{"paper_id":"2f1aa032-b70e-400b-b050-ea1578fed0f9","body_text":"Multi-functional phytoglycogen-derived hydrogel dressings promote the fast closure of diabetic wound in vitro and in vivo | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Multi-functional phytoglycogen-derived hydrogel dressings promote the fast closure of diabetic wound in vitro and in vivo Jingyi Zheng, Bo Pan, Jingya Guo, Tao Zhang, Yujie Lao, Tao Tong, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7222605/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Mar, 2026 Read the published version in Advanced Composites and Hybrid Materials → Version 1 posted 9 You are reading this latest preprint version Abstract Management of chronic diabetic wound was an emerging challenge, and designing a multi-functional hydrogel to promote wound repair is urgent for therapy. We firstly discovered a natural hydrogel dressing from modified phytoglycogen (PG) with cationization and oxidation for the Schiff base cross-linking. In vitro and in vivo studies reveal the hydrogel exhibited the favorable adhesion, self-healing, antibacterial and antioxidant properties, and the optimal CPG2-Gel forms efficient coverage in wound without contamination and infection. In the diabetic wound model, CPG2-Gel expedited the reactive oxygen species (ROS) clearance and immunoregulation, promoting cell proliferation, collagen deposition, and tissue formation to facilitate the wound closure with the healing rate of 1.76-fold compared to commercial dressing. The tumor necrosis factor-α (TNF-α) level was reduced to 87.5%, whereas the vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β) were enhanced up to 1.36 and 2.01 times, respectively. The mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways played crucial roles in mediating the polarization of alternatively activated macrophages (M2 macrophages), thereby facilitating cell proliferation, exerting anti-inflammatory effects, and regulating immune responses. This work can provide a facile and promising strategy for fabricating a multifunctional hydrogel dressing for fast therapy of diabetic wound. natural hydrogel phytoglycogen multi-functional ROS scavenging immunoregulation wound healing Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. Introduction Normal wound healing involves four sequential phases, hemostasis, inflammation, proliferation, and remodeling, critical for maintaining skin integrity and repairing external damage [ 1 – 3 ]. Chronic wounds like diabetic foot ulcers (DFUs) fail to follow this orderly process, attributed to dysregulated inflammation and immune dysfunction [ 2 ]. DFUs, a hyperglycemia-linked complication, affect ~ 6.3% of diabetics globally, with high recurrence/amputation rates and prolonged treatment challenges due to economic burdens and high morbidity [ 3 , 4 ]. Multifunctional wound dressings, particularly hydrogels, are prioritized for diabetic wounds due to their protective, anti-inflammatory, and healing-promoting properties, addressing prolonged inflammation [ 5 – 7 ]. Hydrogels, 3D polymer networks with tunable properties due to water-rich structures, are widely applied in wound dressings [ 8 ]. Their cross-linked architectures (non-covalent/covalent) enable microenvironment regulation, influencing cell behaviors and promoting healing processes like angiogenesis [ 9 – 11 ]. Synthetic polymers (PEG, PCL, PVA) offer robust mechanical properties but suffer from poor biodegradability and cytotoxicity risks [ 12 , 13 ]. However, these polymers, derived from petrochemical sources, were chemically cross-linked to achieve favorable mechanical properties, but they are accompanied by poor biodegradability and potential side effects, including cytotoxicity and chronic rejection [ 14 ]. The distinct properties of hydrogels, including adhesiveness, self-healing ability, and biocompatibility, have been manipulated to meet the specific requirements of potential biomedical applications [ 7 ]. Nevertheless, the limited degradability and cytotoxicity of conventional hydrogels for treating diabetic wounds stem from their intrinsic physicochemical features [ 15 ]. Fabricating hydrogel dressings with multifunctionality remains a significant challenge. To overcome the inflammation and closure issues of chronic wounds, many investigators designed advanced hydrogel dressings with antioxidant, antibacterial, and anti-inflammatory properties from exogenous substances for comprehensive treatment [ 10 , 16 ]. Advanced hydrogels address chronic wound challenges via multifunctional designs: Pranantyo et al.’s dual-functional hydrogel combines antibacterial polyimidazolium and antioxidant N-acetylcysteine [ 7 ]; carbon dots-based platforms provide photothermal antibacterial and anti-inflammatory effects [ 17 ]; AuPt@melanin hybrids regulate glucose/ROS levels to modulate macrophage polarization [ 18 ]. However, existing strategies still rely on exogenous agents (antibiotics, irradiation) and lack natural alternatives [ 11 , 19 , 20 ]. Natural hydrogels (starch, cellulose, alginate) show limited efficacy without RGD peptides/growth factors, highlighting the need for additive-free, multifunctional natural hydrogels in diabetic wound therapy [ 21 , 22 ]. PG, a hydrophilic, highly-branched analog of animal glycogen, is a primary short-term energy storage molecule in biological systems. Its α-1,4-linked linear chains are interconnected by α-1,6 branching linkages, with an average glucose unit length of 10–12, providing three accessible hydroxyl groups for derivatization [ 23 ]. Previously, we isolated PG from sugary-1 maize. It has a compact spherical-dendritic morphology, endowing it with excellent water-binding capacity, low intrinsic viscosity, and high stability due to surface hydroxyl groups [ 24 ]. Experiments showed PG can enhance skin cell energy metabolism by promoting ATP production and accelerating metabolism, increasing hyaluronic acid and collagen synthesis. PG-based formulations have rapid and sustained hydrating effects, reduce skin hyperpigmentation, and offer anti-aging benefits, showing potential in cosmeceuticals [ 25 , 26 ]. However, no prior research reported using naturally-derived hydrogels from modified PG for diabetic wound repair, and the molecular mechanisms of PG-derived hydrogels in immune regulation during diabetic wound healing were unknown at the time of this study. In this work, hydroxyl-functionalized chain segments were used to chemically modify sugary-1 maize-derived natural and renewable phytoglycogen (PG). A novel wound hydrogel dressing was developed via surface cationization, oxidation, and subsequent Schiff base cross-linking. PG, an amylopectin analog with nano-scale globular architecture and macrophage-stimulating activity, has inherent antimicrobial, antioxidant, and immunomodulatory properties [ 25 ]. Grafted quaternary ammonium groups offer antimicrobial activity, and aldehyde groups enhance antioxidant activity and adhesion. In vitro and in vivo studies showed that the optimal CPG2-Gel had superior therapeutic effects on diabetic wounds, healing 1.76 times faster than commercial dressings by scavenging ROS and immunoregulation. Relevant metabolic pathways were elucidated, and the immunomodulatory mechanisms of CPG2-Gel in wound healing were investigated. This study provides a facile strategy to fabricate multifunctional natural hydrogel dressings for chronic diabetic wound closure. 2. Materials and Methods 2.1 Materials Phytoglycogen (PG, MW 1.2×10 7 g/mol) were extracted and purified from sugar-1 maize according to the previous work [ 27 ]. 2,3-Epoxypropyltrimethylammonium chloride (GTAC), ethylenediamine (EDA), sodium periodate (NaIO 4 ), potassium persulfate (K 2 S 2 O 8 ), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) were purchased from Sigma-Aldrich. (St. Louis, MO). Other chemical reagents were of analytical grade. 2.2 Animals Male ICR mice (24–26 g) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China) and used for diabetic wound healing evaluation. All the animal experiments in this work have been approved by the Animal Ethics Committee of China Agricultural University (AW21804202-4-2). 2.3 Chemical derivatization of PG Cationization of PG was obtained using the following procedure. 5 g PG was mixed with 250 mL deionized water, then 15 mL EDA was added with stirring at 50°C for 4 h. Then, an appropriate amount of GTAC was then introduced into the system for 2 h reaction at 50°C. After the reaction is completed, the obtained solution is dialyzed for two days, then diluted with 3 times ethanol and stored at 4℃. The final precipitate was oven-dried and stored for further test. These cationic samples with an initial molar ratio of PG and GTAC for 1:1 and 1:15 were named as CPG1 and CPG2, respectively. Oxidation of PG was obtained using the following procedure. PG was solubilized in deionized water (5%, w/v) and mixed with NaIO 4 at a molar ratio of 2:1. The reaction was carried out at 30°C for 2 h under stirring, and an excess of 10% (v/v) ethylene glycol was added. The resulting solution was dialyzed for two days, and then lyophilized to obtain aldolylated PG (APG). 2.4 Characterizations of PG derivatives Particle size and zeta-potential measurements were recorded using a Zetasizer. Molecular weight distributions were analyzed using a HPSEC-MALLS-RI system. The chemical bonds were determined using FT-IR and NMR. The degree of substitution (DS) and degree of oxidation were calculated according to the standard methods [ 28 , 29 ]. 2.5 Fabrication of PG-derived hydrogel 5% (w/v) APG solution was dropwise added into 10% (w/v) CPG solution. The cross-linking reaction was carried at 30°C to obtain the hydrogel, and marked as CPG1-Gel or CPG2-Gel, respectively, depending on the DS of CPG. 2.6 Statistical analysis All experimental data were presented as the mean ± standard deviation (SD) and each assay was repeated for at least three independent times. The statistical significance was assessed using a student’s t-test and one-way ANOVA analysis. The statistically significant differences were expressed as * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, or ns (no significant), respectively. 