# Multifunctional hydrogel promotes rotator cuff healing through anti-inflammation and vascularization

## TL;DR

A new injectable hydrogel helps heal rotator cuff tears by reducing inflammation and promoting blood vessel growth, showing promise for clinical use.

## Contribution

The development of an LA-CMCS-OHA hydrogel that combines anti-inflammatory and pro-vascularization properties for rotator cuff repair.

## Key findings

- The hydrogel inhibits NF-κB signaling, promoting anti-inflammatory M2 macrophage polarization.
- It enhances VEGF expression, stimulating endothelial cell proliferation and neovascularization.
- In rat models, the hydrogel significantly improved tendon-bone regeneration.

## Abstract

Rotator cuff tears (RCTs) represent a substantial clinical challenge due to their intricate, multi-stage healing process, which encompasses sequential phases of inflammation, proliferation, tissue reconstruction, and remodeling. Disruption of any phase can adversely affect healing and increase the risk of re-tear. To address this issue, we engineered an injectable LA-CMCS-OHA hydrogel by physically blending lactic acid (LA)—a key signaling molecule—into a composite hydrogel system consisting of carboxymethyl chitosan (CMCS) and oxidized hyaluronic acid (OHA). The hydrogel formation was facilitated by a dynamic Schiff base reaction between CMCS and OHA, imparting superior biocompatibility, injectability, and self-healing properties. The LA-CMCS-OHA hydrogel effectively inhibits nuclear factor kappa B (NF-κB) signaling, thereby promoting macrophage polarization toward the anti-inflammatory M2 phenotype and mitigating early inflammatory responses. Additionally, it markedly enhances vascular endothelial growth factor (VEGF) expression, stimulating the proliferation and migration of human umbilical vein endothelial cells (HUVECs) to facilitate neovascularization. These therapeutic effects were comprehensively validated through both in vitro and in vivo studies. Histological and biomechanical assessments using a rat acute RCT model revealed that the LA-CMCS-OHA hydrogel significantly facilitates tendon-bone regeneration. Collectively, these findings highlight the LA-CMCS-OHA hydrogel as a promising therapeutic strategy for RCTs with strong potential for clinical translation.

Schematic diagram illustrates the regenerative process of LA-CMCS-OHA hydrogel for treating rotator cuff tears. (A) Preparation of the LA-CMCS-OHA hydrogel. (B) The LA-CMCS-OHA hydrogel mitigates the inflammatory response via the NF-κB pathway, stimulates VEGF secretion, promotes endothelial cell proliferation and vascularization, and establishes a favorable microenvironment for tendon-bone reconstruction.Image 1

•Lactic acid is a significant signalling molecule involved in tissue repair and disease development.•LA-CMCS-OHA hydrogel promotes macrophage polarization toward M2 anti-inflammatory phenotype by inhibiting NF-κB pathway.•The LA-CMCS-OHA hydrogel enhances vascular endothelial growth factor secretion, thereby facilitating neovascularization.•The LA-CMCS-OHA hydrogel creates a microenvironment for RCT repair, showing huge potential for clinical translation.

Lactic acid is a significant signalling molecule involved in tissue repair and disease development.

LA-CMCS-OHA hydrogel promotes macrophage polarization toward M2 anti-inflammatory phenotype by inhibiting NF-κB pathway.

The LA-CMCS-OHA hydrogel enhances vascular endothelial growth factor secretion, thereby facilitating neovascularization.

The LA-CMCS-OHA hydrogel creates a microenvironment for RCT repair, showing huge potential for clinical translation.