Controlling Cellular Fate using Micromachines

项目摘要 多细胞的关键是组成身体的各种细胞之间的协调互动。事实上， 胚胎的形成、细胞类型多样性的建立以及组织和器官的形成都依赖于细胞间的相互作用。 通信因此，可以说生物学最重要的原则之一涉及“一组细胞 改变相邻细胞的行为，导致它们改变形状、有丝分裂速率或命运。 在体外复制生物模式和细胞命运的常规方法受到多种限制。 以前关于理解模式形成的工作依赖于提供全局刺激和研究反应- 扩散介导的细胞培养物中细胞命运的模式化。另一种方法是生成形态素 使用信号分子图案化表面或光遗传学梯度。然而，所有现有方法都产生 静态的模式，既不精确的空间也不对细胞的命运进行时间控制。 我的研究小组旨在通过一个独特而新颖的网络生物系统来克服这一关键挑战， 微型机器人以闭环方式引导生物系统，以实现特定位置的功能， 减少噪音-引导细胞命运，导致细胞结构的形成。灵感来自于“人在其中” 循环”的方法，工程系统必须与复杂的，生活的个人，我们提出了一个 “微机器人在环”方法，其中细胞之间的物理信号被微机器人控制的 输入，以提供优异的时空精度和反馈控制，指导细胞的行为。 我们在未来五年的努力将集中在设计和制造微型机器人沿着 微型机器人自动驱动的控制算法。我们会用这些微型机器人 在细胞系统中的精确位置处的形态发生素，其将仅在那些位置处改变细胞命运。我们 也将使用这种技术来控制多层蜂窝结构的形成。我们将扩展 这是通过将微型机器人与类器官连接到三维组织。 这项工作很重要，因为它将证明组织体积中的单个细胞是如何被激活的。 在空间和时间上被定位用于操纵。此方法对以下内容应用了更多动态控制： 分化因子，这允许增加对复杂的细胞命运和分化的理解 癌症、发展或纤维化期间的事件，只是许多应用中的几个。

PROJECT SUMMARY Key to multicellularity is the coordinated interaction of the various cells that make up the body. Indeed, patterning of embryos, establishment of cell type diversity, and formation of tissues and organs all rely on cell-to-cell communication. Thus, arguably one of the most important principles of biology involves “one group of cells changing the behavior of an adjacent set of cells, causing them to change their shape, mitotic rate, or fate”. Conventional methods of reproducing biological patterns and cell-fate in vitro suffer from multiple limitations. Previous work on understanding pattern formation has relied on delivering global stimuli and studying reaction- diffusion mediated patterning of cell fates in the cell culture. Another method has been to generate morphogen gradients using signaling molecule patterned surface or optogenetics. However, all current methods produce static patterns and give neither precise spatial nor temporal control over the cell fate. My research group aims to overcome this critical challenge, via a unique and novel cyber-bio system, in which microrobots direct the biological system, in a closed loop approach, to enable position-specific functionality and reduce noise – to direct cellular fate leading to the formation of cellular structures. Inspired by “human-in-the loop” approaches for engineering systems that must interact with complex, living individuals, we propose a “µrobot-in-the-loop” approach in which physical signaling among cells is substituted with microrobot-controlled inputs to afford excellent spatiotemporal precision and feedback control in directing cell behavior. Our efforts in the next five years would focus on designing and fabricating microrobots along with developing control algorithms for automated actuation of the microrobots. We will use these microrobots to deliver morphogens at precise positions in a cellular system which would alter cell fate at those positions only. We would also use this technology for controlling the formation of multilayer cellular structures. We would extend this to three dimensional tissues by interfacing microrobots with organoids. The proposed work is important because it would demonstrate how individual cells in a tissue volume can be spatially and temporally targeted for manipulation. This methodology applies more dynamic control over differentiation factors, which allows for increased understanding of complicated cell fate and differentiation events during cancer, development, or fibrosis as just a few of many applications.