A Biomimetic Norepinephrine-Loaded Aligned Mineralized Collagen Scaffold for Coordinated Neurovascular, Osteogenic, and Immunomodulatory Repair of Critical-Sized Bone Defects.

Abstract

Effective regeneration of critical-sized bone defects requires integrated coordination among osteogenesis, neurogenesis, angiogenesis, and immune modulation-yet most biomaterials fail to address these dimensions simultaneously. Here, a norepinephrine-loaded, biomimetic mineralized electrocompacted collagen scaffold (NE-MEC) is developed that integrates structural anisotropy and sustained biochemical activity to promote integrated bone repair. Fabricated through isoelectric focusing, mechanical stretching, and amorphous calcium phosphate mineralization, NE-MEC mimics the composition and ordered alignment of native bone and preserves the characteristic D-periodicity of collagen fibrils. The mineralized electrocompacted collagen alone promotes osteogenic differentiation of rat bone marrow mesenchymal stem cells. Upon norepinephrine incorporation, this osteoinductive effect is further enhanced, accompanied by early-stage upregulation of nerve growth factor, which supporting peripheral nerve repair and inducing calcitonin gene-related peptide (CGRP) production. In turn, CGRP enhances both osteogenic differentiation and neovascularization. Meanwhile, NE-MEC also stimulates vascular endothelial growth factor A expression in the regenerating bone tissue and modulates macrophage polarization. Together, these effects establish a regenerative circuit that orchestrates osteogenic, neurogenic, angiogenic, and immunomodulatory processes, offering a promising biomaterial platform for synergistic skeletal repair.