# Engineered bilayer hydrogel with spatiotemporal drug and oxygen delivery for diabetic wound microenvironment reprogramming

## TL;DR

A smart bilayer hydrogel was developed to deliver drugs and oxygen in a controlled way to improve healing in diabetic wounds.

## Contribution

The novel contribution is a spatiotemporally responsive hydrogel that combines drug release, oxygen delivery, and anti-fouling properties for diabetic wound healing.

## Key findings

- The hydrogel achieved a 99.1% wound closure rate by day 14.
- The platform reprograms macrophages from M1 to M2 phenotype to reduce inflammation.
- The bilayer structure provides antibacterial, anti-inflammatory, and oxygenation functions.

## Abstract

The impaired healing of diabetic wounds primarily stems from persistent inflammation, a hypoxic microenvironment, and heightened susceptibility to infection. However, most existing studies focus on simple functional stacking, rather than aligning with the dynamic pathological repair process, which hinders the maximization of therapeutic efficacy of the repair materials. In this study, an intelligently responsive, bilayer anti-fouling nanocomposite hydrogel (Ca@Q-E@SGH) was developed for spatiotemporally synergistic therapy via spatiotemporal drug and oxygen delivery strategies. Its core component (Ca@Q-E) consists of calcium peroxide encapsulated by phenylboronic acid-modified quaternary ammonium chitosan, with epigallocatechin gallate (EGCG) linked via boronate esters. This dynamic bond enables ROS/glucose-responsive EGCG release to reprogram macrophages from the M1 to M2 phenotype, mitigating early-stage inflammation. As the matrix degrades, sustained oxygen is released from CaO2, supporting vascularization during tissue remodeling. Furthermore, the bilayer hydrogel structure is designed to provide multiple protective functions: the lower layer rapidly crosslinks to encapsulate the functional nanoparticles, while the upper layer forms a highly hydrophilic anti-fouling coating that effectively prevents pathogen adhesion. Collectively, this integrated platform combines intelligent microenvironment-responsive drug release for antibacterial and anti-inflammatory effects, followed by sequential oxygen delivery aligned with the wound healing stages, along with physical anti-fouling protection. As a result, the treated wounds achieved a remarkable closure rate of 99.1% by day 14. This study presents a comprehensive strategy for diabetic wound management by seamlessly integrating smart anti-inflammatory action, prolonged oxygen supply, and efficient anti-fouling capacity into a single coordinated platform.