Facile Fabrication of Injectable Multifunctional Hydrogels Based on Gallium-Polyphenol Networks with Superior Antibacterial Activity for Promoting Infected Wound Healing

A Novel Study on Multifunctional Hydrogels for Promoting Infected Wound Healing

In the current clinical setting, infected wounds, especially those caused by antibiotic-resistant pathogens, have become a major challenge. These chronic or hard-to-heal wounds often suffer from delayed healing processes due to excessive inflammation, bacterial biofilm formation, and the decreasing efficacy of antibiotics. However, existing treatment methods, such as antibiotic therapy and traditional wound dressings, struggle to simultaneously address issues related to infection, antibiotic resistance, and tissue regeneration. Against this backdrop, multifunctional hydrogels, with their three-dimensional structures resembling the extracellular matrix, have emerged as promising advanced wound dressings. Yet, achieving low-cost and simple preparation methods for hydrogels that are antimicrobial, anti-inflammatory, antioxidant, self-healing, and biocompatible remains an unresolved scientific challenge.

Recently, a team of scientists from institutions including Fuzhou University and Fujian Medical University, led by researchers such as Minglang Zou and Da Huang, developed a novel injectable multifunctional hydrogel, based on metal-phenolic networks (MPN). This chitosan-tannic acid-gallium-based hydrogel (CS-TA-Ga³⁺ hydrogel, abbreviated as CTG hydrogel) was systematically evaluated for its efficacy in promoting infected wound healing. This article is based on the research paper authored by Minglang Zou et al., which was published in Advanced Healthcare Materials in 2025.

Research Workflow and Methods

This study introduced a simple yet effective “one-step” method for preparing CTG hydrogel. The process involved forming a metal-phenolic network between tannic acid (TA) and trivalent gallium ions (Ga³⁺), which was further combined with the naturally antibacterial polymer chitosan (CS). This approach avoided the tedious steps often associated with the preparation of multifunctional hydrogels.

1. Hydrogel Preparation and Optimization
   First, the research team optimized the conditions for forming metal-phenolic networks by adjusting the proportionality between tannic acid (TA) and trivalent gallium ions (Ga³⁺). Ultraviolet-visible spectroscopy (UV-Vis) revealed that the bis-coordination state between TA and Ga³⁺ was the most suitable bonding configuration. Subsequently, by introducing chitosan (CS) at various concentrations, the optimal mass ratio of CS, TA, and Ga³⁺ was determined to be 6:5:4.

2. Morphological and Structural Characterization
   Using scanning electron microscopy (SEM), the researchers observed the internal porous structure of CTG hydrogels, with pore diameters measuring approximately 10 microns, making them suitable for absorbing wound exudate and promoting gas exchange. X-ray photoelectron spectroscopy (XPS) confirmed the presence of gallium in its +3 valence state, while Fourier transform infrared (FTIR) spectroscopy verified the formation of hydrogen and coordination bonds between tannic acid, gallium, and chitosan.

3. Rheological and Self-Healing Properties
   Rheological tests demonstrated that CTG hydrogels exhibited excellent shear-thinning properties, allowing them to adapt to irregular wound shapes through injection. After being cut and reconnected, the hydrogels displayed rapid self-healing and enhanced mechanical stability.

4. pH Responsiveness and Drug Release
   The hydrogels showed responsiveness to acidic environments. In acidic conditions (pH < 6.5, typical of inflamed wounds), the TA-Ga³⁺ network and hydrogen bonds within the hydrogel disassociated, enabling the release of tannic acid and gallium ions with antibacterial and anti-inflammatory properties. Experiments revealed that over 72 hours, cumulative releases of gallium and tannic acid reached 60% and higher, respectively, with the rate significantly influenced by pH changes.

Experimental Results and Key Findings

1. In Vitro Biocompatibility
   Experiments using RAW264.7 macrophages and NIH-3T3 fibroblasts demonstrated that CTG hydrogels were non-toxic and supported long-term cell proliferation. Additionally, hemolysis assays showed excellent blood compatibility, with hemolysis rates below 5%.

2. Antibacterial and Antibiofilm Properties
   The hydrogels achieved nearly 100% antibacterial efficacy against common pathogens like Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Acinetobacter baumannii (A. baumannii), and Pseudomonas aeruginosa (P. aeruginosa), as well as antibiotic-resistant strains like MRSA and CRE. Their exceptional antibacterial performance is attributed to the “Trojan horse” mechanism of gallium ions, which is independent of traditional antibiotics. Furthermore, CTG hydrogels significantly inhibited biofilm formation, reducing residual biofilm to less than 20%.

3. Antioxidant and Anti-Inflammatory Features
   The hydrogels exhibited remarkable antioxidant capacity, achieving free radical (DPPH· and ABTS+·) scavenging rates of approximately 90%. In cellular experiments, they significantly reduced ROS levels in oxidative stress environments. Additionally, the hydrogels effectively suppressed the overexpression of inflammatory cytokines, such as TNF-α and IL-1β, in macrophages.

4. Histological Analysis and Wound Healing Assessment
   In a full-thickness infected skin wound mouse model, CTG hydrogels achieved a wound healing rate of 95.58%, outperforming the control and other treatment groups. Histological staining revealed greater epidermal thickness, granulation tissue density, and collagen deposition in the CTG group, as well as the formation of new hair follicles and skin appendages.

5. Hemostatic Performance
   In both mouse tail and liver injury models, CTG hydrogels significantly reduced bleeding time, shortening the hemostasis period by more than half and minimizing blood loss.

Research Significance and Innovations

This study addresses the limitations of previous multifunctional hydrogels, such as complex preparation processes and high costs, by developing a low-cost and easily prepared material with superior multifunctionality suitable for infected wound healing. By combining the unique properties of chitosan, tannic acid, and trivalent gallium, the CTG hydrogel not only effectively combats antibiotic-resistant pathogens but also offers antioxidant, anti-inflammatory, and hemostatic benefits. This research provides a robust theoretical foundation and technical support for developing next-generation medical dressings and advancing clinical applications.

By showcasing its unparalleled comprehensive properties, the CTG hydrogel offers a novel perspective for treating infected wounds, promising extensive applications and potential market value.