# ROS-responsive adhesive nanocomposite hydrogel promotes tendon-to-bone healing by modulating the inflammatory microenvironment and pro-differentiation

## TL;DR

A new ROS-responsive hydrogel was developed to improve tendon-to-bone healing by reducing inflammation and promoting cell differentiation.

## Contribution

The novel TPGA@CZB hydrogel combines mechanical support, drug release, and microenvironment modulation for tendon-to-bone regeneration.

## Key findings

- The hydrogel showed excellent adhesion and mechanical properties suitable for tissue repair.
- It effectively released baicalin in response to ROS, reducing inflammation and promoting cell differentiation.
- In vivo studies confirmed enhanced collagen remodeling and tissue regeneration at the injury site.

## Abstract

Natural functional regeneration of the tendon–bone interface in rotator cuff repair surgery remains a major challenge and requires the development of innovative therapeutic strategies. Hydrogels with biomechanical adaptability and regenerative microenvironment modulation are promising candidates for treating such injuries. In this study, an ROS-responsive adhesive nanocomposite hydrogel (TPGA@CZB) was developed to enhance tendon-to-bone interface repair by on-demand drug release to modulate the inflammatory microenvironment and promote cell differentiation. The hydrogel consisted of baicalin (Ba)-loaded Cu-Zn bimetallic-organic framework (CZB), N-[tris(hydroxymethyl) methyl] acrylamide (THMA), poly(ethylene glycol) diacrylate (PEGDA) and phenylboronic acid modified methacrylated gelatin (GelMA-CPBA). Owing to its multi-crosslinked structure, TPGA@CZB exhibits excellent adhesive properties (lap shear strength reaching 110.90 ± 15.38 kPa) and mechanical adaptability (compressive strain exceeding 80% and tensile strain of 196.24 ± 3.87%). Additionally, TPGA@CZB demonstrated favorable ROS-responsive release characteristics, with the cumulative release of Ba in H2O2 solution (63.90 ± 4.76% at 96 h) being significantly higher than that in PBS solution (48.39 ± 1.56% at 96 h). Furthermore, cellular experiments revealed that TPGA@CZB effectively scavenged intracellular ROS, inhibits the NF-κB signaling pathway, regulates macrophage polarization and promotes osteogenic differentiation and chondrogenesis. In vivo studies confirmed that TPGA@CZB treatment effectively optimized collagen remodeling, enhanced osteogenesis and cartilage formation, as well as modulated the inflammatory microenvironment at the injury site. In conclusion, this nanocomposite hydrogel integrates “mechanical support—controlled drug release—microenvironment regulation” into a single platform, offering a promising multifunctional therapeutic strategy for enhancing tendon–bone interface regeneration.