Thermo-responsive Bioink for Personalized 3D Printed Scaffolds with Antioxidant and Fibroblast Delivery to Accelerate Diabetic Wound Healing

Three-dimensional (3D) bioprinting is a promising field in tissue engineering, and the mechanical properties and biocompatibility of bioinks are essential factors. This study introduces a biocompatible, thermoresponsive poly(organophosphazene)-based bioink with excellent mechanical properties that provides effective drug release. First, we synthesized the Tyr-PPZ polymer, which contained an isoleucine ethyl ester, amino-methoxy poly(ethylene glycol), and tyramine. The Tyr-PPZ polymer was dissolved in phosphate-buffered saline to prepare TP bioink. The presence of hydrophobic components facilitated the homogeneous diffusion of caffeic acid into the bioink and conferred antioxidant properties. The PC bioink, prepared by incorporating caffeic acid into TP bioink, not only exhibited stable antioxidant properties but also showed excellent extrudability and printability due to its shear-thinning and recovery properties, which enabled the fabrication of various 3D scaffolds. Printed 3D scaffolds maintained high mechanical properties at body temperature (37 °C), which ensured scaffold stability for 30 d without additional cross-linking. In addition, to enhance diabetic wound healing through antioxidant properties and fibroblast delivery, PCC bioink was formulated by loading fibroblasts into PC bioink. Three-dimensional scaffolds fabricated using PCC bioink exhibited high cell viability for 7 d and promoted tissue regeneration in diabetic mice. In addition, PCC bioink provided antioxidant effects and accelerated wound closure, thick granulation tissue formation, and angiogenesis. This technology is promising as a next-generation bioink platform for diabetic wound treatment through a high-resolution 3D bioprinting scaffold that effectively delivers antioxidants and fibroblasts.