(1075-B) Functional perfused human tissue models via 3D soft microfluidics

Abstract: The vascularization of engineered tissues and organoids remains a major challenge in developing physiologically relevant in vitro models that fully capture the complexity of human tissues and organs.
Although multiple approaches have been developed to vascularize in vitro tissues, generating dense networks of small-scale vessels to provide physiologically relevant perfusion of large de novo tissues has proven challenging. It has therefore not been possible to culture large 3D tissues thus far.
Here, we develop LiveGrid, a perfused-organ-on-chip platform suitable for generating and maintaining tissues derived from pluripotent or primary cells. This 3D microfluidic approach based on 2-photon laser stereo-lithography allows the perfusion of multi-mm³ tissue constructs by creating synthetic 3D capillary networks. Using this platform, we generate viable, functional, and morphologically complex tissues protected from hypoxia and necrosis during long-term in-vitro culture. Single cell RNA sequencing data and immunohistochemistry reveal that differentiation of neural tissue is significantly accelerated and that liver tissue remains functional after long-term culture upon perfusion.
LiveGrid is specifically designed to produce reliable and spatially defined perfusion of 3D tissues with reproducible phenotypes for drug discovery and tissue engineering applications. In particular, we develop and validate a human drug clearance assay, uniquely suitable for slowly metabolizing drugs which cannot currently be evaluated in conventional assays.
This platform opens the door to generating human tissue models at unprecedented scales and complexities, bringing truly biomemtic models for drug discovery, disease modeling, and regenerative medicine applications.