Sulfonated chitosan hydrogels reprogram the inflammatory niche for accelerated skin regeneration

Spatiotemporal 4D-printed shape-memory scaffold with a triple-acting liposomal strategy for the treatment of infectious bone defects.

Ion-releasing dental varnishes vary in composition and pH responsiveness, influencing remineralization efficacy. This study aimed to compare pH-responsive multi-ion release profiles of (1) sodium fluoride (NaF) varnish, (2) casein phosphopeptide-amorphous calcium phosphate (CPP-ACP)/NaF varnish, and (3) a newly synthesized NaF/nanohydroxyapatite (nHA)‑loaded chitosan (CS) hydrogel. Seventy-two sound primary canine specimens were prepared with standardized enamel windows and allocated to eight groups (n = 9) by material and buffer pH (5.5 or 7.0). Test materials included NaF varnish, CPP-ACP/NaF varnish, and experimentally formulated NaF/nHA-loaded CS hydrogel. Samples were individually immersed in buffer solutions at pH 5.5 and pH 7.0. Solutions were renewed at 4, 24, 72, and 168h, and analyzed by ion chromatography for fluoride, phosphate, and calcium concentrations. pH stability was monitored. Data were evaluated by 3-way repeated measures ANOVA and one-way ANOVA with Tukey's post hoc (p < 0.05). At pH 5.5, CPP-ACP/NaF varnish yielded the highest cumulative fluoride release with peak fluoride output in the first four hours (22.40 ± 0.23 ppm). NaF/nHA-loaded CS hydrogel exhibited the highest calcium release in the first four hours (11.40 ± 0.20 ppm) and sustained both calcium (30.20 ± 0.20 ppm) and phosphate (36.20 ± 0.20 ppm) through 168h. Phosphate release peaked at 24h for both the NaF/nHA-loaded CS hydrogel and the CPP-ACP/NaF varnish under both pH conditions. At pH 7.0, all ion releases were significantly reduced (p < 0.001), though relative material rankings remained the same. Buffer pH remained stable throughout (p > 0.05). While CPP-ACP/NaF varnish maximized early fluoride output, the NaF/nHA-loaded CS hydrogel demonstrated the most sustained multi-ion release under acidic conditions. These distinct pH-dependent kinetics suggest rapid fluoride delivery for early lesion resistance and sustained multi-ion release for extended remineralization.

Structure-function relationships in chitosan hydrogel spheres as a platform for silver nanoparticle stabilization and catalytic performance driven by macromolecular architecture.

Diatoms are environmentally responsive photosynthetic microorganisms whose growth dynamics and biosilicification processes are tightly regulated by external physicochemical conditions. However, conventional bulk cultivation and existing microfluidic platforms often fail to provide stable three-dimensional confinement together with dynamic environmental control, limiting long-term quantitative analysis at single-cell resolution. Here, we present a permeable hydrogel microreactor system integrated with microfluidic perfusion and a neural network-based image analysis workflow for on-chip investigation of diatom growth dynamics. Monodisperse alginate/carboxymethyl chitosan hydrogel microspheres were engineered to stably confine individual Cyclotella cryptica cells while permitting efficient molecular exchange. The microreactors were immobilized within a perfused microfluidic device, enabling long-term cultivation and real-time imaging under dynamically regulated conditions. Coupled with this neural network-based approach for segmentation and contour extraction, we quantitatively reconstructed single-cell growth trajectories and division events, achieving a specific growth rate of 1.874 d-1 under perfusion, which represents a 5.5-fold increase over batch controls. Furthermore, dynamic copper exposure enabled concentration-dependent stress profiling, yielding EC50 values of 8.53 μM (growth inhibition) and 7.25 μM (proliferation inhibition) at single-cell resolution. This platform offers a versatile analytical framework for resolving cellular heterogeneity and environmental responses in photosynthetic microorganisms under precisely controlled microenvironments.