3. Results and discussion 3.1 Fabrication and Characterization of PG-derived Hydrogel The cationization/oxidation of PG was demonstrated in Fig. 1 a. EDA/GTAC molecules were covalently grafted onto PG’s glucose units, releasing Cl⁻ counterions to generate positively charged cationic PG (CPG1/CPG2) with higher Mw/Rz than native PG (Table S1 ). DS values (grafted groups/available sites) reached 18.5% for CPG1 and 38.15% for CPG2. Oxidation cleaved C-2 and C-3 hydroxyls into dialdehyde groups, reducing Mw/Rz (Table S1 ). Zeta-potential increased post-modification, peaking at 28.78 ± 4.32 mV for CPG2 due to surface-bound quaternary ammonium groups. Monodisperse nanoparticles were confirmed (Fig. S1 a).¹H NMR showed -N⁺(CH₃)₃ (3.20 ppm) and -N-CH₂- (2.60 ppm) peaks in CPG [ 30 ]. FT-IR revealed N-H bending (1,512 cm⁻¹), CH₃-N⁺ vibrations (1,440 and 1,071 cm⁻¹), and APG’s aldehyde peak (1,740 cm⁻¹) [ 31 ]. CPG (10%) and APG (5%) mixed 1:1 formed Schiff base hydrogels via cross-linking (Fig. 1 d). Hydrogel fabrication was rapid and simple, involving mixing the two solutions to yield a hydrogel network. Compared to CPG1, CPG2, and APG (Fig. S1 b), Fig. 1 e showed a prominent stretching vibrational absorption peak at 1,645 cm⁻¹, indicative of the characteristic imine bond (C = N) in Schiff base bonds [ 32 ]. SEM showed CPG2-Gel’s denser structure than CPG1-Gel (Fig. 1 f and S2), attributed to CPG2’s higher DS enabling more Schiff base bonds. The swelling capacity of PG-derived hydrogels was evaluated in Fig. 2a. Ideal wound dressings should have an absorptive swelling rate of 100%-900% [ 33 ]. Both hydrogels showed time-dependent swelling, reaching about 200% equilibrium after 6 hours, indicating good water absorption. CPG2-Gel had better swell due to its porous structure and high cross-linking density. Degradation analysis (Fig. 2b) showed mass loss over time: 39.90 ± 1.96% for CPG1-Gel and 26.54 ± 1.36% for CPG2-Gel after 11 hours. CPG2-Gel degraded slower because of stronger cross-linking. Lap shear testing (ASTM-F2255) on glass substrates (Fig. 2c) showed CPG2-Gel had better adhesion than CPG1-Gel, due to more-N + (CH 3 ) 3 groups enhancing hydrophilicity [ 34 – 36 ]. Injectable performance tests with methyl blue-containing hydrogels on glass showed both maintained ‘Z’ patterns (Fig. S3). CPG2-Gel had finer structure due to its denser matrix and higher cationization. Both adhered well to stretched fingers. Rheological tests showed viscoelastic 3D networks. Strain sweep (0.1-3% strain: G’ >G’’; higher strain: G’’ >G’) (Fig. S4a), frequency sweep (stable at 0.1–100 rad/s) (Fig. S4b), and cyclic strain tests confirmed self-healing (modulus back to baseline after high-strain cycles) (Fig. 2e) [ 35 , 36 ]. 3.2 In Vitro Antioxidant and Antibacterial Activities of PG-derived Hydrogel Antioxidant hydrogel effectively reduces chronic wound oxidative stress, improves microenvironment and cellular metabolism, and accelerates wound healing. To evaluate the in vitro antioxidant effect of PG-derived hydrogel, ABTS and DPPH radical scavenging assays were conducted. IC 50 , the antioxidant concentration for 50% clearance, with a lower value indicating stronger scavenging ability [ 37 ]. Tables S2 and S3 show a concentration-dependent scavenging efficiency for chemically modified PG and PG-derived hydrogel. As concentration rose, scavenging rate increased. Figure 2f and 2g show CPG2-Gel had superior ABTS and DPPH scavenging at 1.0 mg/L and 30 mg/L by IC 50 comparison, likely due to CPG2’s higher cationic substitution degree. GTAC modification increased PG’s surface positive charge density, enhancing electrostatic interactions with negatively charged free radicals and scavenging efficiency. APG had the lowest IC 50 , contributing to the hydrogel’s antioxidant properties. Diabetic wound infections delay healing due to antibiotic resistance challenges [ 38 ]. Current treatments involving antibiotic and antimicrobial additives have been challenged by the increasing prevalence of antimicrobial resistance [ 39 , 40 ]. Consequently, antibacterial hydrogel dressings have emerged as a critical solution for optimizing the microenvironment to accelerate chronic wound closure. The antibacterial properties of PG-derived hydrogels were evaluated using S. aureus and E. coli as model organisms. Their antimicrobial efficacy was assessed via co-culture experiments, with results presented in Figs. 2h-2k. The MIC, defined as the lowest concentration of an antibacterial agent that inhibits visible bacterial growth under specified conditions, was determined. Lower MIC values indicate enhanced effectiveness against pathogens [ 41 ]. The antibacterial performance of PG-derived hydrogels was quantified using the plate count method. As shown in Fig. 2h, CPG2-Gel demonstrated a 50% reduction in MIC against S. aureus and a 29.3% reduction against E. coli compared to CPG1-Gel. Furthermore, CPG2-Gel exhibited significantly larger inhibition zone diameters of 31.5 ± 0.60 mm (for S. aureus ) and 22.8 ± 0.94 mm (for E. coli ), as illustrated in Figs. 2i, 2j, and S5. Its higher DS (degree of substitution) introduced positively charged groups that disrupted bacterial membranes via electrostatic attraction [ 42 ]. SEM revealed morphological changes in bacteria co-cultured with the hydrogel. In contrast to control bacteria (exposed to phosphate-buffered saline, PBS), which appeared intact and smooth, S. aureus and E. coli exposed to CPG2-Gel displayed partially damaged cell walls and pronounced shrinkage (Figs. S6 and 2k). Based on these findings, CPG2-Gel was selected as the optimal hydrogel for subsequent experiments due to its enhanced antibacterial efficacy compared to CPG1-Gel. 3.3 Biocompatibility and ROS Scavenging Properties To evaluate the biocompatibility of PG-derived hydrogels, hemolysis and cytotoxicity assays were conducted. In the hemolysis assay, the hemolysis rate of both PG and CPG2-Gel was found to be below 2% (Fig. 3 a), indicating excellent blood compatibility. Subsequently, cytotoxicity tests were performed using CPG2-Gel at varying concentrations. Notably, at a concentration of 0.01 mg/mL, the cell survival rate exceeded 90%, demonstrating excellent biocompatibility. RAW 264.7 and HDF cells were then cultivated in a 0.01 mg/mL PG-derived hydrogel solution for 48 hours. Pure cultures of RAW 264.7 and HDF cells served as the blank control group, while live/dead staining was employed to assess hydrogel biocompatibility. As illustrated in Fig. 3 c, the cell mortality of CPG2-Gel was significantly lower compared to the control group. Post-staining analysis revealed that the majority of cells exhibited vitality (green fluorescence), with only a small number of dead cells (red fluorescence) observed under microscopy (Figs. 3 d and 3 e). No statistically significant differences were observed between CPG2-Gel and the control group, further confirming their good biocompatibility. To investigate the hydrogel’s impact on cell migration, a scratch healing model was established. As shown in Fig. 3 f, the PG-derived hydrogel significantly enhanced the migration capacity of HDF cells compared to the control group. Collectively, these findings underscore the excellent biocompatibility of the PG-derived hydrogel and its capacity to promote HDF cell proliferation. ROS production was identified as a critical mediator of secondary injury in diabetic wounds, necessitating the indispensable ROS-scavenging capacity of natural hydrogels for effective wound healing. DPPH and ABTS radical-scavenging assays demonstrated that PG-derived hydrogel could effectively eliminate free radicals. To further validate its ROS-scavenging efficacy, RAW 264.7 and HDF cells were co-cultured with CPG2-Gel following H₂O₂ treatment. In the positive control group, cells were subjected to H₂O₂ treatment without hydrogel intervention, with sterile PBS used as a substitute. The DCFH-DA probe was employed to quantify intracellular ROS levels across all groups (Figs. 3 g and 3 h). Fluorescence microscopy revealed negligible fluorescence in untreated controls, while H₂O₂ treatment induced marked fluorescence enhancement, confirming substantial ROS generation. Notably, CPG2-Gel intervention significantly reduced ROS fluorescence intensity in both RAW 264.7 and HDF cells. Flow cytometry analysis further corroborated these findings, showing ROS rates decreased from 28.43 ± 1.68% (RAW 264.7) and 35.58 ± 2.26% (HDF) in H₂O₂-treated controls to 7.33 ± 0.54% and 6.46 ± 0.25%, respectively, in CPG2-Gel-treated groups (Fig. 3 i). Collectively, these results confirmed that PG-derived hydrogel effectively mitigates oxidative stress-induced cellular damage, demonstrating its therapeutic potential for diabetic wound management. 3.4 Therapeutic Performance on Diabetic Wounds We investigated the effect of PG-derived hydrogel (CPG2-Gel) on diabetic mouse wound healing using a 1-cm-diameter full-layer wound model. Circular diabetic wounds were treated with CPG2-Gel and commercial Tegaderm dressing, and wound healing was monitored at 3, 7, and 14 days. Digital photos showed gradual healing in both groups. The wound healing rates of the CPG2-Gel group at 3 and 7 days were 1.93 and 1.76 times those of the Tegaderm group respectively, achieving fast healing within two weeks (Figs. 4 b and 4 c). There had been attempts to integrate antioxidant additives with wound dressings, which might be accompanied by the risk of an exclusion reaction caused by the extra substance [ 28 ]. No wound infection or inflammation was observed with CPG2-Gel, indicating its excellent antibacterial property. During the 14-day period, the CPG2-Gel group had significantly expedited wound closure, with a healing rate of 70.77%, higher than the Tegaderm or control group (Fig. 4 d). Importantly, it was known that the continuous increase of oxidative stress products could promote the dysfunction of the cells around the wound, which finally led to delayed wound healing [ 43 ]. The antioxidant effect of CPG2-Gel on the wound tissue was further explored by assessing the levels of malondialdehyde (MDA), reduced glutathione (GSH), total antioxidant capacity (T-AOC), and total superoxide dismutase (T-SOD) activity after 3 days of treatment. Compared with the control and Tegaderm groups, the activities of GSH, T-SOD, and T-AOC in the wound tissue were significantly increased by CPG2-Gel (Figs. 4 e- 4 h). This