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Regeneration of Multi-Layered Vocal Fold Mucosa

多层声带粘膜的再生

基本信息

批准号：
9982291
负责人：
Nathan Welham
金额：
$ 58.64万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982291
关键词：
3-Dimensional Adaptive Immune System Allografting Animal Model Biocompatible Materials Biological Biology Biomechanics Canis familiaris Cell Culture Techniques Cells Clinic Clinical Clinical Trials Collection Data Disease Dysphonia Engineering Environment Epithelial Cells Evaluation Excision Extracellular Matrix Fibroblasts Funding Future Goals Graft Survival Grant Human Immune response Immunologics Immunology Impairment Implant In Vitro Injections Injury Interdisciplinary Study Investigational Drugs Isotope Labeling Lamina Propria Longitudinal Studies Measurement Medial Modeling Morphology Mucous Membrane Natural regeneration Nature Outcome Output Patients Performance Phase Physiological Polysaccharides Positioning Attribute Preparation Process Proteins Proteome Proteomics Quality Control Quality of life Research Rheology Safety Series Structure System Technology Time Tissue Engineering Tissue Grafts Tissues Transgenic Mice Trauma Voice Work adaptive immune response biological systems clinical application clinical implementation clinical predictors clinical translation clinically significant cohesion crosslink experimental study handicapping condition human tissue immunogenicity implantation improved in vivo insight meetings mouse model pre-clinical preclinical efficacy preclinical safety regenerative residence response restoration scaffold statistics viscoelasticity vocal cord

项目摘要

Severe vocal fold (VF) mucosal injury and its associated voice impairment (dysphonia) is a debilitating and challenging clinical problem with few treatment options, none of which are consistently effective. In patients with such tissue impairment or loss, an engineered VF mucosa would provide a biomechanically appropriate tissue graft for voice restoration. During our previous funding cycle, we engineered such a VF mucosa via organotypic culture of primary vocal fold fibroblasts and epithelial cells from human donors. In a series of preclinical experiments, the engineered mucosa recapitulated the structure and physiologic function of native human tissue. In the current application, we propose a natural extension of our prior work by advancing characterization of the in vitro tissue engineering process at the biological system level (Aim 1), studying remodeling and the adaptive immune response to the engineered mucosa following in vivo heterotopic implantation (Aim 2), and studying long-term physiologic and immunologic outcomes following in vivo orthotopic implantation (Aim 3). These experiments will generate important preclinical safety and efficacy data. We will combine the planned experimental work with regulatory and clinical manufacturing milestones (Aim 4), with a final goal of holding a pre-Investigational New Drug meeting with the FDA by the end of the grant. The tissue engineering technology outlined in this application has the potential to transform treatment of the most recalcitrant VF tissue disorders encountered in the clinic.

严重的声带（VF）粘膜损伤及其相关的语音障碍（发音困难）是一种使人衰弱的，具有挑战性的临床问题，治疗选择很少，没有一种是持续有效的。在这种组织损伤或损失的情况下，工程化VF粘膜将提供生物力学上合适的组织相容性。组织移植用于声音恢复。在我们之前的资助周期中，我们通过来自人类供体的原代声带成纤维细胞和上皮细胞的器官型培养。在临床前实验中，工程化粘膜重现了天然粘膜的结构和生理功能，人体组织。在当前的应用中，我们提出通过推进我们之前工作的自然扩展在生物系统水平上表征体外组织工程过程（目标1），研究体内异位后工程粘膜的重建和适应性免疫应答植入（目标2），并研究体内植入后的长期生理和免疫结果这些实验将产生重要的临床前安全性和功效数据。我们将联合收割机计划的实验工作与监管和临床生产里程碑（目标4）相结合，最终目标是在拨款结束前与FDA举行一次新药研究前会议。本申请中概述的组织工程技术有可能改变大多数临床上遇到的易发性VF组织疾病。