Three-Dimensional Bioprinting of Biphasic Nanobioink for Enhanced Diabetic Wound Healing

Abstract

The healing of chronic diabetic wounds remains a major healthcare problem due to their inherently hypoxic microenvironment, which results from vascular damage and increased tissue oxygen demand, severely limiting adenosine triphosphate (ATP) production and impairing the healing process. Ensuring both oxygen supply and ATP delivery presents a significant challenge due to markedly different diffusion rates of gases and energy-carrying molecules complicating synchronized and sustained delivery. To tackle this challenge, we report a three-dimensional (3D) bioprinted gelatin methacrylate (GelMA)/alginate construct with a coaxial structure, incorporating biphasic bioinks containing oxygen-generating calcium peroxide (CaO₂) nanoparticles and ATP-releasing liposomes. This construct features an inner layer containing CaO₂ nanoparticles for sustained oxygen release and an outer layer with ATP-encapsulated liposomes to provide cellular energy. By balancing the fast gas release with the slow ATP diffusion, our scaffold enhances cell proliferation and viability under hypoxic conditions, effectively accelerating diabetic wound healing in a type II diabetic mouse model. This work not only provides a strategic approach for designing scaffolds requiring controlled delivery of multiple molecules but also offers an effective intervention for chronic wound healing. Our coaxial bioprinting approach fundamentally differs from traditional blending techniques by offering precise spatial control over distinct therapeutic agents, ensuring optimized synchronized release kinetics. Unlike conventional strategies that lack accurate spatiotemporal coordination, our scaffold effectively aligns oxygen and ATP delivery profiles with cellular metabolic demands, significantly enhancing therapeutic efficacy. This coaxial printing strategy offers significant potential for expanding the delivery of a wider range of nanomaterials, enabling the development of multifunctional, responsive systems with precise control over each therapeutic delivery, thereby driving progress in regenerative medicine.