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.

项目摘要 该奖项将加速我的长期目标，以开发微生物生理系统以改善人类 药理学效率，降低了小动物模型的毒性和缓解。模型 体外的心血管系统（血管，心肌，肾上腺髓质）主要仅限于简化 2D结构，尚未评估组织组织相互作用。因此，结构/功能关系， 并且由组织组织驱动和神经驱动的细胞 - 细胞相互作用仍然鲜为人知。那，国会议员 这概括了人类心血管系统的关键组成部分，包括与物理相关的剪切 流动，氧饱和度，生物电刺激，原发性人体内皮，平滑肌，心肌细胞， 铬蛋白细胞和人类自主神经元将是推进科学发现的宝贵工具， 医疗保健，化合物筛查和生物医学研究。当前的国会议员通常使用专用设备 和传统的微型制造技术通过岩石摄影与聚二甲基硅氧烷（PDMS）一起制造，制造 微流体水暖难度以及几乎不可能控制氧气，以及分析物损失的潜力。 因此，需要使用偏离PDM的新制造方法。我们在这里的方法描述了 将激光制造，切割和组装的MPS应用于完全人性化的系统。有科学 以及开发新工具以识别复合毒性并降低新工具的临床紧迫性 临床试验期间的复合属性。通过将我的优势应用于生物材料，器官芯片设计， 生物电子学和神经工程，我们将加速3D鲁棒的仪器MPS的发展 心血管系统的平台。该项目中解决的一个基本问题将是能够 在可扩展平台中整合用于刺激和记录神经，肾上腺和心脏的仪器 活动以更好地阐明自主神经系统和复合毒性的影响。我们会利用的 一个统计模型，以识别细胞命运，功能和确定基于性别的差异反应中的驱动因素 国会议员的自主平衡。这些创新模型将整合干细胞的最新进展 分化和我们经过验证的“切割和组装”制造方法，可以广泛传播这些器官平台。