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

• 批准号: 10275117
• 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
• 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/10275117
• 关键词: 3-Dimensional; 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; Pharmacology; Physiological; Plumbing; Scientific Advances and Accomplishments; Smooth Muscle; Statistical Models; Structure; Structure-Activity Relationship; System; Techniques; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicity Tests; Work; base; bioelectricity; design; improved; innovation; innovative technologies; instrument; instrumentation; lithography; microphysiology system; nerve supply; polydimethylsiloxane; relating to nervous system; response; screening; sex; stem cell differentiation; three dimensional cell culture; tool

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 这一奖项将加速我开发微生理系统以改善人类健康的长期目标 降低毒性和对小动物模型的依赖的药理功效。的模型 心血管系统(血管、心肌、肾上腺髓质)的体外研究主要局限于简化 2D结构，尚未对组织-组织相互作用进行评估。因此，结构/功能关系， 而由组织组织和神经支配驱动的细胞间相互作用仍然知之甚少。因此，国会议员 它概括了人类心血管系统的关键组成部分，包括生理上相关的剪切力 血流量，血氧饱和度，生物电刺激，原代人体内皮细胞，平滑肌，心肌细胞， 嗜铬细胞和人类自主神经细胞将是推动科学发现的宝贵工具， 医疗保健、化合物筛选和生物医学研究。目前的MPS一般使用专门的设备 和传统的通过聚二甲基硅氧烷(PDMS)软光刻的微细加工技术，制造 微流控管道难以控制氧气，也几乎不可能控制氧气，并有可能造成分析物损失。 因此，需要偏离PDMS的新的制造方法。我们在这里的方法描述了 激光制造、切割和组装的MPS应用于完全人性化的系统。有一种科学的 以及临床上迫切需要开发新的工具来识别化合物毒性并减少新的 临床试验期间的化合物磨损。通过运用我在生物材料、器官芯片设计方面的长处， 生物电子学和神经工程学，我们将加快开发强大的3D、仪表化MPS 心血管系统的平台。该项目解决的一个根本问题将是能够 在可扩展平台中集成用于刺激和记录神经、肾上腺和心脏的仪器 活动，以更好地阐明对自主神经系统和化合物毒性的影响。我们会驾驭 一种统计模型来确定细胞命运、功能的驱动因素，并确定基于性别的差异反应 下院议员的自主平衡。这些创新模型将整合干细胞领域的最新进展。 差异化和我们久经考验的“切割和组装”制造方法来广泛传播这些器官平台。