indicated that CPG2-Gel could stimulate the ability to scavenge free radicals and reduce oxidative damage in the living body, and a protective effect was performed during the growth of cells and tissues. It’s well-known that excessive inflammation impedes wound healing, so effective inflammation management is crucial. On the 3rd day after wound dressing treatment, relevant inflammatory marker levels in wound tissue were evaluated. In the CPG2-Gel group, IL-6 and TNF-α levels were 2 and 5 times lower than in the control group respectively, and compared to Tegaderm, there were obvious decreases in these pro-inflammatory factors, indicating CPG2-Gel’s prominent anti-inflammatory effect at the wound site (Figs. 4 i and 4 j). A decreasing HMGB-1 level was also observed, suggesting an overall anti-inflammatory effect of the PG-derived hydrogel (Fig. 4 k). In chronic wounds, hyperglycemia and immune dysfunction impair the M1-to-M2 macrophage transition [ 44 ]. After 3 days, immunohistochemical staining of the M2 marker CD206 in wound tissue showed enhanced M2 macrophage infiltration and distribution in the CPG2-Gel group compared to the control and Tegaderm groups, while the fluorescence intensity of the M1 marker CD86 was reduced (Fig. 4 l). This indicates that CPG2-Gel can induce M1-to-M2 macrophage polarization, regulate the inflammatory microenvironment, and facilitate wound healing. Overall, CPG2-Gel can accelerate the inflammatory-to-proliferative transition in vivo, reduce oxidative stress, and regulate the inflammatory system. 3.5 In Vivo Immunoregulation Promoted Cell Proliferation and Angiogenesis Excessive inflammation challenges diabetic wound healing due to infection and impaired neovascularization. Granulation tissue formation, collagen deposition, and angiogenesis are key histological indicators. Immunohistochemical methods detected cell proliferation markers (PCNA and Ki67) to evaluate healing rates [ 45 ]. The CPG2-Gel group had significantly higher PCNA, Ki67, and CD31 (an angiogenesis index [ 46 ]) expression than the control and Tegaderm groups (Fig. 5 a). This finding correlated with increased capillary density and mature angiogenesis, corroborated by quantitative VEGF analysis (Fig. 5 d). Masson staining revealed incomplete wound closure in control and Tegaderm groups, accompanied by poor collagen organization and minimal muscle fiber regeneration (Figs. 5 b- 5 f). H&E staining demonstrated enhanced fibroblast proliferation in CPG2-Gel-treated wounds (Fig. 5 b). Transforming growth factor-β (TGF-β) content analysis after 14 days of treatment showed significantly higher TGF-β levels in the CPG2-Gel group (Fig. 5 c), indicating increased extracellular matrix (ECM) production [ 47 ]. Histological evaluation revealed well-organized collagen deposition (blue staining) and muscle fiber regeneration (red staining) in CPG2-Gel-treated wounds. Quantitative analysis demonstrated that CPG2-Gel increased type I collagen content by 21.19% and type III collagen by 12.08% compared to control and Tegaderm groups (Figs. 5 e and 5 f). Overall, CPG2-Gel enhances cellular proliferation, collagen deposition, and angiogenesis in diabetic wounds, accelerating healing via better ECM remodeling and vascularization. The immunomodulatory capacity of wound dressings is crucial for wound closure and angiogenesis through MAPK pathway regulation [ 48 ]. As illustrated in Figs. 6 a- 6 c, 6 i, and 6 j, CPG2-Gel treatment significantly reduced extracellular signal-regulated kinase 1/2 (ERK1/2) (28.3%), p38 (37.8%), and c-Jun N-terminal kinase (JNK) (30.6%) phosphorylation ( p < 0.05), inactivating MAPK signaling [ 49 ] and suppressing M1 macrophage polarization (CD206 downregulation) [ 50 ]. As depicted in Figs. 6 d- 6 f and 6 i, AKT1 phosphorylation inhibition (36.8%) blocked IκBα/NF-κB p65 activation, reducing pro-inflammatory cytokines TNF-α (29.7%) and IL-6 (31.9%). Studies had shown that NF-κB was a critical regulator during the early inflammation stages; it mediated various immune responses while inducing pro-inflammatory factors like IL-1β, IL-6, and TNF-α [ 51 ]. Our results indicated that the joint inhibition of both the MAPK and NF-κB pathways had reduced the production of pro-inflammatory factors TNF-α and IL-6 (Fig. 6 j). Additionally, STAT6-mediated M2 polarization was enhanced via JAK1 activation [ 52 ], promoting arginase-1 and chitinase-like protein-3 expression [ 53 ]. Dual pathway inhibition created an anti-inflammatory microenvironment favoring tissue repair. As shown in Figs. 6 g- 6 i, CPG2-Gel significantly increased P-JAK1 and P-STAT6 levels ( p < 0.01), with relative expressions 1.5 and 2.0 times higher than the control. It effectively suppressed NF-κB and MAPK pathway over-activation, inhibited M1-type polarization, and reduced CD206 expression. Activation of the JAK1/STAT6 pathway promoted M2-type polarization and enhanced CD86 expression. RAW 264.7 cell proliferation and differentiation were related to decreased AKT1 and NF-κB levels and increased p-JAK1 and p-STAT6 levels. Inhibiting NF-κB while activating JAK1/STAT6 co-regulated TGF-β and VEGF expression increases. The Nrf2/ARE pathway activated antioxidant enzymes to clear ROS [ 54 ]. Inhibition of the NF-κB pathway decreased ROS levels [ 55 ]. This study showed that down-regulating phosphorylated IκBα and NF-κB p65 inhibited the NF-κB pathway (Fig. 6 j), reducing ROS, MDA, and increasing SOD and GSH. Reduced ROS inhibited IKK oxidative activation, preventing IκB phosphorylation and degradation, keeping NF-κB p65 in the cytoplasm and reducing inflammation [ 56 ]. We confirmed that CPG2-Gel mediated macrophage polarization via MAPK, NF-κB, and JAK-STAT pathways, modulating anti-inflammatory responses and ROS levels. 4. Conclusion In summary, our work pioneered the exploration of a cross-linked natural and cost-effective PG-derived hydrogel, which was incorporated with two chemically modified glucans: the antibacterial CPG and the antioxidative APG. This multi-functional hydrogel inherently had antibacterial and antioxidative properties, and was demonstrated to have favorable adhesion, rheological characteristics, and biocompatibility, along with ROS scavenging and immunoregulatory capabilities. These properties collectively accelerated the wound closure process in diabetic wounds. Unlike previous hydrogel dressings, this natural hydrogel was used simply, conveniently, and safely, and was devoid of exogenous additives such as metal compounds, growth factors, antibiotics, or nanoparticles. This indicated that a straightforward and promising strategy was developed for a biocompatible alternative for practical clinical applications. Furthermore, through the investigation of metabolic signaling regulatory pathways, the precise mechanism underlying immune regulation by PG-derived hydrogels during the diabetic wound healing process was elucidated. The experimental results were expected to provide valuable guidelines for investigating the role of intelligent hydrogels in the medical treatment of chronic wounds, as well as for designing novel multi-purpose active ingredients for skincare formulations. Declarations Conflict of interest The authors declare that they have no conflict of interest. Author contributions J.Y.Z. performed the experimental work of PG derivatives and PG-derived hydrogel. T.T., J.Y.G. and Y.J.L advised on the design and interpretation of in vivo diabetic mouse wound model experiments. W.M., M.M, T.Z., and Z.Y.J. advised on the design and interpretation of all experiments and directed the overall project. J.Y.Z., W.M. and M.M. wrote and edited the manuscript. B.P. and B.H. edited the manuscript. M.M. acquired the funding to support this project. Funding The work was financially supported by the National Key R&D Program of China (2022YFF1100101), the National Natural Science Foundation of China (32130084), Natural Science Foundation of Jiangsu Province (BK20211530) and the Research Program of State Key Laboratory of Food Science and Resources, Jiangnan University (No. SKLF-ZZB-202416). References Wang Y, Liu K, Wei W, Dai H (2024) A multifunctional hydrogel with photothermal antibacterial and antioxidant activity for smart monitoring and promotion of diabetic wound healing. Adv. Funct. Mater. 34(38): 2402531. 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21:36:50\",\"extension\":\"html\",\"order_by\":17,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":160222,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"earlyproof.html\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7222605/v1/22d8d32677989963eef424c5.html\"},{\"id\":91901546,\"identity\":\"76d04933-cfa5-4642-9e2f-a96bd96932ac\",\"added_by\":\"auto\",\"created_at\":\"2025-09-22 21:36:50\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":1602118,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eStructural characterization of PG-derived hydrogel. (a)\\u003c/strong\\u003e Schematic diagram of the fabrication process of PG-derived hydrogel.\\u003cstrong\\u003e (b)\\u003c/strong\\u003e Zeta-potential and \\u003cstrong\\u003e(c)\\u003c/strong\\u003e \\u003csup\\u003e1\\u003c/sup\\u003eH NMR spectra of chemical modified PG. \\u003cstrong\\u003e(d)\\u003c/strong\\u003e Photograph showing the formation of PG-derived hydrogel by mixing APG and CPG solutions. \\u003cstrong\\u003e(e)\\u003c/strong\\u003e FT-IR spectra of PG-derived hydrogels. \\u003cstrong\\u003e(f)\\u003c/strong\\u003e SEM image of CPG2-Gel. Scale bar, 100 μm.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7222605/v1/0f24838f2664932d5f632ff6.png\"},{\"id\":91901433,\"identity\":\"505cf74f-fe1a-4774-8fe5-af6f7b23d125\",\"added_by\":\"auto\",\"created_at\":\"2025-09-22 21:28:49\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":1967786,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003ePhysicochemical and functional properties of CPG1-Gel and CPG2-Gel. (a) \\u003c/strong\\u003eSwelling property and \\u003cstrong\\u003e(b) \\u003c/strong\\u003edegradation property of hydrogel. \\u003cstrong\\u003e(c)\\u003c/strong\\u003e Force/displacement curves. \\u003cstrong\\u003e(d)\\u003c/strong\\u003e Injection and remolding into specific shape of hydrogel. The hydrogel was stained with methyl blue or methyl violet, respectively. \\u003cstrong\\u003e(e)\\u003c/strong\\u003eAlternate strain sweeps of hydrogels. \\u003cstrong\\u003e(f)\\u003c/strong\\u003e ABTS and \\u003cstrong\\u003e(g)\\u003c/strong\\u003eDPPH scavenging activity of hydrogel. \\u003cstrong\\u003e(h)\\u003c/strong\\u003e Antibacterial activities, \\u003cstrong\\u003e(i) \\u003c/strong\\u003einhibition zone diameter, \\u003cstrong\\u003e(j)\\u003c/strong\\u003e images of antibacterial zone on the culture plates, and \\u003cstrong\\u003e(k)\\u003c/strong\\u003e SEM images of \\u003cem\\u003eS. aureus\\u003c/em\\u003e and \\u003cem\\u003eE. coli\\u003c/em\\u003eco-cultured with CPG2-Gel. Scale bar, 5 μm.