Intervertebral disc degeneration (IDD), a principal cause of chronic low back pain, is characterized by nucleus pulposus cell (NPC) apoptosis and currently lacks effective therapies. Through integrated multi-omics and Mendelian randomization analyses, we identified isochorismatase domain-containing 1 (ISOC1) as a key therapeutic target. To achieve controlled, context-specific expression within the acidic disc microenvironment, we designed an injectable, pH-responsive polyvinyl alcohol-phenylboronic acid-functionalized chitosan (PVA-csPBA) hydrogel for delivery of modified ISOC1 mRNA (modRNA). Mechanistically, ISOC1 promotes BIRC6-mediated ubiquitination and proteasomal degradation of MYC, thereby suppressing its transcriptional target SBSN. Suppression of the MYC/SBSN pathway directly ameliorates lactate-induced mitochondrial dysfunction and apoptosis in NPCs, preserving cellular viability and extracellular matrix homeostasis. In a rat IDD model, localized delivery of PVA-csPBA@ISOC1 modRNA effectively maintained disc hydration, mitigated nucleus pulposus tissue degeneration, and reduced annulus fibrosus fibrosis without observable systemic adverse effects. In summary, this work not only validates ISOC1 as a druggable target and elucidates its protective mechanism via inhibition of the MYC/SBSN pathway, but also establishes pH-responsive hydrogel-based modRNA delivery as a potent and precise regenerative strategy for counteracting IDD progression.

While gelatin-based conductive hydrogels can acquire electrophysiological signals over multiple days, the statistical consistency and analytical utility of these long-term recordings for data-driven interpretation remain inadequately assessed. To address this, we developed a gelatin-quaternary ammonium chitosan (GT-QCS) hydrogel electrode that leverages a rapid, temperature-triggered sol-gel transition. Its fluid precursor conforms to complex skin topographies, forming a strongly adhesive interface within two minutes. The ionically crosslinked network shows high stretchability (∼400% strain), tissue-matched modulus (∼73 kPa), strong adhesion (544.1 mN cm-1), breathability (WVTR ≈ 605 g m-2 day-1), and low dehydration (∼13% water loss after 30 days). This combination enables stable, week-long acquisition of high-fidelity sEMG, ECG, and EEG signals. The utility of these signals for data-driven analytics was quantitatively validated through a convolutional neural network, which achieved high accuracy in gesture recognition using the long-term sEMG data. Furthermore, the electrode-skin impedance and EEG signal fidelity remained stable over a seven-day period, outperforming standard conductive paste that typically dries within hours. This work demonstrates how phase-transition-enabled hydrogel electrodes can bridge material design with data-driven physiological analysis, offering a general approach for intelligent wearable bioelectronics.

Poor aqueous solubility and consequently low bioavailability of various NSAIDs (non-steroidal anti-inflammatory drugs) usually result in high and multiple dosing with potentially serious side effects. Therefore, systems for the effective transport of NSAIDs through the GIT (gastrointestinal tract), ensuring enhanced bioavailability, remain in high demand. In the present work, we studied chitosan (CS) hydrogel lyophilizates as carrier systems for a model NSAID, namely ibuprofen (IBU). The CS-IBU lyophilizates were prepared from homogeneous or heterogeneous CS-IBU hydrogels to assess their influence on the resulting lyophilizate microstructure and IBU dissolution profiles. To gain a complex view of the CS-IBU behavior and its practical consequences, dissolution profiles of free IBU (reference) and CS-associated IBU (CS-IBU) were examined and compared to each other at variable pH (1.2 and 6.5) in two separate dissolution systems and in one discontinuous dissolution system mimicking GIT conditions. The results of dissolution experiments were supported by kinetic model data. This study demonstrated that the dissolution of IBU from the CS-IBU lyophilizates is affected by two main pH-dependent competitive effects; i.e., dissolved CS acts as an IBU solubilizer and the undissolved CS matrix serves as an IBU trap, which could be used in the rational design of innovative stimuli (pH)-responsive oral dosage forms of IBU.

