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Summary:
This study developed a magnesium-based hierarchical porous scaffold made using low-temperature deposition modeling, loaded with alpha-lipoic acid ethyl ester (ALA-Eth), referred to as LMA. The scaffold combines hierarchical pores, magnesium ions, and ALA-Eth to support nerve, blood vessel, and bone repair in high-glucose environments. In vitro, it was shown to improve Schwann cell neurotrophic function and endothelial cell angiogenesis, and to promote BMSC osteogenesis through both conditioned media and direct action. In diabetic rat femoral condyle defects, LMA promoted neurovascularized bone regeneration; transcriptome and cell analyses suggest involvement in nerve, vascular, bone, redox, and bioenergy pathways.
01
Research Background
Repairing bone defects in diabetes is limited by the high-sugar pathological environment. Accumulation of reactive oxygen species, peripheral neuropathy, and microvascular damage lead to insufficient oxygen and nutrient supply and disrupted nerve-bone signaling. Early nerve sprouting and new blood vessel formation are important for repair, but current strategies often overlook restoring the neurovascular network. ALA has antioxidant and neuroprotective effects but is limited by its half-life, solubility, and bioavailability; ethyl ester can help improve delivery. Magnesium ions support blood vessel, nerve, and bone regeneration, so a multifunctional scaffold that can locally and continuously release active components is needed.
02
Main Content
Using PLCL/PLGA as the base material, L-shaped scaffolds were printed with LDM; LM was obtained by adding magnesium sulfate; LMA was obtained by loading ALA-Eth. The hierarchical pore structure provides a framework for tissue ingrowth, with large pores facilitating nutrient exchange and vascular infiltration, and micropores supporting protein adsorption and neuron adhesion. Magnesium ions together with ALA-Eth support vascular and nerve repair. The study systematically characterized the physicochemical properties, release, and degradation, evaluated neural, vascular, and osteogenic effects under high glucose conditions, and verified neurovascularized bone regeneration in a diabetic rat model.
03
Study Design
ALA-Eth was prepared and characterized; L, LM, and LMA scaffolds were printed to observe morphology, elements, mechanics, degradation, and the release of ALA and magnesium. In vitro, RSCs, HUVECs, and BMSCs were cultured under high glucose to assess proliferation, gene expression, protein levels, migration, tube formation, ALP, and ARS, and conditioned media was used to analyze the indirect effects of neural/vascular cells on osteogenesis. In vivo, a femoral condyle defect model was established in STZ-induced diabetic rats, combining subcutaneous implantation, Micro-CT, histology, immunofluorescence, and transcriptomics to analyze bone, blood vessels, nerves, and redox/energy metabolism.
04
Results
LMA has interconnected hierarchical pores, ALA-Eth is well distributed, magnesium and sulfur are even, mechanical strength is enhanced, degradation is relatively linear, and active components are continuously released. Under high sugar conditions, LMA improves Schwann cell viability, migration, and neurotrophic factor expression, boosts endothelial cell viability, migration, tube formation, and expression of vascular-related genes/proteins; its conditioned medium promotes BMSC osteogenesis. Direct co-culture promotes BMSC spreading, osteogenic genes, ALP, mineralization, and RUNX2/OCN. In diabetic models, LMA improves bone parameters, increases collagen and new bone, and enhances OCN, CD31, and β3-tubulin expression; transcriptome and cell analyses show enrichment in neural, vascular, osteogenic, redox, and bioenergetic pathways, reduces ROS, and improves antioxidant capacity, mitochondrial membrane potential, and ATP.
05
Ideas for Further Exploration
This study suggests that repairing bone defects in diabetes requires simultaneously restoring the nerve and vascular microenvironment, as well as regulating redox balance and energy metabolism. LMA integrates graded pores, magnesium ions, and ALA-Eth, providing a material approach for neurovascularized bone regeneration. The original text points out that free ALA comparisons on the scaffold level are still needed to distinguish the contribution of ethyl delivery; most neurovascular indicators are correlational and require pathway disruption and early in situ analysis to confirm causality; future work could optimize release timing, cell interactions, and long-term safety to further understand the neuro-vascular-bone coupling mechanism.
Original source:
Journal of Nanobiotechnology
Pub Date: 2026-09-03
DOI: 10.1186/s12951-026-04991-1
Miaoxuan Dai, Beilei Liu, Xiaomeng Zhang, Meifei Lian, Yi Zhang, Tingyu Wang, Hongchang Lai
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