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7222605/v1/7c7d10d7b7a256e0be14778d.png\"},{\"id\":91901436,\"identity\":\"89fa9ff7-5083-4a27-bdf8-170aa2cbadf9\",\"added_by\":\"auto\",\"created_at\":\"2025-09-22 21:28:50\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":2188001,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eEvaluation of the biocompatibility and intracellular ROS scavenging properties of PG-derived hydrogel. (a) \\u003c/strong\\u003eHemolysis test of CPG2-Gel. \\u003cstrong\\u003e(b)\\u003c/strong\\u003e Cell viability of RAW 264.7 and HDF cells co-cultured with of CPG2-Gel. \\u003cstrong\\u003e(c)\\u003c/strong\\u003e Cell mortality and live/dead staining images of \\u003cstrong\\u003e(d)\\u003c/strong\\u003e RAW 264.7 and \\u003cstrong\\u003e(e)\\u003c/strong\\u003e HDF cells co-cultured with of CPG2-Gel for 48 h (green for live cells, red for dead cells). Migration image and migration rate of \\u003cstrong\\u003e(f)\\u003c/strong\\u003e HDF cells with and without CPG2-Gel treatment for 24 h. \\u003cstrong\\u003e(g), (h) \\u003c/strong\\u003eFluorescence imaging illustrating the decrease of intracellular ROS in\\u003cstrong\\u003e \\u003c/strong\\u003eRAW 264.7 and HDF cells challenged with H\\u003csub\\u003e2\\u003c/sub\\u003eO\\u003csub\\u003e2 \\u003c/sub\\u003e(150 μm), scale bar, 100 μm. \\u003cstrong\\u003e(i)\\u003c/strong\\u003e Flow cytometry results of DCFH-DA fluorescence in RAW 264.7 and HDF cells, both in regular condition and when exposed to hydrogel.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7222605/v1/fbc59e237988ee8d349042a5.png\"},{\"id\":91901437,\"identity\":\"27f03fe3-5c6e-4de7-8ba2-89dc0d803f6e\",\"added_by\":\"auto\",\"created_at\":\"2025-09-22 21:28:50\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":3001895,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eTherapeutic performance of PG-derived hydrogel on diabetic wound. (a) \\u003c/strong\\u003eSchematic of the timeline of animal experiments for the therapeutic effects of CPG2-Gel. \\u003cstrong\\u003e(b)\\u003c/strong\\u003e Representative photographs of the diabetic wounds at day 0, 3, 7, and 14. \\u003cstrong\\u003e(c) \\u003c/strong\\u003eSimulated \\u003cem\\u003ein vivo\\u003c/em\\u003e wounds closure traces for different treatments for 14 days: Control, Tegaderm, and CPG2-Gel. \\u003cstrong\\u003e(d) \\u003c/strong\\u003eStatistical analysis of the wound healing areas (n = 4). Oxidative stress indexes \\u003cstrong\\u003e(e) \\u003c/strong\\u003eMalondialdehyde (MDA); \\u003cstrong\\u003e(f)\\u003c/strong\\u003e Reduced glutathione (GSH); \\u003cstrong\\u003e(g)\\u003c/strong\\u003e Total superoxide dismutase (T-SOD) and \\u003cstrong\\u003e(h) \\u003c/strong\\u003eTotal antioxidant capacity (T-AOC)) of diabetic mice after different treatments for 3 days: Control, Tegaderm, and CPG2-Gel (n = 4). The inflammatory cytokine expression levels (\\u003cstrong\\u003ei)\\u003c/strong\\u003e IL-6, \\u003cstrong\\u003e(j) \\u003c/strong\\u003eTNF-α, and \\u003cstrong\\u003e(k)\\u003c/strong\\u003e HMGB-1 of wounds after different treatments for 3 days: Control, Tegaderm, and CPG2-Gel (n = 4). \\u003cstrong\\u003e(l)\\u003c/strong\\u003e Immunofluorescence of CD86 (green) and CD206 (red) staining in diabetic wound tissue after treatment for 3 days (n = 4). Scale bar, 100 μm.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7222605/v1/2f2fcdb009c85936382303c3.png\"},{\"id\":91901547,\"identity\":\"985c84fd-384f-48a4-90bf-17dda5de971a\",\"added_by\":\"auto\",\"created_at\":\"2025-09-22 21:36:50\",\"extension\":\"png\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":3190900,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eWound healing behaviors of PG-derived hydrogel on diabetic wound. (a) \\u003c/strong\\u003eImmunohistochemical staining’s of PCNA (scale bar, 50 μm), Ki67 (scale bar, 50 μm), and CD31 (scale bar, 100 μm), \\u003cstrong\\u003e(b)\\u003c/strong\\u003eMasson staining (scale bar, 200 μm) and H\\u0026amp;E staining (scale bar, 50 μm) in wounds skin tissue after treatment for 14 days (n = 4). The red arrow indicates the yellowish brown PNCA positive cells, the blue arrow indicates the yellowish brown Ki67 positive cells, and the yellowish brown within the red dashed border represents the vascular endothelial cells at the site of positive immunohistochemical staining. The collagen fibers within the black dotted border are red. The expression levels of \\u003cstrong\\u003e(c)\\u003c/strong\\u003e transforming growth factor (TGF-β) and \\u003cstrong\\u003e(d)\\u003c/strong\\u003e vascular endothelial growth factor (VEGF) was assessed 14 days after different treatments: Control, Tegaderm, and CPG2-Gel (n = 4). Relative quantitative results of \\u003cstrong\\u003e(e) \\u003c/strong\\u003etype I collagen and \\u003cstrong\\u003e(f)\\u003c/strong\\u003e type III collagen in wound tissue after treatment for 14 days (n = 4).\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"5.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7222605/v1/8ce426b8aadbc03e6b0dd472.png\"},{\"id\":91901549,\"identity\":\"32487cc0-3b63-4aaf-8f0c-52426f615fcd\",\"added_by\":\"auto\",\"created_at\":\"2025-09-22 21:36:50\",\"extension\":\"png\",\"order_by\":6,\"title\":\"Figure 6\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":1605084,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eThe related signaling pathways of CPG2-Gel on RAW 264.7 immune regulation and ROS scavenging. \\u003c/strong\\u003eThe relative expression levels of Phospho-p44/42 MAPK (ERK1/2) (Thr202/Tyr204) \\u003cstrong\\u003e(\\u003c/strong\\u003ea, i\\u003cstrong\\u003e)\\u003c/strong\\u003e, Phospho-p38 MAPK (Thr180/Tyr182) \\u003cstrong\\u003e(b, i)\\u003c/strong\\u003e, Phospho-JNK (Thr183/Tyr185) \\u003cstrong\\u003e(c, i)\\u003c/strong\\u003e, Phospho-AKT1 (Ser473) \\u003cstrong\\u003e(d, i)\\u003c/strong\\u003e, Phospho-IκBα (Ser32/36) \\u003cstrong\\u003e(e, j)\\u003c/strong\\u003e, Phospho-NF-κB p65 (Ser536) \\u003cstrong\\u003e(f, i)\\u003c/strong\\u003e, Phospho-JAK1(Tyr1034/1035) \\u003cstrong\\u003e(g, i)\\u003c/strong\\u003e, and Phospho-STAT6 (Tyr641) \\u003cstrong\\u003e(h, i)\\u003c/strong\\u003e in various groups of cells by western blot experiments. Results were mean ± SD for three individual experiments. **\\u003cem\\u003eP\\u003c/em\\u003e\\u0026lt; 0.01.\\u003cstrong\\u003e (j) \\u003c/strong\\u003eCPG2-Gel enhances macrophage resistance to apoptosis, stimulates proliferation, reduces ROS levels, and promotes M2 polarization via the MAPK, NF-κB, and JAK-STAT signaling pathways, red lines indicate inhibition and green lines indicate promotion.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"6.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7222605/v1/fd9eb2290479f7b046a840ad.png\"},{\"id\":104739622,\"identity\":\"fc3db48b-3c7a-412d-8b35-56778d88516e\",\"added_by\":\"auto\",\"created_at\":\"2026-03-16 16:10:28\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":18462565,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7222605/v1/ff38c094-f4ba-4aab-9c58-0c53d1729304.pdf\"},{\"id\":91901458,\"identity\":\"f2cb2454-d1a0-457e-aaab-78421031e27f\",\"added_by\":\"auto\",\"created_at\":\"2025-09-22 21:28:51\",\"extension\":\"docx\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":28005370,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Supplementaryinformation.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7222605/v1/c94fa5072f48e12d8dad884f.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Multi-functional phytoglycogen-derived hydrogel dressings promote the fast closure of diabetic wound in vitro and in vivo\",\"fulltext\":[{\"header\":\"1. Introduction\",\"content\":\"\\u003cp\\u003eNormal wound healing involves four sequential phases, hemostasis, inflammation, proliferation, and remodeling, critical for maintaining skin integrity and repairing external damage [\\u003cspan additionalcitationids=\\\"CR2\\\" citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]. Chronic wounds like diabetic foot ulcers (DFUs) fail to follow this orderly process, attributed to dysregulated inflammation and immune dysfunction [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. DFUs, a hyperglycemia-linked complication, affect\\u0026thinsp;~\\u0026thinsp;6.3% of diabetics globally, with high recurrence/amputation rates and prolonged treatment challenges due to economic burdens and high morbidity [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. Multifunctional wound dressings, particularly hydrogels, are prioritized for diabetic wounds due to their protective, anti-inflammatory, and healing-promoting properties, addressing prolonged inflammation [\\u003cspan additionalcitationids=\\\"CR6\\\" citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]. Hydrogels, 3D polymer networks with tunable properties due to water-rich structures, are widely applied in wound dressings [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]. Their cross-linked architectures (non-covalent/covalent) enable microenvironment regulation, influencing cell behaviors and promoting healing processes like angiogenesis [\\u003cspan additionalcitationids=\\\"CR10\\\" citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]. Synthetic polymers (PEG, PCL, PVA) offer robust mechanical properties but suffer from poor biodegradability and cytotoxicity risks [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]. However, these polymers, derived from petrochemical sources, were chemically cross-linked to achieve favorable mechanical properties, but they are accompanied by poor biodegradability and potential side effects, including cytotoxicity and chronic rejection [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. The distinct properties of hydrogels, including adhesiveness, self-healing ability, and biocompatibility, have been manipulated to meet the specific requirements of potential biomedical applications [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]. Nevertheless, the limited degradability and cytotoxicity of conventional hydrogels for treating diabetic wounds stem from their intrinsic physicochemical features [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]. Fabricating hydrogel dressings with multifunctionality remains a significant challenge. To overcome the inflammation and closure issues of chronic wounds, many investigators designed advanced hydrogel dressings with antioxidant, antibacterial, and anti-inflammatory properties from exogenous substances for comprehensive treatment [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]. Advanced hydrogels address chronic wound challenges via multifunctional designs: Pranantyo et al.