People with diseased or defective vital organs often need organ replacement to survive, but the availability of replacement organs is severely restricted by shortages of suitable tissue-matched donors and complexities such as postmortem organ deterioration and immunological rejection. These problems could be overcome by using high fidelity artificially-grown organs, but achieving that goal faces daunting and long-standing scientific and engineering challenges that this project aims to begin to meet. The project will focus on proof-of-concept generation of microscale patterns in a liver organoid to mimic the anatomical structure of lobules arranged in hexagonal patterns. The researchers will use microrobots to dynamically regulate gene expression in 3D vascularized liver organoids to generate the lobule like patterns. The results of this project will define a new area of robot-assisted biological design. This research will result in new biological rules, synthetic biology tools, and microrobotics that can be applied in numerous disciplines. If successful, another broader impact will be the demonstration of a method that could be used to create a new, in vitro, native-like organoid for biological and medical research, opening the door for research into the creation and repair of synthetic human organs. The project includes research training for graduate students and postdoctoral researchers.

Conventional methods of reproducing biological patterns in vitro suffer from multiple limitations. Previous research on pattern formation has largely relied on delivering global stimuli and studying reaction-diffusion mediated patterning of cell fates in the cell culture. Such methods yield only static patterns and give neither precise spatial nor temporal control over gene expression and resulting biological tissue formation. Current tissue engineering capabilities such as 3D printing and optogenetics are also unable to recapitulate the multiscale self-assembled patterns evident in native-like organs. The proposed approach will enable precise control of microrobots to achieve dynamic control over patterning in 3D biological systems, creating a paradigm shift in the field. The proof-of-concept goal is to modulate localized gene expression in engineered 3D tissue constructs to control the emergence of multiscale patterns. Machine learning will be used to derive and characterize desired multiscale patterns, synthetic biology to endow the stem cells with genetic circuits that can differentiate the cells to form desired tissue constructs, and microrobots to alter localized gene expression to form multiscale patterns in tissue constructs. In particular, the researchers will develop and control microrobots capable of sustaining and carrying engineered sender cells, drive the microrobots and associated sender cells within a vascularized 3D liver organoid to specific locations, and use the microrobot controlled sender cells to communicate with endothelial cells, inducing these endothelial cells to secrete Wnt and generate gradients controlling liver lobule zonation. This patterned lobule zonation will regulate the metabolic activity of the liver organoids.

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.

National Science Foundation (NSF)
Office of International and Integrative Activities (IIA)
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Dragana Brzakovic
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Massachusetts Institute of Technology
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