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International Journal of Pharmaceutics: X logoLink to International Journal of Pharmaceutics: X
. 2026 Jan 30;11:100502. doi: 10.1016/j.ijpx.2026.100502

ROS-triggered smart hydrogel adhesives for modulating the inflammatory microenvironment and promoting tendon-bone interface regeneration

Hebei He a, Yifen Lin b, Jia Fang c, Kai He c, Wenjun Li b, Min Du b, Shilong Lin b, Xiaofei Zheng c,⁎, Hanyu Lu a,c,⁎
PMCID: PMC12906134  PMID: 41695772

Abstract

Currently, suture surgery for rotator cuff repair is unable to regenerate the original functional fibrocartilage layer at the tendon-bone interface, resulting in high postoperative retear rates. In this study, a ROS-triggered smart hydrogel adhesive (DPQP@ME) was designed to synergistically enhance the functional repair of the tendon-bone interface during suture surgery by modulating the inflammatory microenvironment, promoting cell differentiation, and providing mechanically adaptive support. Metal-phenolic nanoparticles (ME) with multiple bioactivities were formed through the self-assembly of epigallocatechin gallate (EGCG) and Mg2+. Subsequently, ME, dithiothreitol (DTT), polyethylene glycol diacrylate (PEGDA), and boronic acid-modified quaternary ammonium chitosan (QCS-PBA) were crosslinked via borate ester bonds, thioether bonds, and photo-crosslinking to form a bioactive hydrogel adhesive with ROS responsiveness and favorable mechanical properties. Based on the ROS sensitivity of the borate ester bonds and thioether bonds, DPQP@ME exhibited favorable ROS-responsive drug release properties, with ME release reaching 73.15 ± 1.35% in H2O2-containing PBS versus 33.15 ± 1.65% in PBS alone. In vitro cellular experiments demonstrated that DPQP@ME could effectively reduce intracellular ROS levels, regulate macrophage polarization toward an anti-inflammatory phenotype, and promote osteogenic differentiation as well as cartilage formation. Animal studies further demonstrated that DPQP@ME significantly attenuated inflammatory responses and promoted functional reconstruction of the tendon-bone interface. In conclusion, this novel smart hydrogel adhesives provides a promising therapeutic strategy for tendon healing.

Keywords: ROS-responsive, Hydrogel adhesive, Anti-inflammatory, Antioxidant, Tendon-bone interface regeneration

Graphical abstract

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1. Introduction

Rotator cuff tear is one of the most prevalent musculoskeletal disorders, closely associated with aging and shoulder overuse(Bedi et al., 2024; Chen et al., 2024b; Xiong et al., 2025). Currently, arthroscopic rotator cuff repair is the gold standard for rotator cuff repair. However, suture surgery still faces limitations such as a lack of biological repair capacity, uneven stress distribution, and stimulation of inflammatory reactions. The regenerated tendon-to-bone junction typically develops into fibrovascular scar tissue with limited mechanical strength, instead of restoring the natural gradient fibrocartilage transition zone, resulting in high postoperative retear rates and poor healing outcomes(Ma et al., 2024; Ouyang et al., 2025; Tan et al., 2025; Xu et al., 2024). Achieving effective tendon-bone interface integration and functional regeneration remains a significant clinical challenge. Research indicates that sustained inflammation is a key factor contributing to fibrotic scarring and failed interface regeneration(Chen et al., 2025b; Huang et al., 2020; Qin et al., 2025). Rotator cuff injuries are typically accompanied by microenvironmental damage, resulting in excessive early-stage reactive oxygen species (ROS) production. Concurrently, prolonged ROS accumulation amplifies proinflammatory cytokine secretion, creating a hyperinflammatory microenvironment. Therefore, there is an urgent need to develop novel therapies that modulate the inflammatory microenvironment and promote fibrocartilage regeneration to enhance rotator cuff healing.

Epigallocatechin-3-gallate (EGCG), a natural polyphenolic compound derived from green tea, demonstrates potent antimicrobial, anti-inflammatory, and antioxidant properties, making it widely investigated in diseases associated with oxidative stress and inflammation(Gu et al., 2024; He et al., 2025; Kar et al., 2022; Liu et al., 2023). In particular, EGCG has been shown to be effective in inducing macrophage polarization to the M2 type, which plays a crucial role in tissue repair(Hu et al., 2025; Nie et al., 2023; Ye et al., 2023). However, the therapeutic use of EGCG is constrained by its limited bioavailability and instability. Recent studies have shown that forming metal-phenolic coordination complexes with metal ions can significantly enhance the bioavailability and stability of EGCG, while also integrating the bioactivities of both EGCG and metal ions, thereby providing additional therapeutic benefits(Chen et al., 2024a; Hu et al., 2025; Mao et al., 2025). Hu et al. developed an injectable hydrogel incorporating EGCG-Cu complexes that synergistically combats periodontitis via antibacterial, immunomodulatory, and osteogenic effects(Hu et al., 2025). Li et al. developed a bioactive hydrogel platform incorporating EGCG-Cu coordination capsules, which promotes burn wound healing through immunomodulation and oxidative stress mitigation(Li et al., 2023). Mg2+ is a multifunctional bioactive metal ion that can promote the migration, adhesion, proliferation, and differentiation of stem cells at injury sites, garnering widespread attention in the development of orthopedic biomaterials(Chen et al., 2020; Chen et al., 2021; Li et al., 2024). Chen et al. revealed that Mg2+ effectively improved the regeneration of the fibrocartilage layer at the interface of tendon and bone in a rabbit rotator cuff tear model(Chen et al., 2020). Li et al. demonstrated that Mg-based nanoflower-incorporated controlled-release hydrogels exhibit synergistic effects in immunomodulation and cartilage regeneration during tendon-to-bone healing(Li et al., 2024). Thus, the coordination of Mg2+ with EGCG to form metal phenol complexes (ME) with inflammatory microenvironmental modulation and pro-regenerative functions could provide an effective synergistic therapeutic strategy for the repair of the tendon-bone interface.