\\u0026rsquo;s dual-functional hydrogel combines antibacterial polyimidazolium and antioxidant N-acetylcysteine [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]; carbon dots-based platforms provide photothermal antibacterial and anti-inflammatory effects [\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e]; AuPt@melanin hybrids regulate glucose/ROS levels to modulate macrophage polarization [\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. However, existing strategies still rely on exogenous agents (antibiotics, irradiation) and lack natural alternatives [\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]. Natural hydrogels (starch, cellulose, alginate) show limited efficacy without RGD peptides/growth factors, highlighting the need for additive-free, multifunctional natural hydrogels in diabetic wound therapy [\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003ePG, a hydrophilic, highly-branched analog of animal glycogen, is a primary short-term energy storage molecule in biological systems. Its α-1,4-linked linear chains are interconnected by α-1,6 branching linkages, with an average glucose unit length of 10\\u0026ndash;12, providing three accessible hydroxyl groups for derivatization [\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]. Previously, we isolated PG from sugary-1 maize. It has a compact spherical-dendritic morphology, endowing it with excellent water-binding capacity, low intrinsic viscosity, and high stability due to surface hydroxyl groups [\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]. Experiments showed PG can enhance skin cell energy metabolism by promoting ATP production and accelerating metabolism, increasing hyaluronic acid and collagen synthesis. PG-based formulations have rapid and sustained hydrating effects, reduce skin hyperpigmentation, and offer anti-aging benefits, showing potential in cosmeceuticals [\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]. However, no prior research reported using naturally-derived hydrogels from modified PG for diabetic wound repair, and the molecular mechanisms of PG-derived hydrogels in immune regulation during diabetic wound healing were unknown at the time of this study.\\u003c/p\\u003e\\u003cp\\u003eIn this work, hydroxyl-functionalized chain segments were used to chemically modify sugary-1 maize-derived natural and renewable phytoglycogen (PG). A novel wound hydrogel dressing was developed via surface cationization, oxidation, and subsequent Schiff base cross-linking. PG, an amylopectin analog with nano-scale globular architecture and macrophage-stimulating activity, has inherent antimicrobial, antioxidant, and immunomodulatory properties [\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e]. Grafted quaternary ammonium groups offer antimicrobial activity, and aldehyde groups enhance antioxidant activity and adhesion. \\u003cem\\u003eIn vitro\\u003c/em\\u003e and \\u003cem\\u003ein vivo\\u003c/em\\u003e studies showed that the optimal CPG2-Gel had superior therapeutic effects on diabetic wounds, healing 1.76 times faster than commercial dressings by scavenging ROS and immunoregulation. Relevant metabolic pathways were elucidated, and the immunomodulatory mechanisms of CPG2-Gel in wound healing were investigated. This study provides a facile strategy to fabricate multifunctional natural hydrogel dressings for chronic diabetic wound closure.\\u003c/p\\u003e\"},{\"header\":\"2. Materials and Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e2.1 Materials\\u003c/h2\\u003e\\u003cp\\u003ePhytoglycogen (PG, MW 1.2\\u0026times;10\\u003csup\\u003e7\\u003c/sup\\u003e g/mol) were extracted and purified from sugar-1 maize according to the previous work [\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e]. 2,3-Epoxypropyltrimethylammonium chloride (GTAC), ethylenediamine (EDA), sodium periodate (NaIO\\u003csub\\u003e4\\u003c/sub\\u003e), potassium persulfate (K\\u003csub\\u003e2\\u003c/sub\\u003eS\\u003csub\\u003e2\\u003c/sub\\u003eO\\u003csub\\u003e8\\u003c/sub\\u003e), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and 2,2\\u0026prime;-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) were purchased from Sigma-Aldrich. (St. Louis, MO). Other chemical reagents were of analytical grade.\\u003c/p\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e2.2 Animals\\u003c/h2\\u003e\\u003cp\\u003eMale ICR mice (24\\u0026ndash;26 g) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China) and used for diabetic wound healing evaluation. All the animal experiments in this work have been approved by the Animal Ethics Committee of China Agricultural University (AW21804202-4-2).\\u003c/p\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e2.3 Chemical derivatization of PG\\u003c/h2\\u003e\\u003cp\\u003eCationization of PG was obtained using the following procedure. 5 g PG was mixed with 250 mL deionized water, then 15 mL EDA was added with stirring at 50\\u0026deg;C for 4 h. Then, an appropriate amount of GTAC was then introduced into the system for 2 h reaction at 50\\u0026deg;C. After the reaction is completed, the obtained solution is dialyzed for two days, then diluted with 3 times ethanol and stored at 4℃. The final precipitate was oven-dried and stored for further test. These cationic samples with an initial molar ratio of PG and GTAC for 1:1 and 1:15 were named as CPG1 and CPG2, respectively.\\u003c/p\\u003e\\u003cp\\u003eOxidation of PG was obtained using the following procedure. PG was solubilized in deionized water (5%, w/v) and mixed with NaIO\\u003csub\\u003e4\\u003c/sub\\u003e at a molar ratio of 2:1. The reaction was carried out at 30\\u0026deg;C for 2 h under stirring, and an excess of 10% (v/v) ethylene glycol was added. The resulting solution was dialyzed for two days, and then lyophilized to obtain aldolylated PG (APG).\\u003c/p\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e2.4 Characterizations of PG derivatives\\u003c/h2\\u003e\\u003cp\\u003eParticle size and zeta-potential measurements were recorded using a Zetasizer. Molecular weight distributions were analyzed using a HPSEC-MALLS-RI system. The chemical bonds were determined using FT-IR and NMR. The degree of substitution (DS) and degree of oxidation were calculated according to the standard methods [\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e].\\u003c/p\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e2.5 Fabrication of PG-derived hydrogel\\u003c/h2\\u003e\\u003cp\\u003e5% (w/v) APG solution was dropwise added into 10% (w/v) CPG solution. The cross-linking reaction was carried at 30\\u0026deg;C to obtain the hydrogel, and marked as CPG1-Gel or CPG2-Gel, respectively, depending on the DS of CPG.\\u003c/p\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e2.6 Statistical analysis\\u003c/h2\\u003e\\u003cp\\u003eAll experimental data were presented as the mean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;standard deviation (SD) and each assay was repeated for at least three independent times. The statistical significance was assessed using a student\\u0026rsquo;s t-test and one-way ANOVA analysis. The statistically significant differences were expressed as *\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05, **\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01, ***\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001, ****\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.0001, or ns (no significant), respectively.\\u003c/p\\u003e\\u003c/div\\u003e\"},{\"header\":\"3. Results and discussion\",\"content\":\"\\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e\\n \\u003ch2\\u003e3.1 Fabrication and Characterization of PG-derived Hydrogel\\u003c/h2\\u003e\\n \\u003cp\\u003eThe cationization/oxidation of PG was demonstrated in Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003ea. EDA/GTAC molecules were covalently grafted onto PG\\u0026rsquo;s glucose units, releasing Cl⁻ counterions to generate positively charged cationic PG (CPG1/CPG2) with higher Mw/Rz than native PG (Table \\u003cspan class=\\\"InternalRef\\\"\\u003eS1\\u003c/span\\u003e). DS values (grafted groups/available sites) reached 18.5% for CPG1 and 38.15% for CPG2. Oxidation cleaved C-2 and C-3 hydroxyls into dialdehyde groups, reducing Mw/Rz (Table \\u003cspan class=\\\"InternalRef\\\"\\u003eS1\\u003c/span\\u003e). Zeta-potential increased post-modification, peaking at 28.78\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.32 mV for CPG2 due to surface-bound quaternary ammonium groups. Monodisperse nanoparticles were confirmed (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003eS1\\u003c/span\\u003ea).