Magnesium-containing Hierarchical Porous Scaffold Incorporating Alpha-Lipoic Acid Ethosomes for Neurovascularized Bone Regeneration under Diabetic Conditions

Diabetes mellitus severely impairs bone regeneration due to a compromised neurovascular microenvironment. Current therapeutic approaches frequently overlook the need to support neurovascular repair under hyperglycemic conditions, leading to suboptimal bone defect healing. To address these challenges, we developed a low-temperature deposition modeling (LDM)-printed magnesium-containing scaffold incorporating alpha-lipoic acid-encapsulated ethosomes (ALA-Eth), termed the LMA scaffold. In this design, the hierarchical porous structure provided a framework for tissue ingrowth, while magnesium ions and ALA-Eth were introduced to endow the scaffold with the capacity to support vascular and neural repair. In vitro assessments demonstrated that the scaffold enhanced the neurotrophic activity of Schwann cells (SCs) and improved the angiogenic function of endothelial cells under hyperglycemic conditions. Furthermore, osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) was facilitated not only by conditioned medium from scaffold-treated SCs and endothelial cells, but also by the direct osteoinductive activity of the composite scaffold. In vivo implantation in diabetic rat femoral condyle defects revealed that the scaffold promoted neurovascularized bone regeneration. Transcriptomic and cellular analyses further indicated that this regenerative profile was associated with neural, vascular and osteogenic pathways, alongside redox regulation and bioenergetic processes. Collectively, these findings support the potential of the LMA scaffold as a multifunctional biomaterial strategy for neurovascularized bone regeneration under diabetic conditions.