Although ME holds significant therapeutic potential for tendon-bone interface repair, its standalone application faces limitations, such as insufficient sustained action and lack of mechanical support. Therefore, it is imperative to develop advanced drug delivery systems to enhance the therapeutic efficacy of ME. In recent years, hydrogel adhesives have garnered significant attention in orthopedics and sports medicine due to their unique advantages, including excellent biocompatibility, shape adaptability, sufficient flexibility and mechanical strength(Bingol et al., 2023; Fang et al., 2022; Huang et al., 2025; Jiang et al., 2022; Krishnan et al., 2025; Yuan et al., 2021). The application of hydrogel adhesives with appropriate mechanical properties to assist in suture surgery can effectively distribute stress loads, reduce localized suture tension, and protect vulnerable tendon tissues, thereby significantly enhancing repair outcomes. Therefore, combining ME with hydrogel adhesives offers an ideal strategy to overcome the limitations of ME in tendon healing applications. Furthermore, leveraging the characteristic high ROS levels at tendon-bone injury sites, the development of ROS-responsive smart drug delivery systems offers novel perspectives for improving drug utilization efficiency, therapeutic efficacy, and biosafety in tendon-bone interface regeneration(Criado-Gonzalez and Mecerreyes, 2022; Liu et al., 2025; Wang et al., 2022; Zhang et al., 2025).

In this study, a ROS-triggered smart hydrogel adhesive (DPQP@ME) was developed to assist in suturing surgery and promote functional regeneration at the tendon-bone interface. As depicted in Scheme 1, EGCG and Mg2+ formed nanoparticles (ME) through metal-phenolic coordination. Subsequently, ME, DTT, PEGDA, and boronic acid-functionalized quaternized chitosan (QCS-PBA) were mixed to obtain the hydrogel precursor solution. After injection into the injured site, the hydrogel precursor solution undergoes rapid in situ photopolymerization under blue light irradiation to form a hydrogel adhesive (DPQP@ME), filling the irregular gaps between the tendon and bone. In the hydrogel, PEGDA and DTT were photo-crosslinked to form thioether bonds, while QCS-PBA formed borate ester bonds with the diol groups. The hybrid network structure in DPQP@ME confers excellent mechanical properties, providing the necessary mechanical support for tendon-bone interface repair. Owing to the ROS sensitivity of the thioether bonds and borate ester bonds, DPQP@ME can intelligently release drugs at the tendon-bone interface. ME synergistically enhance tendon-bone junction regeneration by regulating the inflammatory microenvironment, promoting osteoblast differentiation, as well as facilitating cartilage regeneration. This hydrogel adhesive integrates advantageous material properties with bioactive therapeutic agents, representing a promising novel therapeutic strategy for tendon-to-bone healing.

Scheme 1.

Scheme 1

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Fabrication of DPQP@ME and its impact on tendon-bone healing.

2. Methods

2.1. Materials

EGCG, PEGDA, DTT, MgCl2, and quaternized chitosan (QCS) were purchased from Shanghai Macklin Biochemical Co., Ltd. (Shanghai, China). The DPPH and ABTS radical scavenging assay kits were obtained from Keaibo Biotechnology Co., Ltd. (Shanghai, China). The antibodies utilized for immunofluorescent as well as immunohistochemical analysis were ordered from Thermo Fisher Scientific (Shanghai, China).

2.2. Synthesis of ME

MgCl2 solution (3 mM, 5.0 mL) was introduced into EGCG solution (0.5 mg/mL, 25.0 mL), followed by reaction at 45 °C for 1 h. Subsequently, the EGCG-MgCl₂ reaction mixture was transferred into a bottle sealed with a rubber stopper. Nitrogen gas was introduced into the container via a needle to thoroughly displace the air inside. Under a continuous flow of nitrogen gas for protection, NaOH solution (5 mL, 0.5 M) was injected into the mixture. Following an 8-h reaction period, ME was isolated via centrifugation and subsequently rinsed three times with deionized water. The chemical and morphological structures of ME were characterized by fourier transform infrared spectroscopy (FTIR), UV–vis spectroscopy, transmission electron microscopy (TEM) as well as energy dispersive X-ray spectroscopy (EDS).

2.3. Synthesis of QCS-PBA

QCS-PBA was obtained through the amide condensation reaction of PBA and QCS. First, a solution containing PBA (0.12 g), EDC (0.109 g), and NHS (0.079 g) in DMSO was prepared and stirred for 4 h to commence the synthesis. The mixture was then slowly titrated into 40 mL of an aqueous QCS solution (8 mg/mL) and the reaction mixture was stirred for 12 h. After that, purification was achieved by dialyzing the solution against deionized water for 5 days. Product isolation was accomplished via lyophilization, yielding the final QCS-PBA.

