Robotic micromanipulation for patterned and complex organoid biofabrication.

Abstract

Organoids have emerged as powerful models for recapitulating tissue physiology and pathology in biomedical research. However, the need for consistent and complex manufacturing of organoids remains a challenge. The absence of standardization and quality control of cells dispersed within extracellular matrices impedes the widespread application of organoids. Here, we introduce a micromanipulation platform that effectively constrains cell distribution to enable patterned and complex organoid biofabrication. This system integrates multidimensional cell sense technology to provide real-time feedback, enabling adaptive fluid dynamics control that robustly compensates for seeding-induced nonlinear fluidic perturbations. Through this closed-loop control, the micromanipulation platform effectively restrains the spatial distribution of multiple cell types, promoting consistent self-assembly. Using this platform, we have successfully achieved programmable organoid manufacturing as well as the construction of assembloids composed of multiple cell types that better mimic mature organ microenvironments. This supports advancements in organoid-based biomechanism discovery, drug screening, and other organoid-related investigations.