A Hydrogel-Based Cellular Model of the Human Vocal Fold

基于水凝胶的人类声带细胞模型

• 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
• 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

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