In situ cancer vaccines hold strong potential for addressing tumor heterogeneity by using the patient's own tumor as a personalized antigen source. However, their efficacy remains limited by insufficient antigen capture and inefficient cytosolic delivery. Here, we report an in situ antigen capture and delivery platform, DOX/PDiT@Gel, in which the pH-responsive function is provided by the polymer PDiT, while the hydrogel serves as a local retention matrix. In this system, doxorubicin (DOX) and a cationic polymer, PEG-DIPAMA-TAT (PDiT), are co-encapsulated within an oxidized dextran/carboxymethyl chitosan hydrogel. DOX induces immunogenic cell death, releasing diverse tumor antigens, while PDiT captures these antigens in situ via electrostatic interactions and promotes endo/lysosomal escape under acidic conditions. The hydrogel allows localized delivery of the therapeutic components at the postoperative tumor site. In vitro studies showed that PDiT markedly promoted antigen internalization, cross-presentation, and dendritic cell maturation. In murine models of postoperative recurrence and bilateral breast tumors, local treatment with DOX/PDiT@Gel inhibited the growth of both recurrent and distant tumors, together with stronger dendritic cell activation and enhanced memory T cell responses. Overall, this platform effectively amplifies antitumor immunity and offers a versatile strategy for personalized cancer immunotherapy.

Numerous types of wounds are at risk for infection, such as burn wounds, traumatic wounds, surgical wounds, chronic ulcer wounds, and radiologic wounds. The repair of infectious wounds depends on specific microenvironments, including moderate hydration, reactive oxygen scavenging, antimicrobial, anti-inflammatory, and angiogenic conditions. To effectively promote the repair of infectious wounds and reduce the risk of infection spread, we developed a multifunctional bilayer wound dressing (MBWD) that simultaneously meets these criteria. The inner layer (DMOG@PCL/ASC) consists of a polycaprolactone (PCL)/fish collagen (ASC) nanofiber decorated with coaxial microparticles containing dimethyloxalylgcine (DMOG). The three-dimensional pore structure of nanofibers offers numerous adhesion sites for cells, and the gradual release of DMOG can promote angiogenesis. The outer layer consists of a glycidyl methacrylate-modified carboxymethyl chitosan hydrogel loaded with cerium oxide nanozymes (M-CMCS/CeO2). This M-CMCS hydrogel provides a moist microenvironment and exhibits antimicrobial properties. The localized release of CeO2 can deliver antioxidant effects, combat microbes, and modulate inflammation. In vivo studies confirmed that the MBWD dressing can enhance the healing of infectious and diabetic wounds by providing rapid antimicrobial, anti-inflammatory, and pro-angiogenic effects. Therefore, this combined system of nanofibers and hydrogels, each loaded with specific functional components, offers an effective strategy for treating infectious wounds.

Bacterial infection and biofilm formation are major barriers to effective wound healing, often leading to persistent inflammation, delayed tissue repair, and chronic wound conditions. To address these issues, a chitosan-based hydrogel patch embedded with silver-decorated two-dimensional magnesium oxide nanosheets (Cs-AMO) was developed as a multifunctional wound dressing. Morphological analysis confirmed the formation of porous 2-D MgO nanosheets uniformly decorated with Ag nanoparticles and well dispersed within the chitosan matrix. Owing to the combined effects of Ag+ ion release, reactive oxygen species generation, and contact-mediated antibacterial interactions, the Cs-AMO hydrogel patch showed nearly complete antibacterial inhibition (∼100%) against both Gram-negative and Gram-positive bacteria. In addition, the hydrogel exhibited strong antibiofilm activity, achieving biofilm inhibition of up to 82% against E. coli and 83% against B. subtilis, as confirmed by crystal violet assay and confocal microscopy. Cytocompatibility studies using HEK-293 cells revealed up to 85% cell viability, indicating favourable biocompatibility. Furthermore, in vivo evaluation using an infected rat wound model demonstrated accelerated wound healing, achieving 96% wound closure by day 12 post-treatment, along with effective bacterial clearance, reduced inflammation, and enhanced tissue regeneration compared to the control groups. Overall, the developed Cs-AMO hydrogel patch demonstrates strong potential as an antibacterial and antibiofilm wound dressing for the treatment of infected wounds.

