The application of engineered biomaterials for wound healing has been pursued since the beginning of tissue engineering. Here, we attempt to apply functionalized lignosulfonates to confer antioxidation to tissue microenvironments and to deliver oxygen to accelerate vascularization and healing responses without causing inflammatory responses. The results from fibrosis array shows that thiolated lignosulfonate in methacrylated gelatin can effectively attenuate fibrotic responses of human dermal fibroblasts. Elemental analysis of oxygen releasing nanoparticles shows the positive incorporation of calcium peroxide. Composites including nanoparticles of lignosulfonate and calcium peroxide release around 0.05% oxygen per day at least for 7 days. Stiffness can be precisely modulated to avoid adverse inflammatory responses. Injection of lignin composites with oxygen generation nanoparticles enhanced the formation of blood vessels and promoted infiltration of alpha-smooth muscle actin+ fibroblasts over 7 days. At 30 days after surgery, the lignin composite with oxygen generating nanoparticles remodels the collagen architecture resembling to the reticular pattern of normal collagen and leave minimal scars. Thus, our study shows the potential of functionalized lignosulfonate for wound healing applications requiring balanced antioxidation and controlled release of oxygen.

The application of engineered biomaterials for wound healing has been pursued since the beginning of tissue engineering. Here, we attempt to apply functionalized lignin to confer antioxidation to the extracellular microenvironments of wounds and to deliver oxygen from the dissociation of calcium peroxide for enhanced vascularization and healing responses without eliciting inflammatory responses. Elemental analysis showed 17 times higher quantity of calcium in the oxygen-releasing nanoparticles. Lignin composites including the oxygen-generating nanoparticles released around 700 ppm oxygen per day at least for 7 days. By modulating the concentration of the methacrylated gelatin, we were able to maintain the injectability of lignin composite precursors and the stiffness of lignin composites suitable for wound healing after photo-cross-linking. In situ formation of lignin composites with the oxygen-releasing nanoparticles enhanced the rate of tissue granulation, the formation of blood vessels, and the infiltration of α-smooth muscle actin+ fibroblasts into the wounds over 7 days. At 28 days after surgery, the lignin composite with oxygen-generating nanoparticles remodeled the collagen architecture, resembling the basket-weave pattern of unwounded collagen with minimal scar formation. Thus, our study shows the potential of functionalized lignin for wound-healing applications requiring balanced antioxidation and controlled release of oxygen for enhanced tissue granulation, vascularization, and maturation of collagen.