# Tannic acid-assisted mechanical training transforms natural hydrogels into robust and bioactive membranes for guided bone regeneration

## TL;DR

A new method strengthens natural hydrogels for bone regeneration, making them tough and effective in healing bone defects under stress.

## Contribution

A tannic acid-assisted stretching strategy that enhances hydrogel mechanical strength and bioactivity for guided bone regeneration.

## Key findings

- TAWS increased hydrogel Young's modulus 22.16-fold and toughness 12.31-fold.
- GHT membranes retained 80% of their mass after 28 days in simulated body fluid.
- GHT membranes improved bone volume fraction by 2.68-fold in a mandibular defect model.

## Abstract

Guided bone regeneration (GBR) membranes are widely used for the treatment of bone defects. Natural hydrogels are promising candidates for GBR membranes owing to their excellent bioactivity and controllable degradability, but their clinical translation is restricted by inherent mechanical weakness. Inspired by tendon-strengthening mechanisms in athletes, we propose a tannic acid (TA)-assisted wet-stretching (TAWS) strategy to transform gelatin methacryloyl (GelMA) hydrogels into mechanically robust GBR membranes. During stretching, GelMA chains are directionally aligned while TA establishes multivalent hydrogen bonds between adjacent fibers, synergistically reinforcing the network. The resulting TA-trained (GHT) membranes achieved a 22.16-fold increase in Young's modulus and a 12.31-fold enhancement in toughness. In parallel, TAWS markedly slowed degradation kinetics and enhanced physiological stability, enabling GHT membranes to retain ∼80 % of their initial mass after 28 days in SBF. Beyond reinforcement, TA imparted potent ROS-scavenging and immunomodulatory activity. In vitro, GHT membranes enhanced stem cell survival, proliferation, and osteogenic differentiation under oxidative stress. In a mandibular defect model under elevated oxidative and inflammatory challenge, GHT reduced ROS levels (DHE fluorescence) to 53.76 % of the untreated ROS-upregulated group and increased bone volume fraction (BV/TV) by approximately 2.68-fold at 4 weeks and 2.21-fold at 8 weeks, outperforming the Bio-Gide® membrane. Collectively, TAWS provides a scalable platform to engineer multifunctional hydrogel membranes that integrate mechanics, stability, and regenerative performance for advanced GBR.

Image 1

•TAWS strategy turns soft hydrogels into tough and oriented GBR barriers.•TA crosslinking enables hydrogel to modulate osteogenic microenvironment.•GHT membranes promote mandibular bone regeneration in inflammatory defects.

TAWS strategy turns soft hydrogels into tough and oriented GBR barriers.

TA crosslinking enables hydrogel to modulate osteogenic microenvironment.

GHT membranes promote mandibular bone regeneration in inflammatory defects.