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A Hydrogel-Based Cellular Model of the Human Vocal Fold

基于水凝胶的人类声带细胞模型

基本信息

批准号：
10604269
负责人：
Xinqiao Jia
金额：
$ 49.67万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604269
关键词：
Acoustics Adopted Affect Aging Air Air Movements American Animal Model Apoptosis Architecture Basement membrane Biochemical Biology Biomechanics Biophysics Calibration Cell model Cells Cellular Morphology Chemical Exposure Chemicals Cicatrix Clinical Communities Connective Tissue Consensus Cues Custom Data Decision Making Deposition Development Disease Elasticity Engineering Epithelial Cells Epithelium Extracellular Matrix FGF2 gene FUS-1 Protein Fibroblasts Fibrosis Functional disorder Future Gene Expression Growth Factor Health Human Hydrogels In Situ In Vitro Intervention Lamina Propria Larynx Ligation Lung Mechanical Stress Mechanics Mesenchymal Mesenchymal Stem Cells Methodology Methods Microfluidic Microchips Microfluidics Modeling Molecular Monitor Motion Multipotent Stem Cells Muscle Myofibroblast Operative Surgical Procedures Organ Parents Pathologic Permeability Pharmaceutical Preparations Pharmacotherapy Phenotype Phonation Physiological Physiology Pliability Predisposition Process Proliferating Property Protein Kinase Research Side Signal Transduction Stratified Epithelium Stratified Squamous Epithelium Stream Structure TGFB1 gene Testing Therapeutic Tissue Engineering Tissue Microarray Tissue Model Tissues Trachea Treatment Efficacy Voice cytokine design efficacious treatment epithelial injury fasudil fibrogenesis fundamental research graphene healing human tissue improved induced pluripotent stem cell inhibitor interfacial interstitial mechanical properties mimetics miniaturize pharmacologic prevent real time monitoring repaired rho sensor sound spatiotemporal tissue injury vocal cord vocalis muscle wound healing

项目摘要

Project Summary Voice is produced when the vocal folds are driven into a wave-like motion by the airstream from the trachea, converting aerodynamic energy and airflow into acoustic energy in the form of sound. Each vocal fold consists of a pliable vibratory layer of connective tissue, known as the lamina propria (LP), sandwiched between a muscle and a stratified squamous epithelium (EP). Numerous environmental, mechanical and pathological factors can damage this delicate tissue, resulting in vocal fold scarring that affects millions of Americans with limited treatment options. Although there is a general consensus on the pathophysiology of vocal fold scarring, the molecular and cellular mechanisms that control unremitting fibrosis remain poorly understood. Studies on other fibrotic diseases suggest that fibroblasts, epithelial cells and the interstitial matrix are active players in fibrogenesis. This project aims to engineer a reliable, physiologically relevant in vitro tissue model that can be used to investigate vocal fold development, health, and disease, and more importantly, to facilitate the development and testing of new treatment options. We propose to develop a microengineered organ chip that integrates the epithelial and mesenchymal cells in a tissue-mimetic configuration with built-in airflow to stimulate phonation. Using the microfluidic model, we will investigate how damage to the epithelium initiates fibrosis, how the fibrotic extracellular matrix (ECM) sustains fibrosis and how myofibroblast proliferation and matrix deposition continue unabated. Finally, we will calibrate our model with an antifibrotic growth factor that has shown efficacy in treating vocal fold scarring, and test a promising pharmacological inhibitor that has not been previously tested in the context of vocal fold scarring. Highly efficient bioorthogonal tetrazine ligation will be used to establish the initial LP matrix surrounding healthy fibroblasts and to introduce compositional and mechanical alterations that promote fibroblast activation. Pluripotent and multipotent stem cells will be guided to differentiate into vocal fold- like epithelial cells and fibroblasts by adopting a development paradigm and through systematic manipulation of the engineered microenvironment. Piezoresistive strain sensors embedded in the sidewalls of the microfluidic channels will be used to monitor tissue stiffness and EP permeability in situ. The microengineered tissue model will be characterized in terms of cell phenotype, microstructure, mechanical properties and physiological function. For comparison purposes, a stand-alone, human-sized vocal fold model will be developed and characterized employing methodologies established in the laryngology field. Data generated from this project should significantly impact fundamental research related to vocal fold scarring and provide critical information on therapeutic decision-making in the near future.

项目总结