\\u0026sup1;H NMR showed -N⁺(CH₃)₃ (3.20 ppm) and -N-CH₂- (2.60 ppm) peaks in CPG [\\u003cspan class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e]. FT-IR revealed N-H bending (1,512 cm⁻\\u0026sup1;), CH₃-N⁺ vibrations (1,440 and 1,071 cm⁻\\u0026sup1;), and APG\\u0026rsquo;s aldehyde peak (1,740 cm⁻\\u0026sup1;) [\\u003cspan class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e]. CPG (10%) and APG (5%) mixed 1:1 formed Schiff base hydrogels via cross-linking (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003ed). Hydrogel fabrication was rapid and simple, involving mixing the two solutions to yield a hydrogel network. Compared to CPG1, CPG2, and APG (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003eS1\\u003c/span\\u003eb), Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003ee showed a prominent stretching vibrational absorption peak at 1,645 cm⁻\\u0026sup1;, indicative of the characteristic imine bond (C\\u0026thinsp;=\\u0026thinsp;N) in Schiff base bonds [\\u003cspan class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e]. SEM showed CPG2-Gel\\u0026rsquo;s denser structure than CPG1-Gel (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003ef and S2), attributed to CPG2\\u0026rsquo;s higher DS enabling more Schiff base bonds. The swelling capacity of PG-derived hydrogels was evaluated in Fig.\\u0026nbsp;2a. Ideal wound dressings should have an absorptive swelling rate of 100%-900% [\\u003cspan class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e]. Both hydrogels showed time-dependent swelling, reaching about 200% equilibrium after 6 hours, indicating good water absorption. CPG2-Gel had better swell due to its porous structure and high cross-linking density. Degradation analysis (Fig.\\u0026nbsp;2b) showed mass loss over time: 39.90\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.96% for CPG1-Gel and 26.54\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.36% for CPG2-Gel after 11 hours. CPG2-Gel degraded slower because of stronger cross-linking. Lap shear testing (ASTM-F2255) on glass substrates (Fig.\\u0026nbsp;2c) showed CPG2-Gel had better adhesion than CPG1-Gel, due to more-N\\u003csup\\u003e+\\u003c/sup\\u003e(CH\\u003csub\\u003e3\\u003c/sub\\u003e)\\u003csub\\u003e3\\u003c/sub\\u003e groups enhancing hydrophilicity [\\u003cspan class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e\\u0026ndash;\\u003cspan class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e]. Injectable performance tests with methyl blue-containing hydrogels on glass showed both maintained \\u0026lsquo;Z\\u0026rsquo; patterns (Fig. S3). CPG2-Gel had finer structure due to its denser matrix and higher cationization. Both adhered well to stretched fingers. Rheological tests showed viscoelastic 3D networks. Strain sweep (0.1-3% strain: G\\u0026rsquo; \\u0026gt;G\\u0026rsquo;\\u0026rsquo;; higher strain: G\\u0026rsquo;\\u0026rsquo; \\u0026gt;G\\u0026rsquo;) (Fig. S4a), frequency sweep (stable at 0.1\\u0026ndash;100 rad/s) (Fig. S4b), and cyclic strain tests confirmed self-healing (modulus back to baseline after high-strain cycles) (Fig.\\u0026nbsp;2e) [\\u003cspan class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e].\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e\\n \\u003ch2\\u003e3.2 \\u003cem\\u003eIn Vitro\\u003c/em\\u003e Antioxidant and Antibacterial Activities of PG-derived Hydrogel\\u003c/h2\\u003e\\n \\u003cp\\u003eAntioxidant hydrogel effectively reduces chronic wound oxidative stress, improves microenvironment and cellular metabolism, and accelerates wound healing. To evaluate the in vitro antioxidant effect of PG-derived hydrogel, ABTS and DPPH radical scavenging assays were conducted. IC\\u003csub\\u003e50\\u003c/sub\\u003e, the antioxidant concentration for 50% clearance, with a lower value indicating stronger scavenging ability [\\u003cspan class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e]. Tables S2 and S3 show a concentration-dependent scavenging efficiency for chemically modified PG and PG-derived hydrogel. As concentration rose, scavenging rate increased. Figure\\u0026nbsp;2f and 2g show CPG2-Gel had superior ABTS and DPPH scavenging at 1.0 mg/L and 30 mg/L by IC\\u003csub\\u003e50\\u003c/sub\\u003e comparison, likely due to CPG2\\u0026rsquo;s higher cationic substitution degree. GTAC modification increased PG\\u0026rsquo;s surface positive charge density, enhancing electrostatic interactions with negatively charged free radicals and scavenging efficiency. APG had the lowest IC\\u003csub\\u003e50\\u003c/sub\\u003e, contributing to the hydrogel\\u0026rsquo;s antioxidant properties. Diabetic wound infections delay healing due to antibiotic resistance challenges [\\u003cspan class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e]. Current treatments involving antibiotic and antimicrobial additives have been challenged by the increasing prevalence of antimicrobial resistance [\\u003cspan class=\\\"CitationRef\\\"\\u003e39\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e40\\u003c/span\\u003e]. Consequently, antibacterial hydrogel dressings have emerged as a critical solution for optimizing the microenvironment to accelerate chronic wound closure. The antibacterial properties of PG-derived hydrogels were evaluated using \\u003cem\\u003eS. aureus\\u003c/em\\u003e and \\u003cem\\u003eE. coli\\u003c/em\\u003e as model organisms. Their antimicrobial efficacy was assessed via co-culture experiments, with results presented in Figs. 2h-2k. The MIC, defined as the lowest concentration of an antibacterial agent that inhibits visible bacterial growth under specified conditions, was determined. Lower MIC values indicate enhanced effectiveness against pathogens [\\u003cspan class=\\\"CitationRef\\\"\\u003e41\\u003c/span\\u003e]. The antibacterial performance of PG-derived hydrogels was quantified using the plate count method. As shown in Fig. 2h, CPG2-Gel demonstrated a 50% reduction in MIC against \\u003cem\\u003eS. aureus\\u003c/em\\u003e and a 29.3% reduction against \\u003cem\\u003eE. coli\\u003c/em\\u003e compared to CPG1-Gel. Furthermore, CPG2-Gel exhibited significantly larger inhibition zone diameters of 31.5\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.60 mm (for \\u003cem\\u003eS. aureus\\u003c/em\\u003e) and 22.8\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.94 mm (for \\u003cem\\u003eE. coli\\u003c/em\\u003e), as illustrated in Figs.\\u0026nbsp;2i, 2j, and S5. Its higher DS (degree of substitution) introduced positively charged groups that disrupted bacterial membranes via electrostatic attraction [\\u003cspan class=\\\"CitationRef\\\"\\u003e42\\u003c/span\\u003e]. SEM revealed morphological changes in bacteria co-cultured with the hydrogel. In contrast to control bacteria (exposed to phosphate-buffered saline, PBS), which appeared intact and smooth, \\u003cem\\u003eS. aureus\\u003c/em\\u003e and \\u003cem\\u003eE. coli\\u003c/em\\u003e exposed to CPG2-Gel displayed partially damaged cell walls and pronounced shrinkage (Figs. S6 and 2k). Based on these findings, CPG2-Gel was selected as the optimal hydrogel for subsequent experiments due to its enhanced antibacterial efficacy compared to CPG1-Gel.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e\\n \\u003ch2\\u003e3.3 Biocompatibility and ROS Scavenging Properties\\u003c/h2\\u003e\\n \\u003cp\\u003eTo evaluate the biocompatibility of PG-derived hydrogels, hemolysis and cytotoxicity assays were conducted. In the hemolysis assay, the hemolysis rate of both PG and CPG2-Gel was found to be below 2% (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003ea), indicating excellent blood compatibility. Subsequently, cytotoxicity tests were performed using CPG2-Gel at varying concentrations. Notably, at a concentration of 0.01 mg/mL, the cell survival rate exceeded 90%, demonstrating excellent biocompatibility. RAW 264.7 and HDF cells were then cultivated in a 0.01 mg/mL PG-derived hydrogel solution for 48 hours. Pure cultures of RAW 264.7 and HDF cells served as the blank control group, while live/dead staining was employed to assess hydrogel biocompatibility. As illustrated in Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003ec, the cell mortality of CPG2-Gel was significantly lower compared to the control group. Post-staining analysis revealed that the majority of cells exhibited vitality (green fluorescence), with only a small number of dead cells (red fluorescence) observed under microscopy (Figs. \\u003cspan class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003ed and \\u003cspan class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003ee). No statistically significant differences were observed between CPG2-Gel and the control group, further confirming their good biocompatibility. To investigate the hydrogel\\u0026rsquo;s impact on cell migration, a scratch healing model was established. As shown in Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003ef, the PG-derived hydrogel significantly enhanced the migration capacity of HDF cells compared to the control group. Collectively, these findings underscore the excellent biocompatibility of the PG-derived hydrogel and its capacity to promote HDF cell proliferation.\\u003c/p\\u003e\\n \\u003cp\\u003eROS production was identified as a critical mediator of secondary injury in diabetic wounds, necessitating the indispensable ROS-scavenging capacity of natural hydrogels for effective wound healing. DPPH and ABTS radical-scavenging assays demonstrated that PG-derived hydrogel could effectively eliminate free radicals. To further validate its ROS-scavenging efficacy, RAW 264.7 and HDF cells were co-cultured with CPG2-Gel following H₂O₂ treatment. In the positive control group, cells were subjected to H₂O₂ treatment without hydrogel intervention, with sterile PBS used as a substitute. The DCFH-DA probe was employed to quantify intracellular ROS levels across all groups (Figs. \\u003cspan class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003eg and \\u003cspan class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003eh). Fluorescence microscopy revealed negligible fluorescence in untreated controls, while H₂O₂ treatment induced marked fluorescence enhancement, confirming substantial ROS generation. Notably, CPG2-Gel intervention significantly reduced ROS fluorescence intensity in both RAW 264.7 and HDF cells. Flow cytometry analysis further corroborated these findings, showing ROS rates decreased from 28.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.68% (RAW 264.7) and 35.58\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.26% (HDF) in H₂O₂-treated controls to 7.33\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.54% and 6.46\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.25%, respectively, in CPG2-Gel-treated groups (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003ei). Collectively, these results confirmed that PG-derived hydrogel effectively mitigates oxidative stress-induced cellular damage, demonstrating its therapeutic potential for diabetic wound management.