Micropore-Confined ROS-Responsive 3D-Printed Shell-Core Scaffolds for Long-Term NO Release to Orchestrate Immunomodulation and Angiogenesis in Diabetic Bone Defect Repair.

Abstract

The healing of diabetic bone defects is critically impaired by multifaceted pathological factors, including immune dysregulation, persistent inflammation, excessive reactive oxygen species (ROS), and impaired vascular-osteogenic coupling. Although nitric oxide (NO) holds promise for its anti-inflammatory and regenerative properties, its clinical translation is limited by a short half-life and uncontrolled release, failing to match chronic diabetic bone repair. Herein, we present an MP-LAS scaffold based on a micropore-confinement strategy, which transforms release kinetics from a "burst-exhaustion" mode to a sustained, on-demand output. The scaffold is fabricated by 3D printing coupled with phase separation, featuring a core of ROS-degradable hydrogel loaded with L-arginine (L-Arg) and a shell of nano-hydroxyapatite/polycaprolactone (nHA/PCL) with interconnected microporosity. The well-designed micropores precisely confine the ROS/L-Arg reaction, triggering localized degradation of the core and controllable L-Arg release for subsequent in situ NO generation. This system maintains a stable NO supply for 3 months, avoiding burst-release toxicity while continuously neutralizing pathological ROS. Both in vitro and in vivo evaluations demonstrate that this dual action synergistically modulates macrophage M2 polarization, angiogenesis, and osteogenic differentiation, ultimately facilitating diabetic bone regeneration via NO-mediated vascular-osteogenic coupling. This work offers a novel, versatile micropore-confined platform for precise molecule delivery in complex pathological microenvironments.