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

某些血管化组织，如外血视网膜屏障，由于生理和解剖上的主要差异，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，是一种替代动物模型的方法，可以研究复杂的组织系统。MPS可以结合患者特异性干细胞进行个性化治疗，并且很容易扩展到更大规模的研究中。该项目将支持开发一种新的MPS，该MPS可以控制物理、生化和细胞信号信号，以指导微血管组织的发育，包括形成可灌注血管所需的信号。预计这项工作的成功完成将有助于更好地理解物理、生化和细胞信号传导线索如何指导微血管发育，并为临床前药物测试建立一种替代动物模型的方法。这项工作将支持培训来自不同背景的年轻科学家，并为他们从事研究和教育事业做好准备。调查人员积极致力于增加多样性，并使高中生接触到可能的STEM职业机会。此外，从这项研究中获得的发现将通过许多外展活动和项目分享，包括：教授教师，本科生和高中生指导，以及在公共活动中发表演讲，如年度Benoit实验室Alex的柠檬水摊。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。血管化组织的MPS要么放弃灌注的微血管，要么依赖于过度简化的内皮细胞排列的流体通道。微血管组织是三维的，具有组织特异性的分子运输、血管构建和旁腺组织串扰特性。工程细胞外基质（eECM）由聚乙二醇（PEG）水凝胶与基质金属蛋白酶（MMP）可降解肽交联组成，并与细胞粘附配体功能化，已被证明支持血管发生。在这个项目中，血管源性eECM将被引入到微血管网络发展的新型MPS中。具体来说，压力/流量和eECM生物物理和生化线索将被探索，以指导骨、唾液腺和视网膜特异性的体内样可灌注微血管的发展。成功完成上述目标将阐明血流在微血管发育中的作用，推进mps的发展，并增加我们对介导内皮细胞血管发生的eECM生化线索的理解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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.