This review discusses the principles underlying stimuli-responsive behavior of hydrogels and how these properties contribute to their biomimetic functions and applications.

Hydrogels have numerous biomedical applications including synthetic matrices for cell culture and tissue engineering. Here we report the development of hydrogel based multifunctional matrices that not only provide three-dimensional structural support to the embedded cells but also can simultaneously provide potentially beneficial dynamic mechanical and electrical cues to the cells. A unique aspect of these matrices is that they undergo reversible, anisotropic bending dynamics in an electric field. The direction and magnitude of this bending can be tuned through the hydrogel crosslink density while maintaining the same electric potential gradient, allowing control over the mechanical strain imparted to the cells in a three-dimensional environment. The conceptual design of these hydrogels was motivated through theoretical modeling of the osmotic pressure changes occurring at the gel-solution interfaces in an electric field. These electro-mechanical matrices support survival, proliferation, and differentiation of stem cells. Thus, these new three-dimensional in vitro synthetic matrices, which mimic multiple aspects of the native cellular environment, take us one step closer to in vivo systems.

The integration of three-dimensional micropatterning with microfluidics provides a unique opportunity to create perfusable tissue constructs in vitro. Herein, we have used this approach to create a tumor-on-chip with endothelial barrier. Specifically, we photopatterned a mixture of endothelial cells and cancer spheroids within a gelatin methacrylate (GelMA) hydrogel inside of a microfluidic device. The differential motility of endothelial and cancer cells in response to a controlled morphogen gradient across the cell-laden network drove the migration of endothelial cells to the periphery while maintaining the cancer cells within the interior of the hydrogel. The resultant endothelial cell layer forming cell-cell contact via VE-Cadherin junctions was found to encompass the entire the GelMA hydrogel structure. Furthermore, we have also examined the potential of such tumor-on-a-chip system as a drug screening platform using Doxorubicin, a model cancer drug.