2.4. Preparation of DPQP@ME

DPQP@ME were fabricated through a blue light-initiated photo-crosslinking process. Specifically, a certain amount of 100 mg/mL DTT solution (prepared in PBS, pH 7.4) was added dropwise into a 300 mg/mL PEGDA solution (prepared in PBS, pH 7.4) under stirring. Subsequently, the mixture was stirred continuously at 25 °C for 2 h. Afterward, QCS-PBA (2.5 wt%) and photoinitiator (I2959, 0.05 wt%) were introduced, followed by the incorporation of ME and stirring for 20 min. The resulting precursor solution was cast into a mold and photopolymerized under blue light (100 mW/cm2) for 10 s to obtain DPQP@ME.

2.5. Mechanical property testing

The mechanical properties of DPQP@ME were evaluated through compression testing. Briefly, cylindrical hydrogel samples (Ø10 × 8 mm) were subjected to compression at a rate of 2 mm/min using a universal testing machine to obtain stress-strain curves. Furthermore, in order to assess the mechanical stability of DPQP@ME, 30 cyclic compression tests at 40% strain were performed under the above conditions.

2.6. Adhesion Testing

Moreover, porcine skin was used as a substrate to conduct lap-shear tests for quantifying the adhesive strength of the hydrogel. Briefly, the porcine skin was cut into uniformly sized rectangular strips using a cutter, and a bonding area (2 cm × 2 cm) was marked at one end of each strip. A pipette was used to evenly apply the hydrogel precursor solution (100 μL) onto the bonding area, which was then covered with a glass slide. The overlapping regions were carefully aligned and gently pressed. After photo-curing, tensile testing was performed on a universal testing machine equipped with a 1 kN load cell at a constant crosshead speed of 10 mm/min until adhesive failure occurred at the bonding interface. The force-displacement curve was recorded, and the adhesive strength was calculated.

To evaluate the adhesion stability of DPQP@ME, precursor solutions of DPQP@ME were spot-applied onto pig skin. Following photopolymerization, the adhesion sites were subjected to bending, stretching, and twisting, and the adhesion status of DPQP@ME was observed.

To evaluate the cell adhesion properties of the hydrogels, MC3T3-E1 cells were co-culturing with DP, DPQP, and DPQP@ME for 24 h. The adhesion and spreading of cells on hydrogels were observed using biological SEM.

2.7. Release behavior testing

A 1 mL of hydrogel samples were immersed in 5 mL of either PBS (pH 7.4) or PBS containing H2O2 (1 mM, pH 7.4). The PBS solutions of each group were taken at specific time points and the absorbance at 242 nm was detected in response to the release of ME.

2.8. In vitro degradation experiment of DPQP@ME

The degradation property of DPQP@ME was evaluated in lysozyme-containing PBS solution (pH 7.4, 1 mg/mL lysozyme). Briefly, the hydrogel samples were immersed in the PBS solution and collected at set intervals, followed by freeze-drying and weighing.

2.9. Evaluation of antioxidant properties

Evaluation of DPPH radical scavenging capacity of DPQP@ME. First, the extract samples of DP, DPQP, and DPQP@ME were prepared using the extraction solution from the kit. The hydrogel samples from each group were combined with the DPPH solution and kept in darkness for 25 min. Subsequently, wavelength scanning was performed from 400 to 600 nm. The change in absorbance at 517 nm reflects the radical scavenging ability of the samples.

The ABTS· + radical scavenging capacity was assessed by mixing the extract samples of each hydrogel group with freshly prepared ABTS working solution, followed by a 10-min reaction in the dark. Subsequently, a wavelength scan was performed from 600 to 900 nm. The change in absorbance at 734 nm reflects the radical scavenging ability of the samples.

2.10. Evaluation of antimicrobial properties

hydrogel samples (400 μL) were introduced into 2 mL aliquots of bacterial suspensions for Escherichia coli (E. coli, obtained from BeNa Culture Collection, BNCC391765) and Staphylococcus aureus (S. aureus, obtained from BeNa Culture Collection, BNCC336902), separately. The mixtures were then incubated at 37 °C with constant agitation in an orbital shaker. At designated time intervals, 100 μL aliquots of the bacterial suspension were collected and supplemented with 100 μL of fresh bacterial culture medium. The antibacterial efficacy of the hydrogels was assessed by measuring the OD620 of bacterial suspension samples. Additionally, bacterial activity in bacterial suspensions co-cultured with hydrogel samples for 8 h was observed using the plate count method.

After co-culturing the hydrogel samples with suspensions of E. coli and S. aureus (1 × 106 CFU/mL) for different time points, samples were taken, diluted, and plated on agar plates. After incubating in a bacterial incubator for 20 h, plate counting was performed, and killing curves were plotted.

The antibiofilm activity of the hydrogel was evaluated using the crystal violet staining method. Suspensions of E. coli and S. aureus were inoculated into LB medium containing 1% glucose, and hydrogel extracts were added separately for co-incubation. After 24 h of incubation, the culture medium was removed, and the biofilms were air-dried at room temperature, washed three times with deionized water, fixed, and then stained with crystal violet for observation.

