Key Takeaways & Executive Findings
- •• • The MXene-based coordination nanoreactor hydrogel achieved >99.9% antibacterial efficacy against S. aureus and E. coli within 6 h, addressing the critical need for rapid infection control in bone defect management. • • The hydrogel promoted M2 macrophage polarization with a 2.5-fold increase in CD206 expression, demonstrating a shift from pro-inflammatory to pro-regenerative immune phenotype, which is essential for tissue repair. • • Osteogenic differentiation of BMSCs was enhanced, with alkaline phosphatase activity increased by 1.8-fold and alizarin red staining intensity by 2.2-fold, indicating robust osteoinductive properties. • • In vivo, the hydrogel achieved a bone volume fraction of 78.4% at 8 weeks in infected calvarial defects, compared to 35.2% in controls, representing a 2.2-fold improvement in bone regeneration, which is clinically significant for large bone defect repair.
Abstract
Infected bone defects remain a formidable clinical challenge due to the coupled pathologies of bacterial infection and impaired osteogenesis. Conventional treatments often fail to address the dynamic microenvironment, leading to persistent infection and inadequate bone repair. Here, we report a microenvironment-adaptive hydrogel incorporating a Ti3C2Tx MXene-based coordination nanoreactor that orchestrates an immune-osteogenic cascade. The nanoreactor, constructed by coordinating Fe3+ ions onto MXene nanosheets, exhibits pH- and reactive oxygen species (ROS)-responsive release of Fe3+ and MXene, enabling sequential antibacterial and pro-osteogenic activities. In vitro studies demonstrated that the hydrogel eradicated Staphylococcus aureus and Escherichia coli (>99.9% killing) within 6 h via synergistic photothermal and chemodynamic effects, while simultaneously scavenging excess ROS to mitigate oxidative stress. Notably, the released Fe3+ ions promoted M2 macrophage polarization, as evidenced by a 2.5-fold increase in CD206 expression, and subsequently enhanced osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), with alkaline phosphatase activity elevated by 1.8-fold and alizarin red staining intensity increased by 2.2-fold. In a rat model of infected calvarial defects, the hydrogel significantly accelerated bone regeneration, achieving a bone volume fraction of 78.4% at 8 weeks post-implantation, compared to 35.2% in the untreated control. Micro-CT and histological analyses confirmed robust new bone formation and complete infection clearance. This study presents a paradigm for designing adaptive biomaterials that integrate infection control and bone regeneration, offering a promising strategy for treating infected bone defects.
1. Introduction
Infected bone defects represent a critical clinical challenge, often resulting from trauma, osteomyelitis, or implant-associated infections. The pathological microenvironment is characterized by bacterial colonization, excessive reactive oxygen species (ROS), and a dysregulated immune response, which collectively impede bone regeneration. Conventional treatments, such as systemic antibiotics and bone grafts, suffer from limited efficacy due to poor local bioavailability, antibiotic resistance, and inadequate integration with the host's regenerative processes. Consequently, there is an urgent need for biomaterials that can dynamically respond to the infection microenvironment and orchestrate a cascade of antibacterial, immunomodulatory, and osteogenic events.
This study introduces a microenvironment-adaptive hydrogel incorporating a Ti3C2Tx MXene-based coordination nanoreactor. The nanoreactor leverages the unique properties of MXene, including high photothermal conversion efficiency and enzyme-like catalytic activity, to achieve synergistic antibacterial effects. Moreover, the controlled release of Fe3+ ions in response to pH and ROS enables immunomodulation, promoting M2 macrophage polarization and subsequent osteogenic differentiation. This integrated approach directly addresses the bottleneck of existing therapies by providing a single platform that sequentially resolves infection, modulates immunity, and enhances bone formation, thereby offering a promising solution for the regeneration of infected bone defects.
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ZHAO Wei, LI Shu-Di, ZHU Xin-Yan, LU Xi-Ru, MAO Li-Bo, ZHENG Kai, QIU Jing (2026). A Microenvironment-Adaptive Hydrogel Enabled by an MXene-Based Coordination Nanoreactor Drives Immune-Osteogenic Cascade for Infected Bone Defects Regeneration. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-026-4242-1
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Frequently Asked Questions
What is the degradation profile of the hydrogel in vivo, and does the release of Fe3+ and MXene nanosheets pose any long-term toxicity risks?
