can suffer disabling voice difficulties, and treatment options are limited. An implantable vibrating replacement tissue would revolutionize the treatment of laryngeal disorders. The work described in this proposal optimizes a Cell-based Outer Vocal fold Replacement (COVR) developed by this laboratory, identifies its functions in an animal model, and defines its potential clinical applications. Adult human stem cells isolated from adipose tissue are cultured within fibrin hydrogel to produce a three-dimensional tissue substitute suitable for vocal fold implantation. Preliminary work has developed and implanted the COVR in rabbits, finding excellent vibrational function. This work plans the systematic study of critical questions remaining for vocal fold replacement. Host interactions with implanted cells and matrix will be defined. Influence of pre-existing scar environment and sex will be assessed. Extracellular matrix regeneration will be promoted and mechanical behavior quantified. Successful completion of the proposed research will advance a tissue-engineered vocal fold towards human translation. This work will define suitable clinical scenarios (existing scar versus fresh tissue resection), maximize tissue mimicry of normal vocal folds, and identify mechanisms by which the COVR improves vocal fold wound healing relative to controls. The animal studies in this proposal will provide necessary information to proceed with formal pre-clinical trials.