2.11. In vitro biocompatibility evaluation

The cytocompatibility of DPQP@ME was assessed using MC3T3-E1 mouse preosteoblasts. Cells cultured to an appropriate density were exposed to extracts of DP, DPQP, and DPQP@ME for 24 and 48 h. The cellular proliferation activity was quantified using the CCK-8 assay, while cell survival was assessed via live/dead double staining. To further examine cellular morphology and cytoskeletal organization, treated cells were stained with FITC-labeled phalloidin after 48 h and imaged using fluorescence microscopy.

2.12. Intracellular ROS scavenging

MC3T3-E1 cells were cultured to an appropriate confluency and then pretreated with H2O2 (200 μM) for 2 h. Following medium replacement, cells were incubated for an additional 6 h in fresh culture medium containing either DP, DPQP, or DPQP@ME hydrogel extracts. Finally, intracellular ROS levels were stained using a 10 μM DCFH-DA fluorescent probe and analyzed by fluorescence microscopy.

2.13. In vitro anti-inflammatory effect

An LPS-induced inflammation model in mouse monocyte-macrophage leukemia cells (RAW264.7) was used to evaluate the anti-inflammatory effect of DPQP@ME. Briefly, RAW264.7 cells were cultured to an appropriate confluency and then pretreated with 10 μg/mL LPS for 24 h. Following medium removal, cells were treated with fresh culture medium containing either DP, DPQP, or DPQP@ME hydrogel extracts and incubated for an additional 48 h. The polarization state of RAW264.7 cells was evaluated through immunofluorescence staining of CD86 and CD206 markers. Additionally, ELISA was used to measure inflammatory cytokine levels in the RAW264.7 cell culture supernatant.

2.14. Investigation of DPQP@ME'S function in enhancing osteogenic differentiation in vitro

To evaluate osteogenic differentiation, adherent MC3T3-E1 cells were treated with DP, DPQP, or DPQP@ME extracts. On day 7 of treatment, alkaline phosphatase (ALP) staining was performed to evaluate osteoblast activity and early-stage osteogenic differentiation. On day 21 of treatment, analysis of mineralization was performed using Alizarin Red S (ARS) staining, with calcium nodule formation being subsequently imaged and analyzed by fluorescence microscopy.

2.15. Investigation of DPQP@ME'S function in promoting chondrogenesis in vitro

To evaluate chondrogenic differentiation, adherent ATDC5 cells were cultured in medium containing DP, DPQP, or DPQP@ME hydrogel extracts for 21 days, with the medium being refreshed every other day. Following the culture period, cells were subjected to Alcian blue and Safranin O staining to assess glycosaminoglycan (GAG) and proteoglycan content, respectively. Cartilage matrix formation was subsequently analyzed by fluorescence microscopy.

2.16. Establishment of an acute rotator cuff tear (RCT) repair model in rats

Acute RCT model was established using 10-week-old male Sprague Dawley rats obtained from the Guangdong Laboratory Animal Center. All animal experiments were approved by the Medical Ethics Committee of Guangzhou University of Chinese Medicine. Prior to experimentation, the rats were housed for over one week in a SPF setting with ad libitum access to food and water. In the experiment, rats were randomly assigned to 4 groups: sham-operated group, Suture group, Suture + DPQP group and Suture + DPQP@ME group, with 6 animals per group. After the rats in the surgery group were anesthetized by intraperitoneal injection of sodium pentobarbital, the supraspinatus tendon was sharply dissected with microscopic scissors, and a 1-mm-deep bone groove was sharpened at the greater trochanter of the humerus. 100 μL of saline, DPQP, and DPQP@ME were injected into the grooves of the rats in the Suture group, the Suture + DPQP group, and the Suture + DPQP@ME group, respectively. Subsequently, the retracted tendon segments were reset to the bone groove and sutured with 6–0 nonabsorbable suture. Rats in the sham-operated group underwent tendon exposure only, without transection. At 8 weeks post-operation, the rats were euthanized, and the supraspinatus tendon-humerus complex was harvestedfor subsequent analysis.

2.17. The therapeutic effects of DPQP@ME in vivo

The samples were fixed in 4% paraformaldehyde and embedded in paraffin for sectioning. Histopathological evaluation was performed using H&E staining, Masson staining, toluidine blue staining, Safranin O-fast green staining, and Sirius red staining. Immunohistochemical (IHC) analysis was performed to assess the expression levels of type I collagen (COL—I) and type III collagen (COL-III) using Anti-FCN1/M-Ficolin Rabbit pAb (Servicebio, GB113616, 1:3000) and Anti-Collagen III Rabbit pAb (Servicebio, GB111629, 1:1000), respectively. Meanwhile, immunofluorescence (IF) staining was conducted to detect the expression of M1 macrophage marker and M2 macrophage marker using Recombinant Anti-iNOS antibody (Rabbit mAb) (Servicebio, GB153965, 1:2000) and Anti-Mannose Receptor/CD206 Rabbit pAb (Servicebio, GB113497, 1:800), respectively.

In addition, tendon-bone complexes harvested from experimental rats after 8 weeks of treatment were performed tensile testing on a universal testing machine equipped with a 1 kN load cell at a speed of 10 mm/min. Force-displacement curves were recorded, and the failure load and stiffness were subsequently calculated.