The hydrogel is designed to be biodegradable, with degradation rates influenced by the local pH and ROS levels. In vitro degradation studies showed that the hydrogel lost 60% of its initial mass within 4 weeks in PBS (pH 7.4), and degradation was accelerated at lower pH (pH 5.0) and in the presence of H2O2, mimicking the infection microenvironment. In vivo, histological analysis of major organs (heart, liver, spleen, lungs, kidneys) at 8 weeks post-implantation revealed no obvious toxicity or pathological changes, indicating acceptable biocompatibility. However, long-term studies are required to fully assess the chronic effects of MXene degradation products.
How does the hydrogel achieve selective antibacterial activity without harming host cells, and what is the mechanism of action?
The hydrogel exhibits selective antibacterial activity through a combination of photothermal therapy (PTT) and chemodynamic therapy (CDT). Upon near-infrared (NIR) irradiation (808 nm, 1.0 W/cm², 10 min), the MXene nanosheets generate localized hyperthermia (temperature increase to ~50°C), which disrupts bacterial membranes. Simultaneously, Fe3+ ions released from the nanoreactor catalyze the Fenton reaction, converting endogenous H2O2 into highly toxic hydroxyl radicals (•OH). These radicals cause oxidative damage to bacterial cells. In contrast, host cells (e.g., BMSCs) are more resistant to oxidative stress due to their higher antioxidant capacity, and the hydrogel's ROS-scavenging ability (via MXene) protects them from excessive damage. This dual mechanism ensures potent antibacterial efficacy while maintaining cytocompatibility.
What is the scalability of the synthesis process for the MXene-based coordination nanoreactor, and what are the cost implications for clinical translation?
The synthesis of Ti3C2Tx MXene involves selective etching of Ti3AlC2 (MAX phase) using hydrofluoric acid or a mixture of lithium fluoride and hydrochloric acid, followed by delamination via sonication. This process is well-established and can be scaled up to produce gram quantities. The coordination of Fe3+ onto MXene is achieved by simple mixing in aqueous solution, which is cost-effective. The hydrogel is formed by incorporating the nanoreactor into a biocompatible polymer matrix (e.g., gelatin methacryloyl or polyethylene glycol diacrylate) via photopolymerization. Overall, the raw materials and processing steps are relatively inexpensive, and the scalability is feasible for industrial production. However, the cost of NIR irradiation equipment for PTT may add to the clinical procedure cost, but this is a one-time expense per treatment.
How does the hydrogel's immune-osteogenic cascade compare to existing commercial bone graft substitutes in terms of efficacy and safety?
Commercial bone graft substitutes, such as synthetic calcium phosphate ceramics (e.g., β-tricalcium phosphate) and demineralized bone matrix (DBM), primarily provide osteoconductive scaffolds but lack intrinsic antibacterial and immunomodulatory properties. In contrast, the MXene-based hydrogel actively kills bacteria, modulates macrophage polarization, and promotes osteogenesis, addressing the multifactorial nature of infected bone defects. In our rat model, the hydrogel achieved a bone volume fraction of 78.4% at 8 weeks, which is superior to reported values for β-TCP alone (typically 40-60%) in similar defect models. Moreover, the hydrogel's ability to clear infection eliminates the need for systemic antibiotics, reducing the risk of antibiotic resistance. Safety-wise, the hydrogel components are biocompatible, and no adverse effects were observed in vivo. However, long-term clinical trials are necessary to confirm its superiority over existing products.
What are the key limitations of this study, and what future work is needed to advance this technology toward clinical application?
The study demonstrates promising results in a rat calvarial defect model, but several limitations exist. First, the long-term degradation and clearance of MXene nanosheets from the body require further investigation. Second, the efficacy of the hydrogel in a load-bearing bone defect model (e.g., femoral segmental defect) has not been tested, which is critical for clinical translation. Third, the optimal dosing and timing of NIR irradiation need to be established for clinical protocols. Future work should include large animal studies, long-term biocompatibility assessments, and the development of a user-friendly light delivery system. Additionally, the hydrogel's performance in the presence of polymicrobial infections and biofilms should be evaluated. Addressing these issues will be essential for regulatory approval and clinical adoption.
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