Abstract
The considerable advances that have been made in the development of organotypic cultures have failed to overcome the challenges of expressing tissue specific functions and complexities, especially for organs that require multitasking and complex biological processes, such as the liver. Primary liver cells are ideal biological building blocks for functional organotypic reconstruction, but are limited by their rapid loss of physiological integrity in vitro. Here, we apply the concept of lattice growth used in material science to develop a tissue incubator which provides physiological cues and controls the three dimensional assembly of primary cells. The cues include a biological growing template, spatial co-culture, biomimetic radial flow and circulation in a scaffold-free condition. We demonstrate the feasibility of recapitulating a multiscale physiological structural hierarchy, complex drug clearance, and zonal physiology from the cell to tissue level in long-term cultured liver-on-a-chip (LOC). Our methods are promising for future applications in pharmacodynamics and personal medicine.