Collaborative Research: Modular, vascularized microphysiological systems to study the outer blood retinal barrier

某些血管组织，如外血视网膜屏障，由于主要的生理和解剖学差异，很难用动物模型进行研究。微生理系统(MPS)，也被称为组织芯片，是能够研究复杂组织系统的动物模型的替代方案。MPS可以将患者特定的干细胞整合到个性化药物中，并且很容易扩展到更大规模的研究。该项目将支持开发一种新的MPS，该MPS控制物理、生化和细胞信号提示，以指导微血管组织的发育，包括形成可灌流血管所需的提示。预计这项工作的成功完成将提供对物理、生化和细胞信号信号如何指导微血管发育的更多了解，并建立用于临床前药物测试的动物模型的替代方案。这项工作将支持对来自不同背景的初级科学家的培训，并为他们在研究和教育领域的职业生涯做好准备。调查人员积极主动地努力增加多样性，并让高中生接触到可能的STEM职业机会。此外，这项研究的结果将通过许多外展活动和计划共享，包括：向教师、本科生和高中生提供指导，以及在公共活动中发表讲话，如年度Benoit实验室Alex的柠檬水标准。组织工程和组织芯片技术的进步促进了微生理系统(MPS)作为临床前试验动物模型的替代方案的兴起。用于血管组织的MPS要么放弃了灌流的微血管系统，要么依赖过于简化的内皮细胞排列的流体通道。微血管组织是三维的，具有组织特有的分子运输、血管构筑和旁分泌-组织串扰特性。工程细胞外基质(EECM)由聚乙二醇水凝胶(PEG水凝胶)与基质金属蛋白酶(MMPs)可降解的多肽组成，并由细胞黏附配体功能化，可支持血管生成。在这个项目中，血管生成的eECM将被引入到一种新型的微血管网络开发的MPS中。具体地说，将探索压力/流量和eECM生物物理和生化线索，以指导骨、唾液腺和视网膜特异性的体内可灌流微血管的发展。成功完成提议的目标将阐明FLOW在微血管发育中的作用，推进MPSS的发展，并增强我们对介导内皮细胞血管生成的eECM生化信号的理解。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Certain vascularized tissues such as the outer blood retinal barrier are difficult to study using animal models due to major physiological and anatomical differences. Microphysiological systems (MPS), also known as tissue chips, are an alternative to animal models that enable the study of complex tissue systems. MPS can incorporate patient specific stem cells for personalized medicine and are easily scalable for larger scale investigations. This project will support the development of a new MPS that controls physical, biochemical, and cell signaling cues to guide the development of microvascular tissues, including the cues needed for forming perfusable blood vessels. It is expected that successful completion of this work will provide a greater understanding of how physical, biochemical, and cell signaling cues guide microvessel development and establish an alternative to animal models for pre-clinical drug testing. This work will support the training of junior scientists from diverse backgrounds and prepare them for careers in research and education. The Investigators are proactive in working to increase diversity and expose high school students to possible STEM career opportunities. Further, findings that are made from this research will be shared through numerous outreach activities and programs including: Teach the Teachers, undergraduate and high school student mentorship, and speaking at public engagements such as the Annual Benoit Laboratory Alex’s Lemonade Stand.Advances in tissue engineering and tissue chip technology have catalyzed the rise of microphysiological systems (MPS) as an alternative to animal models for preclinical testing. MPS for vascularized tissues either forego perfused microvasculature or rely on oversimplified endothelial cell-lined fluidic channels. Microvascular tissues are 3D and have tissue specific molecular transport, angioarchitectural, and paracrine-tissue crosstalk properties. Engineered extracellular matrices (eECM) comprised of poly(ethylene glycol) (PEG) hydrogels crosslinked with matrix metalloproteinase (MMP)-degradable peptides and functionalized with cell adhesive ligands have been shown to support vasculogenesis. In this project, vasculogenic eECM will be introduced into a novel MPS designed for microvascular network development. Specifically, pressure/flow and eECM biophysical and biochemical cues will be explored to guide the development of in vivo-like perfusable microvasculature specific to bone, salivary gland, and the retina. Successful completion of the proposed aims will elucidate the role of flow in microvascular development, advance the development of MPSs, and augment our understanding of the eECM biochemical cues that mediate endothelial cell vasculogenesis.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.