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec13\\\" class=\\\"Section2\\\"\\u003e\\n \\u003ch2\\u003e3.4 Therapeutic Performance on Diabetic Wounds\\u003c/h2\\u003e\\n \\u003cp\\u003eWe investigated the effect of PG-derived hydrogel (CPG2-Gel) on diabetic mouse wound healing using a 1-cm-diameter full-layer wound model. Circular diabetic wounds were treated with CPG2-Gel and commercial Tegaderm dressing, and wound healing was monitored at 3, 7, and 14 days. Digital photos showed gradual healing in both groups. The wound healing rates of the CPG2-Gel group at 3 and 7 days were 1.93 and 1.76 times those of the Tegaderm group respectively, achieving fast healing within two weeks (Figs. \\u003cspan class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003eb and \\u003cspan class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003ec). There had been attempts to integrate antioxidant additives with wound dressings, which might be accompanied by the risk of an exclusion reaction caused by the extra substance [\\u003cspan class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e]. No wound infection or inflammation was observed with CPG2-Gel, indicating its excellent antibacterial property. During the 14-day period, the CPG2-Gel group had significantly expedited wound closure, with a healing rate of 70.77%, higher than the Tegaderm or control group (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003ed). Importantly, it was known that the continuous increase of oxidative stress products could promote the dysfunction of the cells around the wound, which finally led to delayed wound healing [\\u003cspan class=\\\"CitationRef\\\"\\u003e43\\u003c/span\\u003e]. The antioxidant effect of CPG2-Gel on the wound tissue was further explored by assessing the levels of malondialdehyde (MDA), reduced glutathione (GSH), total antioxidant capacity (T-AOC), and total superoxide dismutase (T-SOD) activity after 3 days of treatment. Compared with the control and Tegaderm groups, the activities of GSH, T-SOD, and T-AOC in the wound tissue were significantly increased by CPG2-Gel (Figs. \\u003cspan class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003ee-\\u003cspan class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003eh). This indicated that CPG2-Gel could stimulate the ability to scavenge free radicals and reduce oxidative damage in the living body, and a protective effect was performed during the growth of cells and tissues.\\u003c/p\\u003e\\n \\u003cp\\u003eIt\\u0026rsquo;s well-known that excessive inflammation impedes wound healing, so effective inflammation management is crucial. On the 3rd day after wound dressing treatment, relevant inflammatory marker levels in wound tissue were evaluated. In the CPG2-Gel group, IL-6 and TNF-\\u0026alpha; levels were 2 and 5 times lower than in the control group respectively, and compared to Tegaderm, there were obvious decreases in these pro-inflammatory factors, indicating CPG2-Gel\\u0026rsquo;s prominent anti-inflammatory effect at the wound site (Figs. \\u003cspan class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003ei and \\u003cspan class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003ej). A decreasing HMGB-1 level was also observed, suggesting an overall anti-inflammatory effect of the PG-derived hydrogel (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003ek). In chronic wounds, hyperglycemia and immune dysfunction impair the M1-to-M2 macrophage transition [\\u003cspan class=\\\"CitationRef\\\"\\u003e44\\u003c/span\\u003e]. After 3 days, immunohistochemical staining of the M2 marker CD206 in wound tissue showed enhanced M2 macrophage infiltration and distribution in the CPG2-Gel group compared to the control and Tegaderm groups, while the fluorescence intensity of the M1 marker CD86 was reduced (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003el). This indicates that CPG2-Gel can induce M1-to-M2 macrophage polarization, regulate the inflammatory microenvironment, and facilitate wound healing. Overall, CPG2-Gel can accelerate the inflammatory-to-proliferative transition in vivo, reduce oxidative stress, and regulate the inflammatory system.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec14\\\" class=\\\"Section2\\\"\\u003e\\n \\u003ch2\\u003e3.5 \\u003cem\\u003eIn Vivo\\u003c/em\\u003e Immunoregulation Promoted Cell Proliferation and Angiogenesis\\u003c/h2\\u003e\\n \\u003cp\\u003eExcessive inflammation challenges diabetic wound healing due to infection and impaired neovascularization. Granulation tissue formation, collagen deposition, and angiogenesis are key histological indicators. Immunohistochemical methods detected cell proliferation markers (PCNA and Ki67) to evaluate healing rates [\\u003cspan class=\\\"CitationRef\\\"\\u003e45\\u003c/span\\u003e]. The CPG2-Gel group had significantly higher PCNA, Ki67, and CD31 (an angiogenesis index [\\u003cspan class=\\\"CitationRef\\\"\\u003e46\\u003c/span\\u003e]) expression than the control and Tegaderm groups (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003ea). This finding correlated with increased capillary density and mature angiogenesis, corroborated by quantitative VEGF analysis (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003ed). Masson staining revealed incomplete wound closure in control and Tegaderm groups, accompanied by poor collagen organization and minimal muscle fiber regeneration (Figs. \\u003cspan class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003eb-\\u003cspan class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003ef). H\\u0026amp;E staining demonstrated enhanced fibroblast proliferation in CPG2-Gel-treated wounds (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003eb). Transforming growth factor-\\u0026beta; (TGF-\\u0026beta;) content analysis after 14 days of treatment showed significantly higher TGF-\\u0026beta; levels in the CPG2-Gel group (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003ec), indicating increased extracellular matrix (ECM) production [\\u003cspan class=\\\"CitationRef\\\"\\u003e47\\u003c/span\\u003e]. Histological evaluation revealed well-organized collagen deposition (blue staining) and muscle fiber regeneration (red staining) in CPG2-Gel-treated wounds. Quantitative analysis demonstrated that CPG2-Gel increased type I collagen content by 21.19% and type III collagen by 12.08% compared to control and Tegaderm groups (Figs. \\u003cspan class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003ee and \\u003cspan class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003ef). Overall, CPG2-Gel enhances cellular proliferation, collagen deposition, and angiogenesis in diabetic wounds, accelerating healing via better ECM remodeling and vascularization.\\u003c/p\\u003e\\n \\u003cp\\u003eThe immunomodulatory capacity of wound dressings is crucial for wound closure and angiogenesis through MAPK pathway regulation [\\u003cspan class=\\\"CitationRef\\\"\\u003e48\\u003c/span\\u003e]. As illustrated in Figs. \\u003cspan class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003ea-\\u003cspan class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003ec, \\u003cspan class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003ei, and \\u003cspan class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003ej, CPG2-Gel treatment significantly reduced extracellular signal-regulated kinase 1/2 (ERK1/2) (28.3%), p38 (37.8%), and c-Jun N-terminal kinase (JNK) (30.6%) phosphorylation (\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05), inactivating MAPK signaling [\\u003cspan class=\\\"CitationRef\\\"\\u003e49\\u003c/span\\u003e] and suppressing M1 macrophage polarization (CD206 downregulation) [\\u003cspan class=\\\"CitationRef\\\"\\u003e50\\u003c/span\\u003e]. As depicted in Figs. \\u003cspan class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003ed-\\u003cspan class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003ef and \\u003cspan class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003ei, AKT1 phosphorylation inhibition (36.8%) blocked I\\u0026kappa;B\\u0026alpha;/NF-\\u0026kappa;B p65 activation, reducing pro-inflammatory cytokines TNF-\\u0026alpha; (29.7%) and IL-6 (31.9%). Studies had shown that NF-\\u0026kappa;B was a critical regulator during the early inflammation stages; it mediated various immune responses while inducing pro-inflammatory factors like IL-1\\u0026beta;, IL-6, and TNF-\\u0026alpha; [\\u003cspan class=\\\"CitationRef\\\"\\u003e51\\u003c/span\\u003e]. Our results indicated that the joint inhibition of both the MAPK and NF-\\u0026kappa;B pathways had reduced the production of pro-inflammatory factors TNF-\\u0026alpha; and IL-6 (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003ej). Additionally, STAT6-mediated M2 polarization was enhanced via JAK1 activation [\\u003cspan class=\\\"CitationRef\\\"\\u003e52\\u003c/span\\u003e], promoting arginase-1 and chitinase-like protein-3 expression [\\u003cspan class=\\\"CitationRef\\\"\\u003e53\\u003c/span\\u003e]. Dual pathway inhibition created an anti-inflammatory microenvironment favoring tissue repair. As shown in Figs. \\u003cspan class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003eg-\\u003cspan class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003ei, CPG2-Gel significantly increased P-JAK1 and P-STAT6 levels (\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.01), with relative expressions 1.5 and 2.0 times higher than the control. It effectively suppressed NF-\\u0026kappa;B and MAPK pathway over-activation, inhibited M1-type polarization, and reduced CD206 expression. Activation of the JAK1/STAT6 pathway promoted M2-type polarization and enhanced CD86 expression. RAW 264.7 cell proliferation and differentiation were related to decreased AKT1 and NF-\\u0026kappa;B levels and increased p-JAK1 and p-STAT6 levels. Inhibiting NF-\\u0026kappa;B while activating JAK1/STAT6 co-regulated TGF-\\u0026beta; and VEGF expression increases. The Nrf2/ARE pathway activated antioxidant enzymes to clear ROS [\\u003cspan class=\\\"CitationRef\\\"\\u003e54\\u003c/span\\u003e]. Inhibition of the NF-\\u0026kappa;B pathway decreased ROS levels [\\u003cspan class=\\\"CitationRef\\\"\\u003e55\\u003c/span\\u003e]. This study showed that down-regulating phosphorylated I\\u0026kappa;B\\u0026alpha; and NF-\\u0026kappa;B p65 inhibited the NF-\\u0026kappa;B pathway (Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003ej), reducing ROS, MDA, and increasing SOD and GSH. Reduced ROS inhibited IKK oxidative activation, preventing I\\u0026kappa;B phosphorylation and degradation, keeping NF-\\u0026kappa;B p65 in the cytoplasm and reducing inflammation [\\u003cspan class=\\\"CitationRef\\\"\\u003e56\\u003c/span\\u003e]. We confirmed that CPG2-Gel mediated macrophage polarization via MAPK, NF-\\u0026kappa;B, and JAK-STAT pathways, modulating anti-inflammatory responses and ROS levels.