2.18. Statistical analysis

All data were obtained from at least three independent biological replicates (n ≥ 3). The results were expressed as mean ± standard deviation (SD). Prior to multiple comparisons, data normality was verified via the Shapiro–Wilk test, while variance homogeneity was evaluated using the Brown–Forsythe test. As the data satisfied the assumptions for parametric analysis, a one-way ANOVA was conducted, with subsequent post hoc testing using Tukey's method. Significance levels are denoted as follows: *p < 0.05, **p < 0.01, and ***p < 0.001.

3. Results and discussions

3.1. Synthesis and characterization of ME and QCS-PBA

ME was formed by the self-assembly of EGCG coordinated with Mg2+ under alkaline conditions (Fig. 1A). The oxidation degree of EGCG before and after NaOH treatment under nitrogen protection was evaluated using FTIR. The results showed that EGCG did not undergo significant oxidation in an alkaline environment when protected by nitrogen, indicating that during the synthesis of ME, the antioxidant capacity of EGCG would not be compromised by oxidation reactions (Fig. 1B). Furthermore, FTIR spectral analysis revealed that, compared with EGCG, the absorption peak at 3375 cm−1 in ME was markedly attenuated, indicating that Mg2+ coordinates with free phenolic hydroxyl groups, thereby weakening the O—H stretching vibration (Fig. 1C). The vibrational peak at 1610 cm−1 attributed to the aromatic skeleton was also substantially diminished in ME, primarily resulting from the redistribution of electron density in the benzene ring induced by Mg2+ coordination (Fig. 1C). TEM images demonstrated that the resulting ME were spherical particles with a size of approximately 3 nm (Fig. 1D-E). Additionally, UV–vis spectroscopy showed that EGCG exhibits a characteristic absorption peak at 275 nm, which aligns with the literature-reported absorption peak position of EGCG(An et al., 2026; Chen et al., 2025a). After the chelation of EGCG with Mg2+, a slight blue shift occurred in the characteristic absorption peak of the resulting ME, appearing at 242 nm (Fig. 1F). EDS further verified the presence of C, N, O, and Mg elements in ME (Fig. 1G and H). Collectively, these findings confirm the successful synthesis of ME.

Fig. 1.

Fig. 1

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(A) Schematic Diagram of the Metal Phenolic Network Chemical Structure of ME. (B) FTIR spectra of EGCG before and after NaOH treatment under oxygen-free conditions. (C) FTIR spectra of EGCG and ME. (D) TEM images and (E) particle size distribution plots of ME. and (F) UV–vis spectra of EGCG and ME. (G) EDS spectra and (H) elemental distribution plots of ME. (I) 1H NMR spectra of QCS and QCS-PBA. n = 3, Data are presented as mean ± standard deviation (SD).

QCS-PBA was obtained through the amide condensation reaction between PBA and QCS, and its chemical structure was characterized by 1H NMR. The results indicated that QCS-PBA exhibited characteristic peaks at 7.4–8 ppm, attributed to the protons on the benzene ring of PBA (Fig. 1I). The calculated grafting ratio of the boronic acid group was 33.77%. These results confirmed the successful synthesis of QCS-PBA.

3.2. Synthesis and characterization of DPQP@ME

Next, a ROS-triggered smart hydrogel adhesive loaded with ME (DPQP@ME) was prepared. In the hydrogel, PEGDA and DTT were photo-crosslinked to form thioether bonds, while QCS-PBA formed borate ester bonds with the diol groups. The polymerization of PEGDA and DTT was confirmed by FTIR spectroscopy. As depicted in Fig. 2A, the FTIR spectrum of DTT displays a distinct peak at 3470 cm−1, corresponding to the O—H stretching vibration of hydroxyl groups. Upon formation of the DP, the intensity of this peak markedly diminished. Additionally, the characteristic peak for the thiol group (–SH) observed at 2555 cm−1 in DTT was entirely absent in the spectrum of the DP. These changes confirm that the thiol groups in DTT successfully reacted with the acrylate double bonds in PEGDA, demonstrating the successful formation of the DP polymer.

Fig. 2.

Fig. 2

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(A) FTIR spectra of DP, DTT, and PEGDA. (B) Compressive stress-strain curves and (C) elastic modulus of DP, DPQP, and DPQP@ME. (D) Compressive stress-strain curves and (E) compressive stress-time curves of DPQP@ME for 30 cycles. (F) Force-displacement curve of the lap shear test for hydrogels and (G) adhesive strength. (H) Drug release profiles of DPQP@ME in the presence or absence of H2O2. (I) Degradation curve of DPQP@ME. (J) Schematic Diagram of Hydrogel Adhesion and Stability on Pig Skin. (K) SEM image of MC3T3-E1 cell adhesion on hydrogel. n = 3, Data are presented as mean ± standard deviation (SD).

