3D-Bioprinting of ROS-Responsive Curcumin-Loaded Hydrogel Scaffolds via Low-Temperature Extrusion for Enhancing Diabetic Wound Healing
Cong Ma, Huamai Qiu, Yifan Chen, Abdul Mueed, Lijun You
Abstract
Traditional wound dressings rarely provide both three-dimensional multisite cellular adhesion and controlled drug release–two prerequisites for healing chronic, inflammatory wounds such as diabetic ulcers. We, therefore, introduce a single-step strategy in which curcumin, a natural anti-inflammatory and antioxidant, is encapsulated in newly synthesized, reactive oxygen species (ROS)-responsive amphiphilic block copolymers to yield ROS-sensitive, curcumin-loaded nanoparticles. When oxidative injury raises local ROS concentrations, the carriers accelerate drug release to restore the imbalanced wound milieu. To minimize drug degradation during Three-Dimensional Printing (3D-printing) and to maintain micrometer-scale resolution, we formulated a highly thixotropic bioink that extrudes at 37 °C (near-physiological temperature) without secondary curing. The resulting scaffolds integrate two functions: ROS-triggered, site-specific curcumin release and intrinsic radical-scavenging activity. In vitro, the scaffolds demonstrated excellent biocompatibility, supporting multisite adhesion of L929 fibroblasts and RAW264.7 macrophages, while significantly alleviating oxidative stress in fibroblasts. In a murine diabetic wound model, ROS-responsive curcumin-loaded scaffold (ROS-Cur-Scaffold) accelerated closure by attenuating inflammation, promoting angiogenesis, modulating immune cell polarity, and enhancing collagen deposition. Overall, our 3D-printing strategy successfully preserved the drug activity and printing fidelity while generating multifunctional scaffolds that combine biocompatibility with ROS-triggered therapeutic release. Therefore, this integrated approach shows substantial potential for advancing the treatment of chronic wounds, particularly in diabetic ulcer management.