Biofunctionalized Hydrogel Microscaffolds Promote 3D Hepatic Sheet Morphology

Development of artificial tissues providing the proper geometrical, mechanical, and environmental cues for cells is highly coveted in the field of tissue engineering. Recently, microfabrication strategies in combination with other chemistries have been utilized to capture the architectural complexity of intricate organs, such as the liver, in in vitro platforms. Here it is shown that a biofunctionalized poly (ethylene glycol) (PEG) hydrogel scaffold, fabricated using a sphere‐template, facilitates hepatic sheet formation that follows the microscale patterns of the scaffold surface. The design takes advantage of the excellent diffusion properties of porous, uniform 3D hydrogel platforms, and the enhanced‐cell–extracellular matrix interaction with the display of conjugated collagen type I, which in turn elicits favorable Huh‐7.5 response. Collectively, the experimental findings and corresponding simulations demonstrate the importance of biofunctionalized porous scaffolds and indicate that the microscaffold shows promise in liver tissue engineering applications and provides distinct advantages over current cell sheet and hepatocyte spheroid technologies. Spheroid hepatocyte culture, as found in sphere‐templated nonfouling microscaffolds, poses the risk of cell necrosis at the hepatosphere core. Conjugating extracellular matrix (ECM) to these porous scaffolds directs heptatocytes into an advantageous 3D sheet morphology, shown here both experimentally and via Monte Carlo simulation.