Chronic myeloid leukemia remains a significant challenge in cancer treatment because conventional drug delivery systems often fail to provide sustained release and targeted therapeutic effects. To address these limitations, this study a chitosan-based nanocomposite hydrogel system for the controlled delivery of nilotinib, a tyrosine kinase inhibitor used to treat chronic myeloid leukemia. Fe2O3-containing layered double hydroxide nanocomposites into were incorporated chitosan hydrogels under controlled synthesis conditions (70 ± 2°C, stirring speed at 800rpm) to fabricate chitosan nanocomposite hydrogel beads based on LDH and Fe2O3 nanoparticles. Structural characterization using scanning electron microscopy and X-ray diffraction confirmed successful nanoparticle incorporation and the formation of a porous hydrogel network. Nilotinib was incorporated into the hydrogel beads using both in situ and post-synthetic approaches, and drug release was quantified by high-performance liquid chromatography. Among the formulations investigated, the Post-synthetic incorporation of nilotinib into dried hydrogel beads at a concentration of 20% yielded the highest cumulative nilotinib release after six hours (72.895 ± 0.004 µg/mL). Cytotoxicity studies revealed a concentration-dependent inhibition of chronic myeloid leukemia cell lines (BV173, EM-2, CML-T1, and JOSK-M) and indicated acceptable biocompatibility with human umbilical vein endothelial cells. In addition, the nanocomposite hydrogel demonstrated notable antioxidant activity in the DPPH assay. Overall, the developed LDH/Fe2O3-modified chitosan hydrogel system represents a promising platform for the controlled delivery of hydrophobic anticancer agents such as nilotinib.

Multi-crosslinking 2,3-catechol-functionalized chitosan hydrogel: Oxidation-resistive and ROS-scavenging platform for granulation regeneration.

ABSTRACT The present work aimed to synthesize Tetraethyl orthosilicate (T)- crosslinked chitosan (CS) and Guargum (GG) hydrogels with varying compositions (CS-T@GG1, CS-T@GG0.8, and CS-T@GG0.5) and evaluate their application for the removal of methylene blue (MB) dye from aqueous solution. Adsorption of dye on the fabricated hydrogels was conducted in a batch system. The prepared crosslinked hydrogels were characterized using Raman, EDS, SEM, FTIR, XRD, TGA, and particle size analysis. The swelling response of the synthesized hydrogel was investigated in deionized water at different pH levels and electrolyte concentrations. Equilibrium concentrations of dye in aqueous solution and adsorption capacities of adsorbent at various experimental conditions (Different time intervals in batches, solution pH, and initial adsorbate concentration in solution, thermodynamic study at different temperatures, change in enthalpy, entropy, and Gibbs free energy) were evaluated. At pH 12, the dye adsorption efficiency was 82.10% for a 25 ppm methylene blue solution using a 0.025 g/L adsorbent dose at 300 rpm, whereas at neutral pH, the efficiency decreased to approximately 65%. Various kinetic adsorption isotherms and thermodynamic models were simulated mathematically. The pseudo-first-order kinetic model gave the best agreement with the experimental kinetic data, with R2 .99 and the model qe value. Results confirmed that the synthesized hydrogel may be an efficient adsorbent for dye removal. The correlation between the independent variables associated with methyl blue dye adsorption and the dependent parameters was established by analyzing ChemSketch 3D. The hydrogel remained stable for 5 cycles in the stability test.

