Engineering multifaceted 3D human organ platforms for toxicity testing

项目摘要 这一奖项将加速我的长期目标，即开发微生理系统，以改善人类 具有降低的毒性和对小动物模型的依赖的药理学功效。模型 体外心血管系统（血管、心肌、肾上腺髓质）主要限于简化的 2D结构，尚未评价组织-组织相互作用。因此，结构/功能关系， 并且由组织组织和神经支配驱动的细胞-细胞相互作用仍然知之甚少。因此，MPS 它概括了人类心血管系统的关键组成部分，包括生理学相关的剪切， 血流，氧饱和度，生物电刺激，原代人内皮细胞，平滑肌，心肌细胞， 嗜铬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、化合物筛选和生物医学研究。目前的MPS通常使用专门设备 和传统的微制造技术，通过软光刻与聚二甲基硅氧烷（PDMS），使 微流体管道困难以及几乎不可能的氧气控制，以及分析物损失的可能性。 因此，需要偏离PDMS的新的制造方法。我们的方法描述了 应用激光制造、切割和组装的MPS，实现完全人性化的系统。有一个科学 和临床迫切需要开发新的工具，以确定化合物的毒性和减少新的 临床试验期间的复合磨损。通过运用我在生物材料，器官芯片设计， 生物电子学和神经工程学，我们将加速开发强大的3D仪器化MPS 心血管系统的平台。在这个项目中解决的一个基本问题是， 在可扩展平台中集成用于神经、肾上腺和心脏刺激和记录的仪器 活性，以更好地阐明自主神经系统的影响和化合物的毒性。我们将利用 一个统计模型，以确定细胞命运，功能的驱动因素，并确定基于性别的差异反应， 自主神经平衡这些创新模型将整合干细胞领域的最新进展， 差异化和我们成熟的“切割和组装”制造方法，以广泛传播这些器官平台。

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.