Glucose-Responsive Self-Rolling Antioxidant Hydrogel Actuators for a Cell Culture Platform

Three-dimensional (3D) cell culture technology can mimic the physiological characteristics of tissues and organs, making it highly suitable for cell therapy, organ chips, and tissue engineering applications. However, achieving a uniform cell distribution within the 3D matrix while mitigating the effects of reactive oxygen species (ROS) accumulation generated during the 3D cell culture remains a critical challenge. Hydrogel actuators, with their excellent bioactivity and controllable self-rolling behavior, provide an optimal microenvironment for the 3D cell culture. To support normal cellular function, hydrogel actuators must be triggered by external stimuli that are biocompatible with the cell culture process. Glucose, a key intermediate in energy metabolism and biological processes, is ubiquitous in cell culture media and physiological systems. In this work, a glucose-responsive hydrogel actuator (AP@Que/gelatin) with controllable self-rolling behaviors and ROS scavenging capability was constructed for 3D cell culture, which consists of an active layer composed of phenylboronic acid (PBA)-quercetin (Que) complexes and a passive layer of a biocompatible gelatin hydrogel. The hydrogel actuator exhibited excellent glucose response performance, characterized by notable reswelling behavior, favorable ductility, and cytocompatibility. Its self-rolling behavior in high-glucose culture media was synchronized with cell adhesion timelines, enabling its application as a 2D-to-3D dynamic substrate for cell culture and expansion. Meanwhile, Que was released from the hydrogel actuator through the competitive reaction of PBA with glucose and Que. The formation of the 3D tubular architecture during cell culture facilitated cell growth, while the sustained release of Que effectively eliminated ROS generated during cell passaging. These findings highlight the potential of AP@Que/gelatin hydrogel actuators as an advanced platform for a 3D cell culture.