Bone tissue repair and regeneration remain significant clinical challenges, especially in cases of infected bone defects (Chen et al., 2023a). The incidence of infection is notably elevated in open fractures and bone defects communicating with bacterial environments, such as the oral and nasal cavities, posing heightened therapeutic difficulties. The process of bone tissue regeneration involves a cascade of intricate reactions, necessitating the activation of the immune system and microenvironmental regulation (Lin et al., 2021, Zhu et al., 2021). The initial stage typically involves the occurrence and modulation of inflammation, wherein M1 macrophages release pro-inflammatory cytokines and reactive oxygen species (ROS) to trigger excessive fibrosis and healing impediments (Mantovani et al., 2013). Prolonged or excessive inflammation, including that induced by bacterial infections, can lead to the accumulation of excessive ROS and elevated oxidative stress levels. This, in turn, leads to mitochondrial dysfunction in osteoblasts and delayed bone repair (Choi et al., 2022, Jorgensen and Khoury, 2021). A promising strategy involving the development of biocompatible materials capable of inhibiting bacterial adhesion and biofilm formation while alleviating the microenvironmental oxidative stress can expedite the early-stage healing of bone defects. The advancement of materials with such attributes holds potential for enhancing the prospects of bone defect repair and regeneration.

Recent years have witnessed advancements in bone tissue engineering scaffolds; biocompatible hydrogels are considered excellent artificial bone defect repair materials by virtue of their physicochemical similarities to the extracellular matrix (ECM) and their drug loading and delivery capabilities (Xue et al., 2021). The co-mixing of drugs with hydrogels is a relatively simple strategy that significantly enhances the relevant bioactivity of hydrogels. However, this strategy is susceptible to impaired biological effects ascribed to the initial burst release of drugs and the susceptibility of these drugs to deactivation (Sandor et al., 2002). Furthermore, owing to the complexity and variability of the microenvironment in bone defects, the release rate of drugs often struggles to meet the dynamic requirements, inevitably resulting in delayed bone healing (Wang et al., 2023). Developing a smart controlled-release drug delivery system that dynamically responds to oxidative stress environments and microbial infections by incorporating active ingredients serving multiple purposes, such as osteogenesis, antioxidation, and anti-bacteria, sheds light on the materials that can be utilized as scaffolds to repair bone tissue defects.

Under oxidative stress, the excessive generation of ROS exacerbates inflammatory responses at the bone defect, leading to a local pH lower than that of normal tissues (Liang et al., 2019, Tardito et al., 2019). Bacterial metabolism produces lactic acid and acetic acid, further contributing to a decreased local pH and intensified tissue inflammation (Albright et al., 2017). The inherent connection between ROS and the local pH suggests that they may serve as triggers for the release of active components in antioxidative response and antimicrobial defense.

Benzene boric acid and its derivatives belong to Lewis acids. Upon ionization, benzene boric acids can reversibly form covalent bonds with vicinal diol-functionalized substances, generating cyclic boronate complexes that are more hydrophilic. The formation and dissociation of these boronate complexes exhibit high sensitivity to pH and ROS (Chen et al., 2023b, Frasconi et al., 2010, Stubelius et al., 2019). Hence, materials functionalized with boronic acids acquire several advantages, such as a relatively strong affinity, broad-spectrum selectivity, and rapid binding/dissociation kinetics (Liu and He, 2017). Researchers have developed a magnetic graphene/mesoporous silica complex functionalized with boronic acids for the trace detection of aminoglycoside residues in milk (Feng et al., 2018). The affinity between boronic acids and aminoglycosides provides the material with a remarkable capacity for the selective separation of aminoglycosides from intricate matrix. Efficient and convenient glycoprotein imprinting was also realized by controlled directional surface imprinting based on the borate affinity (Wang et al., 2014).

Gelatin methacryloyl (GelMA) possesses arginine-glycine-aspartic acid sequences, which facilitates cell adhesion and provides a favorable three-dimensional (3D) microenvironment for bone tissue healing (Liu et al., 2022). Furthermore, GelMA can undergo stable chemical bonding with 3-acrylamido phenylboronic acid (APBA) through photo-induced unsaturated C = C bonds (Han et al., 2017). After their crosslinking, the formation and dissociation of boronate complexes offered by APBA can serve as a potential smart response to the local microenvironmental pH and/or ROS changes.

Proanthocyanidin is one of the most important polyphenols with rich catechol groups that can effectively scavenge oxidative radicals and activate antioxidant enzymes, thereby protecting tissues from oxidative damage. Studies have demonstrated that proanthocyanidin can promote osteogenesis under oxidative stress and modulate the balance between osteogenesis and osteoclast (Đudarić et al., 2015, Gourlay et al., 2022, Maiuolo et al., 2021). Amikacin is one of the most widely used aminoglycosides with a low resistance potential and superior pharmacokinetic profile. The cationic features endow amikacin with the ability to bind to anionic compounds (such as phospholipids, teichoic acids, and lipopolysaccharides) on the bacterial surface. Therefore, amikacin can increase bacterial permeability, penetrate the cytoplasm to produce high levels of errors in protein synthesis, and eventually lead to bacterial death (Maxwell et al., 2021, Ristuccia and Cunha, 1985).

The present study used the two aforementioned vicinal diol-functionalized substances, proanthocyanidin and amikacin, to bind with APBA, and the obtained boronate complexes were incorporated into the GelMA hydrogel. The hydrogel was expected to respond to bacterial infection and oxidative stress-induced reactions (reduction in the local pH and changes in ROS levels), driving the dissociation of the boronate complexes and leading to the release of proanthocyanidin and amikacin. The proanthocyanidin would foster the early proliferation and differentiation of osteoblasts under oxidative stress, and amikacin would simultaneously exert promising antibacterial effects (Fig. 1).