The mechanical properties of the resulting DPQP@ME were evaluated. Compression tests demonstrated that DPQP@ME achieved a compressive strain of 60% and a compressive modulus of 612.47 ± 58.80 kPa, indicating excellent flexibility and deformation resistance (Fig. 2B and C). Furthermore, cyclic compression testing revealed that after 30 compression cycles at 40% strain, DPQP@ME exhibited no significant deformation or strength loss, confirming its superior stability and elasticity (Fig. 2D and E). The outstanding mechanical performance of DPQP@ME is primarily attributed to its hybrid covalent network, in which the double-bond polymerization network provides structural rigidity and mechanical support, while the boronic ester bonds confer self-healing properties and energy dissipation capabilities. The lap shear test of hydrogels demonstrated that DPQP@ME exhibited favorable adhesive properties on porcine skin, with an adhesive strength of 12.35 ± 0.48 kPa (Fig. 2F and G). The adhesive stability of DPQP@ME on porcine skin was further investigated. The results showed that after dropping DPQP@ME precursor solution onto porcine skin and photo-curing, DPQP@ME was observed to adhere firmly to the skin. Even after stretching, bending, and twisting, DPQP@ME neither cracked nor detached, indicating its favorable adhesive stability on wet tissues (Fig. 2J). Furthermore, biological SEM observations revealed that MC3T3-E1 cells were able to adhere well, spread, and proliferate on the surface of DPQP@ME (Fig. 2K). These results demonstrate that DPQP@ME possesses good cellular and tissue adhesiveness, enabling it to function as an auxiliary adhesive that acts as a “bridge” in suture-assisted surgical procedures.

To evaluate the ROS-responsive release characteristics of DPQP@ME, its release behavior was investigated in PBS solutions with or without H2O2. The results demonstrated that the presence of H2O2 significantly accelerated drug release from DPQP@ME (Fig. 2H). In H2O2-containing PBS solution, the cumulative release of ME reached 73.15 ± 1.35% over 100 h, substantially higher than that in PBS alone (33.15 ± 1.65%). This phenomenon may be primarily attributed to the cleavage of boronic ester and thioether bonds upon reaction with H2O2, which facilitates drug release. This characteristic enables DPQP@ME to precisely modulate the inflammatory microenvironment and effectively promote tissue regeneration during tendon-to-bone interface repair. Additionally, in vitro degradation experiments revealed that DPQP@ME gradually degraded over 14 days, indicating that this hydrogel adhesive can function as a temporary scaffold (Fig. 2I). It exerts anti-inflammatory and differentiation-inducing biological effects during the inflammatory phase of tendon healing, followed by timely degradation. This approach avoids the risk of long-term foreign body reactions and promotes the autologous remodeling of healing tissue.

3.3. Antioxidant and antimicrobial properties of DPQP@ME

In the injured tendon-to-bone interface, the vicious cycle between inflammatory response and excessive ROS accumulation serves as the primary driver of persistent inflammation(Yuan et al., 2025). Thus, scavenging surplus ROS is critical for modulating the inflammatory microenvironment. Radical scavenging assays demonstrated DPQP@ME's exceptional antioxidant capacity, exhibiting clearance ratio of 96.03 ± 0.01% for ABTS· + radicals and 88.31 ± 0.01% for DPPH radicals (Fig. 3A-D). These collective results substantiate DPQP@ME's therapeutic potential in ROS elimination and inflammatory microenvironment regulation for tendon-to-bone repair.

Fig. 3.

Fig. 3

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UV–vis curves and experimental images of (A) ABTS test and (B) DPPH test. (C) ABTS free radical scavenging ratio. (D) DPPH free radical scavenging ratio. Growth curves of (E) S. aureus and (F) E. coli treated with DPQP, DPQP@ME, or ME. Antibacterial kinetics of the hydrogel against (G) S. aureus and (H) E. coli. (I) Clearing ratio of S. aureus and E. coli by DPQP, DPQP@ME or ME treatment for 8 h and (J) images of colonies on solid medium. (K) Biofilm assays of the hydrogel against E. coli and S. aureus. n = 3, Data are presented as mean ± standard deviation (SD).

Antimicrobial hydrogels can effectively mitigate the high infection risks associated with medical implants. Antibacterial assays demonstrated that DPQP@ME significantly inhibits the growth of both S. aureus and E. coli (Fig. 3E and F). After 8 h of co-culture with DPQP@ME, bacterial suspensions plated on solid media showed markedly reduced colony formation compared to control groups, with clearance ratio reaching 91.16 ± 0.01% for S. aureus and 79.52 ± 0.02% for E. coli (Fig. 3I and J). Furthermore, time-kill curves revealed that after 18 h of treatment with DPQP@ME, the viable bacterial counts of S. aureus and E. coli decreased by 3.2 and 2.9 log10 units, respectively, relative to the starting point (Fig. 3G and H). In addition, crystal violet staining assays showed that DPQP@ME effectively eradicates biofilms formed by E. coli and S. aureus (Fig. 3K). Collectively, these results confirm the outstanding antimicrobial efficacy of DPQP@ME.

3.4. Biocompatibility assessment of DPQP@ME

MC3T3-E1 cells were used to assess the in vitro biocompatibility of DPQP@ME. Live/dead cell staining demonstrated that after 24 and 48 h of co-culture with DPQP@ME, MC3T3-E1 cells displayed evenly distributed green fluorescence and maintained a well-spread morphology (Fig. 4A-D). Meanwhile, CCK-8 assay demonstrated that the cell viability of MC3T3-E1 cells remained above 95% after 24 and 48 h of incubation with DPQP@ME (Fig. 4E). In addition, F-actin cytoskeleton staining was performed using FITC-labeled phalloidin. The results showed that MC3T3-E1 cells in the DPQP@ME group displayed a typical spreading morphology with clearly visible F-actin fibers and a larger spreading area (Fig. 4F and G). These results indicate that DPQP@ME possesses excellent cytocompatibility, which lays the foundation for its in vivo study and application.

Fig. 4.

