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

合作研究：模块化、血管化的微生理系统研究外血视网膜屏障

• 批准号: 2308628
• 负责人: Danielle Benoit
• 金额: $ 51.8万
• 依托单位: University of Oregon Eugene
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2308628&HistoricalAwards=false
• 关键词: Collaborative; Research; Modular; vascularized; microphysiological

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.

由于主要的生理和解剖差异，某些血管组织（例如外血视网膜屏障）很难使用动物模型进行研究。微生理系统（MPS），也称为组织芯片，是动物模型的替代品，可以研究复杂的组织系统。MPS可以将患者特异性干细胞用于个性化医疗，并且易于扩展用于更大规模的研究。该项目将支持开发一种新的MPS，该MPS控制物理，生化和细胞信号传导线索，以指导微血管组织的发育，包括形成可灌注血管所需的线索。预计这项工作的成功完成将使人们更好地了解物理、生物化学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替代动物模型。这项工作将支持来自不同背景的年轻科学家的培训，并为他们从事研究和教育事业做好准备。调查人员积极主动地努力增加多样性，并使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分享，包括：教老师，本科生和高中生导师，组织工程和组织芯片技术的进步促进了微生理学系统（MPS）的兴起作为临床前试验动物模型的替代品。 用于血管化组织的MPS要么放弃灌注的微脉管系统，要么依赖于过度简化的内皮细胞内衬的流体通道。微血管组织是3D的，并且具有组织特异性分子运输、血管结构和旁分泌组织串扰特性。由与基质金属蛋白酶（MMP）可降解肽交联并用细胞粘附配体功能化的聚（乙二醇）（PEG）水凝胶组成的工程化细胞外基质（eECM）已显示支持血管发生。在这个项目中，血管生成eECM将被引入到一个新的MPS设计的微血管网络的发展。具体而言，将探索压力/流量和eECM生物物理和生物化学线索，以指导特定于骨、唾液腺和视网膜的体内样灌注微血管系统的发育。成功完成拟议的目标将阐明流动在微血管发育中的作用，推进MPS的发展，并增强我们对介导内皮细胞血管生成的eECM生化线索的理解。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。