Collaborative Research: EAGER: Biomanufacturing: Bioengineering of 3-dimensional brain surrogate tissue models

PI: Demirci, utkanpi: Kaplan, David L.， Proposal Number: 1547806大脑中数以亿计的神经元在密集和纠缠的网络中的协调功能可以被看作是我们独特的高级意识的中心，也是我们对精神分裂症、自闭症和阿尔茨海默氏症等使人衰弱的疾病的脆弱性的中心。研究人员提出了一种独特的声波和丝蛋白生物材料的方法，在一个小盘子里重建复杂的三维大脑网络结构，并用它们来研究它们对脑震荡损伤的实验室模型的反应。通过这些研究，研究人员希望证明这些结构如何帮助科学家更好地理解大脑在健康和患病状态下的运作。大脑的复杂性为科学家研究大脑生理学的分子、细胞和回路水平的行为设置了很大的障碍。需要新的方法和技术来补充和推进现有的体内、体外和体外方法。该研究的目标是开发一种新的柔性生物打印平台，用于体外制造三维（3D）神经组织结构，忠实地模拟大脑中存在的3D电路的生物复杂性、发育、结构和功能。关键的创新包括声学生物模式策略和丝蛋白支架，用于将神经元封装在长寿命的3D多层结构中。为了原型化和验证该结构，研究人员提出了第一个目标，即创建由初级神经元构建的6层皮层回路。在第二个目标中，他们将使用综合神经技术工具箱检查3D电路组织的生理学。电生理学、荧光成像、基因组学和蛋白质组学方法将被用于评估体外3-D神经回路的功能和结构里程碑，包括脑损伤疾病模型。这种研究脑生理学和病理生理学的完全不同的方法有可能为神经科学提供新的工具，由于所提出的先进生物制造方法的普遍适用性，其效用扩展到其他领域。该提案的广泛影响包括高中，本科和研究生水平的科学家参与神经科学，组织工程和生物制造的交叉研究，从而为跨学科科学家的培训提供了一个有用的平台。

PI: Demirci, UtkanProposal Number: 1547791PI: Kaplan, David L. Proposal Number: 1547806 The coordinated function in the brain of billions of neurons in dense and entangled networks can be seen as the epicenter of our unique higher consciousness, as well as of our vulnerability to debilitating diseases, such as schizophrenia, autism and Alzheimer's. The investigators propose a unique approach of sound waves and silk protein biomaterials, to recreate the complex three-dimensional brain network structures in a small dish, and use them to investigate their response to a laboratory model of brain concussion damage. With these studies, the investigators aspire to demonstrate how these constructs may help scientists better understand the workings of the brain in healthy and diseased states.The complexity of the brain poses a large roadblock for scientists to examine molecular, cellular and circuit level behavior of brain physiology. Novel approaches and technologies are needed that complement and advance the existing in vivo, ex vivo and in vitro approaches. The goal of the proposed research is to develop a new flexible bioprinting platform for the in vitro fabrication of 3-dimensional (3D) neural tissue constructs that faithfully mimic the biological complexity, development, architecture and function of 3D circuits present in the brain. The key innovations include the strategy of acoustic biopatterning and silk protein scaffolds for encapsulating neurons in long-lived, 3D multilayered architectures. To prototype and validate the construct, the investigators propose in the first aim to create 6-layer cortical circuits built of primary neurons. In the second aim, they will examine the physiology of the 3D circuit tissues using a comprehensive neuro-technological tool-box. Electrophysiology, fluorescence imaging, genomics and proteomics approaches will be employed to evaluate functional and structural milestones of the developing in vitro 3-D neural circuits, including a brain damage disease model. This radically different approach for investigating brain physiology and pathophysiology has the potential to provide new tools for neuroscience, the utility of which extends to other fields because of the general applicability of the proposed advanced biomanufacturing approaches. The broader impact of this proposal includes the participation of high school, undergraduate and graduate level scientists in research at the intersection of neuroscience, tissue engineering and biomanufacturing, thus presenting a useful platform for the training of interdisciplinary scientists.