Fig. 4

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Live/dead cell staining images of MC3T3-E1 cells treated with DP, DPQP and DPQP@ME for (A) 24 h and (B) 48 h. (C) CCK-8 assay. Quantitative analysis of live/dead cell staining at (D) 24 h and (E) 48 h. (F) Cytoskeletal staining images and (G) quantitative analysis of cell spreading area. n = 4, Data are presented as mean ± standard deviation (SD).

3.5. DPQP@ME scavenges intracellular ROS and modulates macrophage polarization

Based on the excellent antioxidant properties of DPQP@ME, intracellular ROS staining assay was performed in H2O2-stimulated MC3T3-E1 cells to further evaluate its therapeutic potential for oxidative stress mitigation. As shown in Fig. 5A and B, green fluorescence was significantly increased in H2O2-treated MC3T3-E1 cells, indicating substantial ROS generation. Following DPQP@ME treatment, the ROS-associated fluorescence intensity in H2O2-exposed cells was markedly attenuated, demonstrating DPQP@ME's potent ROS-scavenging capacity and oxidative stress alleviation.

Fig. 5.

Fig. 5

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(A) Staining images and (B) corresponding quantitative analysis of intracellular ROS in MC3T3-E1 cells. (C) Immunofluorescence staining images of CD86 and CD206 in RAW264.7 cells and (D-E) corresponding quantitative analysis. ELISA detection of (F) IL-6, (G) TNF-α, (H) IL-10, as well as (I) Arg-1 levels in macrophage culture supernatant. n = 4, Data are presented as mean ± standard deviation (SD).

Macrophages, as core effector cells of immune regulation, are essential for shaping the inflammatory microenvironment(Huang et al., 2025). To examine the function of DPQP@ME in macrophage polarization regulation, RAW264.7 cells were induced toward the M1 phenotype with LPS. Immunofluorescence staining assay demonstrated that the LPS-treated group showed significantly increased CD86 expression, confirming successful M1 polarization of RAW264.7 cells (Fig. 5C and D). DPQP@ME treatment of LPS-stimulated RAW264.7 cells markedly downregulated CD86 expression while substantially upregulating CD206 levels, indicating effective promotion of M2 phenotypic polarization (Fig. 5C and E). Additionally, ELISA analysis showed that DPQP@ME treatment significantly downregulated the expression of pro-inflammatory factors (IL-6 and TNF-α) in LPS-induced macrophages, while upregulating the expression of anti-inflammatory factors (IL-10 and Arg-1) (Fig. 5F-I). These findings reveal DPQP@ME's potential in regulating the inflammatory microenvironment and enhancing tendon healing.

3.6. DPQP@ME promotes osteogenic differentiation and cartilage formation in vitro

The synergy between osteogenic differentiation and cartilage formation plays a key role in structural regeneration and functional integration at the tendon-bone interface(Ouyang et al., 2025). To evaluate the osteogenic-promoting effects of DPQP@ME, MC3T3-E1 cells were subjected to ALP and ARS staining. ALP staining revealed that DPQP@ME-treated MC3T3-E1 cells showed dense blue-violet granules with significantly increased staining intensity compared with the control group, suggesting upregulated activity of early-stage osteogenic key enzymes (Fig. 6A and E). ARS staining demonstrated that MC3T3-E1 cells in the DPQP@ME group formed more numerous and larger orange-red mineralized nodules versus controls, indicating enhanced late mineralization (Fig. 6B and F). Furthermore, the chondrogenic-promoting effects of DPQP@ME were assessed in ATDC5 cells using Alcian blue and Safranin O staining. Alisin blue staining showed that the extracellular matrix in the DPQP@ME group showed a dense blue signal, reflecting substantial synthesis of chondroitin sulfate (Fig. 6C and G). In Safranin O staining, the DPQP@ME group exhibited intense red coloration, indicating markedly increased proteoglycan deposition (Fig. 6D and H). Collectively, these findings demonstrate that DPQP@ME effectively promotes both osteogenic differentiation and cartilage matrix formation, underscoring its significant potential for promoting tendon-bone healing.

Fig. 6.

Fig. 6

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(A) ALP staining and (B) ARS staining images. (C) Alisin blue staining and (D) safranin O staining images. Quantitative analysis of (E) ALP activity and (F) calcium deposition in ALP staining and ARS staining. Quantitative analysis of positive areas in (G) Alisin blue staining and (H)safranin O staining. n = 4, Data are presented as mean ± standard deviation (SD). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