\\u003c/p\\u003e\\n\\u003c/div\\u003e\"},{\"header\":\"4. Conclusion\",\"content\":\"\\u003cp\\u003eIn summary, our work pioneered the exploration of a cross-linked natural and cost-effective PG-derived hydrogel, which was incorporated with two chemically modified glucans: the antibacterial CPG and the antioxidative APG. This multi-functional hydrogel inherently had antibacterial and antioxidative properties, and was demonstrated to have favorable adhesion, rheological characteristics, and biocompatibility, along with ROS scavenging and immunoregulatory capabilities. These properties collectively accelerated the wound closure process in diabetic wounds. Unlike previous hydrogel dressings, this natural hydrogel was used simply, conveniently, and safely, and was devoid of exogenous additives such as metal compounds, growth factors, antibiotics, or nanoparticles. This indicated that a straightforward and promising strategy was developed for a biocompatible alternative for practical clinical applications. Furthermore, through the investigation of metabolic signaling regulatory pathways, the precise mechanism underlying immune regulation by PG-derived hydrogels during the diabetic wound healing process was elucidated. The experimental results were expected to provide valuable guidelines for investigating the role of intelligent hydrogels in the medical treatment of chronic wounds, as well as for designing novel multi-purpose active ingredients for skincare formulations.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eConflict of interest\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare that they have no conflict of interest.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eJ.Y.Z. performed the experimental work of PG derivatives and PG-derived hydrogel. T.T., J.Y.G. and Y.J.L advised on the design and interpretation of \\u003cem\\u003ein vivo\\u003c/em\\u003e diabetic mouse wound model experiments. W.M., M.M, T.Z., and Z.Y.J. advised on the design and interpretation of all experiments and directed the overall project. J.Y.Z., W.M. and M.M. wrote and edited the manuscript. B.P. and B.H. edited the manuscript. M.M. acquired the funding to support this project.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe work was financially supported by the National Key R\\u0026amp;D Program of China (2022YFF1100101), the National Natural Science Foundation of China (32130084), Natural Science Foundation of Jiangsu Province (BK20211530) and the Research Program of State Key Laboratory of Food Science and Resources, Jiangnan University (No. SKLF-ZZB-202416).\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eWang Y, Liu K, Wei W, Dai H (2024) \\u003cem\\u003eA multifunctional hydrogel with photothermal antibacterial and antioxidant activity for smart monitoring and promotion of diabetic wound healing.\\u003c/em\\u003e Adv. Funct. 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Chem. 71(41).\\u003c/li\\u003e\\n\\u003cli\\u003eLampson BL, Ramίrez AS, Baro M, He L, Hegde M, Koduri V, Pfaff JL, Hanna RE, Kowal J, Shirole NH, He Y, Doench JG, Contessa JN, Locher KP, Kaelin WG (2024) \\u003cem\\u003ePositive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-\\u0026kappa;B.\\u003c/em\\u003e Cell 187(9): 2209-2223.e16.\\u003c/li\\u003e\\n\\u003cli\\u003eChen S, Saeed AF, Liu Q, Jiang Q, Xu H, Xiao GG, Rao L, Duo Y (2023) \\u003cem\\u003eMacrophages in immunoregulation and therapeutics.\\u003c/em\\u003e Signal Transduction Targeted Ther. 8(1): 207.\\u003c/li\\u003e\\n\\u003cli\\u003eMasato T, L. DBK, M. VHA, Lydia Z, Keisuke O, Masato H, M. TA, Hiroshi Y, Ting-Lin Y, M. BC, Kenichiro M, Rintaro S, D. YC, Zili X, Hisato I, Zhen W, Kelsey A, Gargi D, Deniz D, K. GJ, Dan H, Jinye D, B. CR, Hideaki M, Kenji M, Sanjay J, Steven VD, D. MJ, Dusan B, Hongzhen H, David A, E. TS, S. KB (2024) \\u003cem\\u003eSensory neurons promote immune homeostasis in the lung.\\u003c/em\\u003e Cell 187(1): 44-61.e17.\\u003c/li\\u003e\\n\\u003cli\\u003eLan X, Wang Q, Liu Y, You Q, Wei W, Zhu C, Hai D, Cai Z, Yu J, Zhang J, Liu N (2024) \\u003cem\\u003eIsoliquiritigenin alleviates cerebral ischemia-reperfusion injury by reducing oxidative stress and ameliorating mitochondrial dysfunction via activating the Nrf2 pathway.\\u003c/em\\u003e Redox Biol. 77: 103406-103406.\\u003c/li\\u003e\\n\\u003cli\\u003eChu T, Wang Y, Wang S, Li J, Li Z, Wei Z, Li J, Bian Y (2024) \\u003cem\\u003eKaempferol regulating macrophage foaming and atherosclerosis through piezo1-mediated MAPK/NF-\\u0026kappa;B and Nrf2/HO-1 signaling pathway.\\u003c/em\\u003e J. Adv. Res.\\u003c/li\\u003e\\n\\u003cli\\u003eMaeda S, Kamata H, Luo J-L, Leffert H, Karin M (2005) \\u003cem\\u003eIKK\\u0026beta; couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis.\\u003c/em\\u003e Cell 121(7): 977-990.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"advanced-composites-and-hybrid-materials\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"achm\",\"sideBox\":\"Learn more about [Advanced Composites and Hybrid Materials](https://link.springer.com/journal/42114)\",\"snPcode\":\"42114\",\"submissionUrl\":\"https://submission.nature.com/new-submission/42114/3\",\"title\":\"Advanced Composites and Hybrid Materials\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false},\"keywords\":\"natural hydrogel, phytoglycogen, multi-functional, ROS scavenging, immunoregulation, wound healing\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7222605/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7222605/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eManagement of chronic diabetic wound was an emerging challenge, and designing a multi-functional hydrogel to promote wound repair is urgent for therapy. We firstly discovered a natural hydrogel dressing from modified phytoglycogen (PG) with cationization and oxidation for the Schiff base cross-linking. \\u003cem\\u003eIn vitro\\u003c/em\\u003e and \\u003cem\\u003ein vivo\\u003c/em\\u003e studies reveal the hydrogel exhibited the favorable adhesion, self-healing, antibacterial and antioxidant properties, and the optimal CPG2-Gel forms efficient coverage in wound without contamination and infection. In the diabetic wound model, CPG2-Gel expedited the reactive oxygen species (ROS) clearance and immunoregulation, promoting cell proliferation, collagen deposition, and tissue formation to facilitate the wound closure with the healing rate of 1.76-fold compared to commercial dressing. The tumor necrosis factor-α (TNF-α) level was reduced to 87.5%, whereas the vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β) were enhanced up to 1.36 and 2.01 times, respectively. The mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways played crucial roles in mediating the polarization of alternatively activated macrophages (M2 macrophages), thereby facilitating cell proliferation, exerting anti-inflammatory effects, and regulating immune responses. This work can provide a facile and promising strategy for fabricating a multifunctional hydrogel dressing for fast therapy of diabetic wound.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Multi-functional phytoglycogen-derived hydrogel dressings promote the fast closure of diabetic wound in vitro and in vivo\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-09-22 21:28:45\",\"doi\":\"10.21203/rs.3.rs-7222605/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2025-10-26T03:44:42+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-10-21T08:42:17+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-10-18T17:00:45+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"324832292172663403261726893580456035554\",\"date\":\"2025-10-13T16:38:09+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"232691319254030348991118940909822718915\",\"date\":\"2025-10-05T08:00:16+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-09-15T02:55:21+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2025-09-12T15:29:43+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2025-07-28T00:21:22+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Advanced Composites and Hybrid Materials\",\"date\":\"2025-07-26T17:11:56+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"advanced-composites-and-hybrid-materials\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"achm\",\"sideBox\":\"Learn more about [Advanced Composites and Hybrid Materials](https://link.springer.com/journal/42114)\",\"snPcode\":\"42114\",\"submissionUrl\":\"https://submission.nature.com/new-submission/42114/3\",\"title\":\"Advanced Composites and Hybrid Materials\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"fd5e127e-8581-43ca-bb4c-e86f1fb027d6\",\"owner\":[],\"postedDate\":\"September 22nd, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2026-03-16T16:06:02+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-7222605\",\"link\":\"https://doi.org/10.1007/s42114-026-01717-7\",\"journal\":{\"identity\":\"advanced-composites-and-hybrid-materials\",\"isVorOnly\":false,\"title\":\"Advanced Composites and Hybrid Materials\"},\"publishedOn\":\"2026-03-12 16:00:12\",\"publishedOnDateReadable\":\"March 12th, 2026\"},\"versionCreatedAt\":\"2025-09-22 21:28:45\",\"video\":\"\",\"vorDoi\":\"10.1007/s42114-026-01717-7\",\"vorDoiUrl\":\"https://doi.org/10.1007/s42114-026-01717-7\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7222605\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7222605\",\"identity\":\"rs-7222605\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}