EAGER: Microfabricated non-linear fractal architectures for propagation and differentiation of human neural progenitors

1144611/亚达瓦尔该奖项由美国国家科学基金会化学、生物工程、环境和运输部的生物技术、生化和生物质工程计划资助，旨在开发受生物启发的新型微制造网络，作为干细胞生长和分化的平台。开发成功的干细胞疗法的挑战包括设计和控制干细胞信号，以调节分化和自我更新之间的平衡。同样关键的是，知识库中存在的空白，基于在人类早期发展过程中引导自我更新和差异化的线索。神经网络形成的研究涉及控制神经细胞和前体细胞的空间位置和连接的能力。然而，由于建筑和功能的复杂性，这一点尤其具有挑战性。设计这类网络的第一步是为生长中的细胞提供拓扑和信号线索，以形成功能连接。在这些工程学考虑的背景下，研究人员通过建立一个仿生框架来模仿早期神经元的发育，神经前体可以根据该框架将自己组织成定向结构，如神经。他们假设，微型制造的非线性分形结构将促进一种放松的、自我支持的利基环境，这将促进与人类神经前体细胞(HNPs)的繁殖相关的细胞命运，并定向向神经元分化。这一提议的智力价值来自于超越现有的研究范式，这些范式侧重于为衬底上细胞的空间组织进行简单化的几何设计。通过模仿允许细胞扩散的生物网络，而不是将它们限制在凹槽或井中，非线性配置可以促进轻松、自我支持的干细胞生态位。通过底物的几何形状以及顺应性和粗糙度来定制非均匀粘附点，PI相信它们将实现多样化的微环境，促进神经前体细胞的繁殖和神经元分化。更广泛的研究影响来自于生物仿生学、微制造和干细胞生物学的整合，这将在应用组织工程以及理解基础神经元发育方面做出关键的变革性贡献。这项研究将导致合成新的仿生细胞培养平台，用于精确控制细胞的生长和间距，并对决定神经结构中组织特征和信号信号的机制产生新的见解，并将有助于神经修复的组织工程。更广泛的教育影响是，向更广泛的受众传播研究成果的巨大潜力，以及学生和普通公众对纳米技术和干细胞研究中最新的跨学科方法感到兴奋。这将通过将研究材料整合到由PI-ENGR 591-纳米生物技术概念和CLSE 561干细胞工程教授的课程内容中来实现。PIS还将参与VCU的暑期课程和其他外展计划，并将开发演讲和实验室模块，使高中生、本科生和普通公众受益。

1144611/ YadavalliThis EAGER award funded by the Biotechnology, Biochemical and Biomass Engineering Program in the Chemical, Bioengineering, Environmental and Transport Division of NSF seeks to develop novel bio-inspired microfabricated networks as platforms for stem cell growth and differentiation. Challenges in the development of successful stem cell therapies involve engineering and control of stem cell cues to regulate the balance between differentiation and self-renewal. Equally critical is the void that exists in the knowledge base on the cues that guide self-renewal and differentiation during early human development. The study of neural network formation involves the ability to control the spatial positioning and connectivity of neuronal cells and progenitors. However, this has been particularly challenging on account of complexity of architecture and function. A first step in designing such networks is to provide topological and signaling cues for the growing cells to form functional connections. In the context of these engineering considerations, the researchers play to mimick early neuronal development via the establishment of a biomimetic framework along which neural progenitors can organize themselves into oriented constructs as nerves. They hypothesize that microfabricated non-linear fractal architectures will promote a relaxed self-supportive niche that will promote cellular fate related to propagation of human neural progenitors (hNPs) and directed differentiation towards neurons. The intellectual merit of this proposal comes from going beyond existing research paradigms that focus on simplistic geometric designs for the spatial organization of cells on substrates. By mimicking a biological network that allows for spreading of the cells instead of confining them in a groove or a well, a nonlinear configuration can promote a relaxed, self-supportive stem cell niche. By the tailoring of non-homogeneous adhesion sites via the geometry and the compliance and roughness of the substrate, the PIs believe they will enable a versatile microenvironment that promotes neural progenitor propagation and neuronal differentiation. The broader research impact stems from the integration of biomimetics, microfabrication and stem cell biology which will make key transformative contributions in applied tissue engineering as well as understanding fundamental neuronal development. The proposed research will lead to synthesizing novel, biomimetic, cell culture platforms for the precise control of cell growth and spacing and yield new insights into the mechanisms determining the organizational features and signaling cues in neural architectures and will contribute to tissue engineering for nerve repair.. The broader educational impact is the enormous potential for communicating research findings to a wider audience and for students and the general public to get excited about the latest interdisciplinary approaches in nanotechnology and stem cell research. This will be achieved via integration of research material into course content taught by the PIs - ENGR 591-Concepts in Nanobiotechnology and CLSE 561 Stem Cell Engineering. The PIs will also be engaged in summer courses and other outreach programs at VCU and will develop presentation and laboratory modules that will benefit high school students, undergraduate students and the general public.