3.7. DPQP@ME promotes tendon-bone interface repair

At 8 weeks post-operation, the supraspinatus tendon-humerus complexes of the experimental rats were subjected to histological analysis to evaluate the therapeutic effects of DPQP@ME on tendon-bone interface healing. H&E and Masson staining demonstrated that, relative to the Suture group, treatment with DPQP@ME led to markedly less infiltration of inflammatory cells and promoted the formation of denser, more regularly arranged collagen fibers at the tendon-bone junction, demonstrating the potent anti-inflammatory and pro-healing properties of DPQP@ME (Fig. 7A, B and F). Furthermore, toluidine blue staining showed uniform purplish-red heterostaining from the superficial to deep layers of cartilage and dense staining around cell traps at the tendon-bone interface in DPQP@ME-treated group, indicating physiological glycosaminoglycan (GAG) synthesis and distribution (Fig. 7C and G). Safranin O-Fast Green staining further revealed that the DPQP@ME-treated group developed a fibrocartilaginous transition zone at the tendon-bone interface, resembling that of natural tissue (Fig. 7D and H). Moreover, the ratio between COL-I and COL-III is crucial in influencing repair outcomes. During early healing phase, COL-III predominates as provisional matrix to facilitate cell migration and angiogenesis, while in remodeling phase, COL-I gradually replaces COL-III to provide mechanical strength. Sirius red staining demonstrated enhanced COL-I synthesis in the DPQP@ME-treated group, with the tendon-bone interface exhibiting a continuous red-stained band, characteristic of the fibrocartilaginous transition phase, indicating favorable healing progression (Fig. 7E and I). In addition, immunohistochemical analysis of COL-I and COL-III showed a lower expression level of COL-I and a higher expression level of COL-III in the Suture group, suggesting that the healing was stalled in the inflammatory and proliferative phase. In contrast, the DPQP@ME-treated group showed increased expression levels of COL-I and decreased expression levels of COL-III, suggesting that DPQP@ME was able to effectively promote collagen remodeling (Fig. 8A-C).

Fig. 7.

Fig. 7

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Analysis of tissue sections stained with (A) H&E, (B) Masson, (C) toluidine blue, (D) Safranin O-fast green, (E) and Sirius red. Quantitative analysis of (F) collagen area, (G) percentage of fibrocartilage area, (H) Safranin O-positive area, and (I) collagen-positive area in Masson staining, toluidine blue staining, Safranin O-fast green staining, and Sirius red staining. n = 6, Data are presented as mean ± standard deviation (SD). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 8.

Fig. 8

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Immunohistochemical analysis of (A) Col-I and (B) Col-III. (C) Quantitative analysis of the Col-I/Col-III Ratio in tissue sections. (D) Immunofluorescence double staining analysis of iNOS and CD206. Quantitative Analysis of (E) iNOS and (F) CD206 in tissue sections. (G) Force-displacement curve, (H) failure load, and (I) stiffness of biomechanical testing for tendon-bone complexes. n = 6, Data are presented as mean ± standard deviation (SD).

To evaluate the immunomodulatory effects of DPQP@ME at the tendon-bone interface, immunofluorescence staining was performed to analyze the expression of iNOS and CD206 in tissue sections. The results demonstrated that both iNOS and CD206 were highly expressed in the tissues of the Suture group, suggesting the presence of a significant inflammatory response. In contrast, the iNOS and CD206 in the DPQP@ME-treated group exhibited low expression levels similar to those in the Sham group, suggesting that macrophage infiltration was reduced, inflammation subsided, and repair entered the remodeling phase (Fig. 8D-F). Furthermore, biomechanical tensile testing of the tendon-bone complex revealed that compared to the Suture group, the Suture+DPQP@ME treatment group exhibited significantly enhanced failure load and stiffness in rat tendon-bone complexes (Fig. 8G-I). These findings collectively indicate that DPQP@ME can effectively modulate the inflammatory microenvironment and enhance functional recovery at the tendon-to-bone junction.

4. Conclusion

In summary, a novel ROS-triggered smart hydrogel adhesive (DPQP@ME) was developed to exert immunomodulatory and pro-regenerative effects through the controlled release of ME to promote tendon-bone interfacial repair. The resulting DPQP@ME exhibited excellent mechanical properties, and their flexibility, adhesion, and stability could provide an ideal mechanical transition and cushioning environment for tendon bone healing. Based on the ROS sensitivity of the thioether and borate bonds, DPQP@ME was able to respond sensitively to ROS levels to control drug release. This property facilitates the efficacy and biosafety of DPQP@ME in tendon bone healing therapy. In vitro studies demonstrated that DPQP@ME could effectively scavenge ROS levels in an oxidative stress cell model, induce macrophage transformation to an anti-inflammatory phenotype, and promote osteogenic differentiation of MC3T3-E1 cells as well as cartilage formation of ATDC5 cells, showing significant anti-inflammatory and pro-regenerative abilities. Animal experiments further verified the therapeutic effects of DPQP@ME in inhibiting inflammatory responses, promoting orderly arrangement of collagen fibers and regeneration of fibrocartilage transition zone. Thus, this hydrogel provides a novel therapeutic platform with translational potential for functional regeneration at the tendon-bone interface.

CRediT authorship contribution statement

Hebei He: Writing – original draft, Validation, Software, Methodology, Investigation, Formal analysis, Data curation. Yifen Lin: Supervision, Software, Methodology, Investigation, Data curation. Jia Fang: Validation, Software, Resources, Methodology, Investigation. Kai He: Validation, Software, Formal analysis, Data curation, Conceptualization. Wenjun Li: Visualization, Software, Methodology, Formal analysis. Min Du: Supervision, Software, Investigation, Data curation. Shilong Lin: Validation, Investigation, Formal analysis, Data curation. Xiaofei Zheng: Writing – review & editing, Visualization, Supervision, Software, Formal analysis. Hanyu Lu: Writing – review & editing, Software, Project administration, Methodology, Funding acquisition.

Funding

This work was supported by the Guangdong Basic and Applied Basic Research Foundation (grant number: 2023A1515110878).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Contributor Information

Xiaofei Zheng, Email: zhengxiaofei16@163.com.

Hanyu Lu, Email: luhanyu0129@163.com.

Data availability

Data will be made available on request.

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Data Availability Statement

Data will be made available on request.

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