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Engineering multifaceted 3D human organ platforms for toxicity testing

设计用于毒性测试的多层面 3D 人体器官平台

基本信息

批准号：
10675647
负责人：
Ryan Alan Koppes
金额：
$ 39.25万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675647
关键词：
3-Dimensional Acceleration Address Adrenal Glands Adrenal Medulla Animal Model Automobile Driving Autonomic nervous system Award Biocompatible Materials Biological Assay Biomedical Research Blood Vessels Cardiac Cardiac Myocytes Cardiovascular Models Cardiovascular system Cell Communication Cells Chromaffin Cells Clinical Clinical Trials Development Endothelium Engineering Equilibrium Equipment Goals Healthcare Human In Vitro Lasers Measures Methods Microfabrication Microfluidics Modeling Myocardium Neurons Organ Oxygen Physiological Plumbing Scientific Advances and Accomplishments Smooth Muscle Statistical Models Structure System Techniques Testing Therapeutic Time Tissues Toxic effect Toxicity Tests Work bioelectricity bioelectronics design fabrication improved innovation innovative technologies instrument instrumentation lithography microphysiology system nerve supply neural pharmacologic polydimethylsiloxane response screening sex stem cell differentiation three dimensional cell culture tool

项目摘要

PROJECT SUMMARY This award will accelerate my long-term goal to develop microphysiological systems to improve human pharmacological efficacy with reduced toxicity and reliance on small animal models. Models of the cardiovascular system (vascular, myocardium, adrenal medulla) in vitro have primarily been limited to simplified 2D structures and have not evaluated for tissue-tissue interactions. As such, the structure/function relationships, and the cell-cell interactions driven by tissue organization and innervation remain poorly understood. Thus, MPS that recapitulates key components of the human cardiovascular system, including physiologically relevant shear flow, oxygen saturation, bioelectric stimulation, primary human endothelial, smooth muscle, cardiomyocytes, chromaffin cells, and human autonomic neurons would be a valuable tool for advancing scientific discovery, healthcare, compound screening, and biomedical research. Current MPS generally utilize specialized equipment and traditional microfabrication techniques via soft lithography with polydimethylsiloxane (PDMS), making microfluidic plumbing difficult as well as nearly impossible control of oxygen, and potential for analyte loss. Therefore, new fabrication approaches that deviate from PDMS are needed. Our approach here describes the application of a laser-fabricated, cut and assembled MPS for a fully humanized system. There is a scientific and clinical urgency for the development of new tools to identify compound toxicity and decrease new compound attrition during clinical trials. By applying my strengths in biomaterials, organ-chip design, bioelectronics, and neuroengineering, we will accelerate the development of robust 3D, instrumented MPS platforms of the cardiovascular system. A fundamental issue addressed in this project will be the ability to integrate, in a scalable platform, instrumentation for stimulation and recording of neural, adrenal, and cardiac activity to better elucidate the impact of the autonomic nervous system and compound toxicity. We will harness a statistical model to identify driving factors in cell fate, function, and identify sex-based differential responses in autonomic balance on the MPS. These innovative models will integrate recent advances in stem cell differentiation and our proven ‘cut & assemble’ fabrication method to broadly disseminate these organ platforms.

项目总结