An Efficient Microfluidic Platform for Organ-Specific Cyclic Multiaxial Loading and Differentiation of Progenitor Cells

Mechanical loading is a fundamental regulator of tissue development, maturation, and function, yet existing in vitro systems predominantly apply uniaxial load/strain to cell-laden hydrogels, limiting their ability to reproduce physiologically relevant multiaxial on-chip tissue mechanics. Here, we present an engineered system to apply controlled multiaxial mechanical loading to real scaffolds with undifferentiated cells. The system enables programmable cyclic stretching and relaxation at the cell scaffold level and is compatible with both cell-laden native scaffold and engineered soft tissues. We have quantified the strain field experienced by the tissue with distinct mechanical loading periods using computation simulations and validated these with systematic experiments, demonstrating reproducible and various organ-relevant multiaxial strain profiles. As proof of concept, we applied the approach to human cardiac tissues, where cyclic multiaxial mechanical loading of mononuclear cells laden native tissue scaffold promoted cardiac structural organization and supports the emergence of spontaneous contractile activity. This approach provides a generalizable method for reproducing physiologically relevant tissue mechanics in vitro and enables systematic investigation of mechano-regulation across a plethora of human tissues.