Diabetic foot ulcer (DFU) is a severe complication of diabetes. This study evaluated the effects and underlying mechanism of baicalin on DFU healing. High glucose (HG)-exposed HaCaT cells and streptozotocin-induced DFU rats were employed as in vitro cell models and in vivo models. Cell viability, migration, and inflammatory cytokine levels were assessed following baicalin (100µg/mL) treatment. A baicalin-loaded carboxymethyl chitosan (CS) hydrogel was prepared, and its therapeutic effects on blood glucose and wound closure were evaluated over 14 days. Bioinformatic analysis, molecular docking, and MAPK1 knockdown were performed to elucidate the mechanism. Baicalin restored HG-reduced HaCaT cell viability (p < 0.01) and migration (p < 0.001), and decreased IL-6, IL-1β, and TNF-α levels. In DFU rats, the hydrogel lowered blood glucose from > 20mM to approximately 10mM (p < 0.001) and accelerated wound healing (p < 0.01). Bioinformatic analysis identified MAPK1 as a key target; molecular docking confirmed strong binding affinity (< - 6kcal/mol). Baicalin upregulated MAPK1 expression (p < 0.01), whereas shRNA-mediated MAPK1 knockdown attenuated the therapeutic effects in vitro and in vivo (p < 0.001). These findings demonstrate baicalin's potential as a DFU treatment through MAPK1 regulation and highlight the need for further research into its molecular mechanisms and clinical applications.

A single drop of unprocessed whole blood, placed at the inlet of a 3D-printed cartridge, yields a quantitative cancer biomarker result in under 15 min-without centrifugation, pipettes, cold-chain reagents, or any laboratory instrument. This is made possible by a silica nanoparticle-chitosan (SiNP-chitosan) nanocomposite that transforms a hydrophobic stereolithography-printed substrate into a near-superhydrophilic, antifouling interface (contact angle 74.3° → 25.3°; Laplace pressure amplified 5.2-fold; fibrinogen adsorption reduced 12-fold), driving autonomous capillary plasma separation directly from finger-prick blood without any external actuation. Anti-GPC3-functionalized gold nanoparticles (AuNPs, ∼30 nm) embedded in chitosan hydrogel beads within the same cartridge transduce antigen binding via localized surface plasmon resonance (LSPR) into two simultaneous, independent optical signals, namely, instrument-free RGB colorimetry (TCS3200/Arduino) for point-of-care use and laboratory-grade LSPR ratiometry for cross-validation-providing intrinsic dual-channel confirmation that no single-transducer platform can match. Glypican-3 (GPC3), an HCC-specific biomarker superior to α-fetoprotein, is detected at LOD = 0.24 ng mL-1 directly from unprocessed whole blood in the same step that separates the plasma. A stereolithography-fabricated device (45 × 18 × 6 mm) incorporates a geometry-programmed micropillar array coated with a silica nanoparticle-chitosan (SiNP-chitosan) nanocomposite. Anti-GPC3-functionalized AuNPs (∼30 nm; TEM core 30.2 ± 2.8 nm) transduce antigen binding into LSPR ratiometric shifts (A₅₈₀/A₅₂₀) and a correlated RGB colorimetric signal, validated in a DEN-induced murine HCC model. The results are as follows: contact angle reduced from 74.3° to 25.3°; Laplace pressure amplified 5.2-fold (86 to 451 Pa); plasma recovery 35-42% of total blood input volume within 30 s; LOD = 0.24 ng mL-1 (LSPR channel)/0.31 ng mL-1 (RGB channel); CV < 10% (both channels); spike recovery 97.3%; ELISA agreement R2 ≈ 0.99; tumor burden correlation R2 ≈ 0.98; diagnostic AUC = 1.00 (95% CI: 0.993-1.000; per timepoint: week 9, AUC = 0.98; week 11, 0.99; weeks 13-16, 1.00) in a controlled inbred murine DEN-HCC model (n = 10 per group). This AUC = 1.00 result must be interpreted in context: it was obtained in a tightly controlled, single-strain, single-sex, small-sample (n = 10 per group) murine cohort and reflects ceiling-level discrimination in a maximally homogeneous preclinical setting. It is not a projection of human diagnostic performance. Such ceiling-level AUC values in small homogeneous animal cohorts are well-documented in biosensor proof-of-concept literature Hanley and McNeal. Radiology 1982, 143, 29-36 and carry a recognized risk of optimistic bias: the controlled model eliminates the inter-individual biological heterogeneity, comorbidity, and preanalytical variability that will reduce AUC substantially in human populations. The AUC is reported to characterize analytical discrimination power of the platform under maximally favorable conditions, not to claim clinical diagnostic performance. This preclinical proof-of-concept platform demonstrates, in a murine DEN-HCC model, a broadly applicable framework for decentralized nanoscale cancer biomarker diagnostics. The RGB channel enables fully instrument-free point-of-care operation; the LSPR channel provides laboratory-grade cross-validation. Prospective human clinical validation is planned before clinical deployment.

