# The Collapse of the Collagen Sponge Microstructure Triggers an Inflammatory Response of Macrophages via the Itgαvβ3/5-Src-RhoC-NF-κB Axis

## TL;DR

This study shows how different cross-linking methods affect collagen sponges' structure and inflammation in macrophages.

## Contribution

The study identifies a specific signaling pathway triggered by microstructural collapse in collagen sponges.

## Key findings

- TG-cross-linked sponges caused macrophage activation via the Itgαvβ3/5-Src-RhoC-NF-κB axis.
- EDC/NHS-cross-linked sponges maintained structure and suppressed inflammation.
- Findings suggest design principles for low-inflammatory collagen biomaterials.

## Abstract

Collagen sponges are widely used for oral tissue regeneration, due to their extracellular matrix-mimetic architecture and excellent biocompatibility. However, in practical biomedical applications, collagen sponges may exhibit hydration-induced structural instability, and there can be associated inflammatory responses under physiological conditions, potentially compromising their regenerative performance. In this study, we investigated how two cross-linking strategies—transglutaminase (TG) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide (EDC/NHS)—modulate the structural stability and inflammatory profiles of collagen sponges. TG-cross-linked sponges exhibited microstructural collapse, associated with macrophage activation and engagement of the Itgαvβ3/5–Src–RhoC–NF-κB signaling axis. In contrast, EDC/NHS-cross-linked sponges preserved a stable porous architecture, effectively suppressing this signaling cascade and establishing a low-inflammatory microenvironment. These findings elucidate a key mechanism by which cross-linking regulates the microstructural integrity of collagen scaffolds and provides in vitro-derived preliminary design principles for developing next-generation collagen biomaterials with low-inflammatory properties.