3D-printed conductive hydrogel scaffolds for bone regeneration: Electromechanical coupling, neurovascular integration, and immunomodulatory strategies

Abstract

Bone defect repair remains a formidable clinical challenge due to the limitations of traditional grafts and scaffolds, such as insufficient mechanical compatibility, minimal bioactivity, and poor biomimicry of bone's complex architecture. Emerging 3D-printed conductive hydrogel scaffolds offer a promising solution by combining the electroactive functionality of conductive materials with the cell-friendly, extracellular matrix-like properties of hydrogels. When fabricated into specific architectures via advanced 3D printing techniques, these composite scaffolds provide active biochemical and biophysical cues that enhance tissue regeneration. They can promote osteogenesis by activating key signaling pathways such as integrin–FAK–ERK and Piezo1/2-mediated calcium influx that upregulates osteogenic transcription factors. Simultaneously, they support neurogenesis and angiogenesis: the scaffold's conductivity and micro-topography guide neural differentiation and axon growth for nerve repair, while electrical stimulation and embedded conductive networks trigger the release of angiogenic factors to foster vascular network formation. These scaffolds also modulate the immune response, for example by polarizing macrophages toward a pro-regenerative M2 phenotype, thereby creating a more favorable healing microenvironment. As a result, 3D-printed conductive hydrogels can orchestrate bone regeneration in concert with vascularization and innervation, transcending the single-functionality of conventional scaffolds. Remaining challenges include ensuring long-term biocompatibility, achieving high-resolution microfabrication without compromising bioactivity, and optimizing electrical stimulation parameters for maximal regenerative benefit. Ongoing research is focused on developing bio-safe conductive composites, refining 3D printing methods, and employing dynamic stimulation strategies to address these challenges and accelerate the translation of conductive hydrogel scaffolds into clinical use.