Surface Potential-Engineered Dentin Promotes Jaw Repair Via Metabolic Reprogramming

To investige the immunoregulatory role of electroactive dentin in jaw repair, and establish its structure-function relationship with surface potential characteristics. Extrafibrillarly-demineralized dentin matrix (EDM) and Poly(allylamine) hydrochloride coated EDM (PEDM) scaffold were fabricated. Comprehensive characterization included surface ζ-potential analysis, scanning electron microscopy, transmission electron microscopy and atomic force microscopy. Bone regeneration was assessed by micro-CT and histomorphometric analysis. CD301b+ macrophage differentiation was assessed using flow cytometry, immunofluorescence and qRT-PCR. Mechanistic insights were obtained via untargeted metabolomics and confirmed by functional validation experiments (metabolites supplementation and related enzymes regulation). Enzymatic alterations were verified by Western blot and qRT-PCR. PEDM scaffold exhibited a reverse surface potential (+16.1 mV vs EDM: -18.5 mV), accompanied with superior bone repair outcomes and amplified CD301b+ macrophage differentiation. Metabolomic mapping revealed a charge-dependent metabolic switch, with PEDM effectively suppressing EDM-associated creatine accumulation through transcriptional silencing of Slc6a8. Functional validation confirmed this metabolic axis by exogenous creating administration or Slc6a8 overexpression reversed PEDM-driven creatine reduction, concomitantly diminishing its CD301b+ macrophage-differentiation capacity by 50%. Our work established dentin matrix as a bioelectrical microarchitecture coordinating immune-metabolic crosstalk during bone healing, revealing two breakthrough insights: 1) Charge-modulated creatine homeostasis dictates CD301b+ macrophage functional commitment, and 2) Surface potential acts as a master regulator of Slc6a8-dependent creatine flux. By bridging immunometabolism with structure-bioelectricity engineering, surface potential-mediated immunomodulation provides new avenues for future material design and healing-associated macrophage niches control in tissue engineering.