The management of glioblastoma multiforme (GBM) remains challenging due to its poor prognosis and extremely high postoperative recurrence rate. Although the Gliadel wafer locally delivers carmustine, its clinical application is limited by suboptimal therapeutic efficacy and poor conformability to irregular resection cavities. To overcome these limitations, we developed a novel drug delivery system based on thermosensitive injectable chitosan-β-glycerol phosphate hydrogel containing doxorubicin-loaded mesoporous silica nanoparticles encapsulated within tumor-derived exosomes (Exo-DMSNs@CS). In an orthotopic mouse GBM relapse model recapitulating clinical tumor resection, the liquid Exo-DMSNs@CS formulation was injected into the surgical cavity and subsequently gelated in situ, achieving seamless adhesion to the irregular resection margins of the cavity. The exosome-coated nanoparticles (Exo-DMSNs), released gradually from chitosan hydrogel, exhibited enhanced tumor-targeting capability via exosome-mediated tumor-homing performance, thereby substantially promoting drug internalization. Compared to non-exosomal controls (DMSNs@CS), Exo-DMSNs@CS markedly suppressed tumor recurrence and prolonged survival. Our findings demonstrate that this Trojan-horse-inspired delivery strategy—leveraging tumor-derived exosomes to encapsulate drug-loaded nanoparticles—enables a localized and precise tumor-targeted drug delivery system, representing a promising therapeutic paradigm for GBM treatment.

Mucoadhesive drug delivery systems (MDDS) improve drug absorption and retention within the gastrointestinal tract by using polymers that bind to the mucosal lining. This prolonged contact increases local drug concentration, enhances bioavailability, and reduces systemic side effects, making the approach particularly effective for colorectal and other digestive tract cancers. By adhering to the mucosa, MDDS extend residence time and can be engineered for targeted release at tumor sites, thereby minimizing toxicity to healthy tissues and overcoming enzymatic barriers that hinder absorption. This study focused on developing mucoadhesive hydrogels embedded with doxorubicin-loaded poly (lactic-co-glycolic acid) nanoparticles (DOX-PLGA NPs) to advance site-specific cancer therapy. The synthesized NPs exhibited a uniform spherical morphology, with an average size of about 97 nm by SEM and a hydrodynamic diameter of 215 nm by DLS, confirming stability with a zeta potential of -30 mV. Incorporating NPs into chitosan hydrogels enhanced porosity, swelling response, and biodegradability, while rheological tests confirmed shear-thinning behavior and improved mechanical resilience-features essential for injectability and mucosal retention. Drug release experiments demonstrated pH-responsive behavior: acidic environments yielded slow, controlled release, while physiological pH triggered faster release. Biological studies indicated that DOX-PLGA hydrogels effectively inhibited cancer cell growth by inducing apoptosis, disrupting mitochondrial function, increasing oxidative stress, and promoting inflammatory markers, alongside glutathione depletion. While chitosan hydrogels alone showed biocompatibility and moderate anticancer activity, the combined NP -hydrogel system displayed synergistic and superior therapeutic effects. These findings support the potential of this stimuli-responsive platform for precise, localized cancer treatment with reduced systemic toxicity.

Glucose-sensitive and 3D-printable dynamic chitosan hydrogels from boronic acid-functionalized chitosan and gallol-functionalized chitosan.

Injectable pH-responsive cross-linked chitosan hydrogel co-delivering methotrexate and diaminoperylene bisimide: Enhanced targeted chemo-photodynamic therapy for breast cancer cells with reduced systemic toxicity