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

## TL;DR

A new scaffold mimics bone structure and delivers norepinephrine to boost bone, nerve, blood vessel, and immune healing together.

## Contribution

A novel scaffold integrating structural alignment and biochemical signaling for coordinated bone regeneration.

## Key findings

- NE-MEC promotes osteogenic differentiation of stem cells and nerve growth factor upregulation.
- Norepinephrine enhances calcitonin gene-related peptide production, aiding bone and blood vessel growth.
- The scaffold modulates macrophage polarization and vascular endothelial growth factor expression.

## 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.

Inspired by the composition and structure of native bone tissue and its complex interplay of biological signals, a norepinephrine‐loaded biomimetic mineralized electrocompacted collagen scaffold (NE‐MEC) is developed capable of simultaneously supporting osteogenesis, neural repair, angiogenesis, and immune modulation. This NE‐MEC scaffold combines biomimetic alignment, bone‐mimicking composition, and sustained biochemical signaling to engage multiple regenerative pathways.