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

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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.