RECODE: Materials-directed differentiation of intestinal organoids of uniform size and shape

类器官是模拟器官功能的实验室生长的细胞簇。它们通常由嵌入三维（3D）支架中的干细胞生长而成。类器官可以帮助筛选个性化药物的新药，并修复受损的组织。类器官再现性对于这些应用至关重要。该项目将开发新的知识和工具，以指导统一的肠道类器官的生产。 在3-D和真实的时间内跟踪修饰的人类肠道干细胞，将指示每个细胞的分化轨迹。此外，将研究类器官周围的机械力的影响，并调节机械特性以驱动分化。该项目将开发新的生物材料和成像技术，并招募多元化的劳动力进入这一新兴领域。类器官代表了体外研究器官结构和功能的最先进系统。它们有几个缺点。没有两个类器官在结构或功能上是相同的。它们只能达到有限的成熟程度。为了解决这些限制，该RECODE项目的目标是开发高度可控的肠道类器官培养系统。初始条件和动态力学环境对类器官发育的影响将被研究。基于生物材料的策略将以阵列化的高通量方式对肠类器官生长、对称性破坏和隐窝图案化施加外在控制。研究围绕三个目标展开。目的1：培养均匀的肠道类器官集落阵列，研究基质力学对类器官生长和细胞命运的影响。目标2：在类器官分化过程中，局部基质力学中的光图案变化指导对称性破缺事件。目的3：研究将肠类器官培养成管状结构的方法，以允许长期培养。这项研究的结果广泛适用于类器官研究领域，因为这些相同的规则可以应用于其他形状和类器官系统。这项工作还探讨了与对称性破缺有关的生命科学“规则”，跨尺度的模式形成和自组装，可以提供类器官系统的定向开发。该项目由ENG/CBET的工程生物学和健康集群以及ENG/CBET的生物力学和机械生物学项目联合支持。该奖项反映了NSF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。

Organoids are lab-grown clusters of cells that mimic organ functions. They are often grown from stem cells that are embedded in three-dimensional (3D) scaffolds. Organoids could help screen new drugs for personalized medicine and repair damaged tissue. Organoid reproducibility is critical for these applications. This project will develop new knowledge and tools to direct the production of uniform intestinal organoids. Tracking of modified human intestinal stem cells, in 3-D and real time, will indicate the differentiation trajectory of each cell. In addition, the effects of mechanical forces surrounding the organoid will be investigated and mechanical properties will be modulated to drive differentiation. The project will develop new biomaterial and imaging technologies, as well as recruit a diverse workforce into this emerging field.Organoids represent state-of-the-art systems for studying organ structure and function in vitro. They have several shortcomings. No two organoids are structurally or functionally identical. They can only achieve a limited extent of maturity. To address these limitations, the objective of this RECODE project is to develop a highly controllable intestinal organoid culture system. The influences that initial conditions and dynamic mechanical environment exert on organoid development will be investigated. Biomaterials-based strategies will exert extrinsic control over intestinal organoid growth, symmetry breaking, and crypt patterning in an arrayed, high throughput fashion. The research is organized around three objectives. Objective 1: Grow arrays of uniform intestinal organoid colonies and study the effects of matrix mechanics on organoid growth and cell fate. Objective 2: Photopattern changes in local matrix mechanics to direct symmetry breaking events during organoid differentiation. Objective 3: Investigate methods to grow intestinal organoids into tubular structures that will allow for long-term culture. The outcomes of this research are broadly applicable to the field of organoid studies, as these same rules can be applied to other shapes and organoid systems. This work also probes life science ‘rules’ related to symmetry breaking, pattern formation and self-assembly across scales that could provide directed development of organoid systems.This project is being jointly supported by the Engineering Biology and Health Cluster in ENG/CBET and the Biomechanics and Mechanobiology Program in ENG/CMMI.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.