Directional Biomimetic Scaffold-Mediated Cell Migration and Pathological Microenvironment Regulation Accelerate Diabetic Bone Defect Repair.

Abstract

Hyperglycemia-induced oxidative stress and inflammation critically impair diabetic bone defect repair. Here, a radially oriented microchannel scaffold (D-GSH@QZ) was developed via a directional freezing technique integrated with photo-cross-linking strategies. The scaffold was fabricated from gelatin methacryloyl, silk fibroin methacryloyl, and nanohydroxyapatite (HAp) to mimic the natural bone matrix, while incorporating quercetin-loaded ZIF-8 nanoparticles (Qu@ZIF-8) for pathological microenvironment modulation. By leveraging the advantages of directionally aligned structures and functional components (Qu@ZIF-8 and HAp), the scaffold facilitated rapid cell infiltration and guided orderly tissue regeneration from the periphery to the interior. Moreover, the scaffold induced macrophage M2 polarization, scavenged excess reactive oxygen species, and restored mitochondrial membrane potential, thereby remodeling the diabetic pathological microenvironment to enhance vascularization and osteogenesis. After implantation in the diabetic bone defect model, the scaffold significantly accelerated tissue repair. Furthermore, transcriptome sequencing of the regenerated tissue <i>in vivo</i> revealed that the scaffold inhibited pathways associated with oxidative stress, inflammation, and bone resorption, including AGE-RAGE, NF-κB, and osteoclast differentiation, while simultaneously activating key pathways related to angiogenesis and bone regeneration, such as TGF-β, PI3K-AKT, and Wnt pathways. These findings indicate that the D-GSH@QZ scaffold can provide an optimal 3D microenvironment for diabetic bone repair.