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Abstract Treating the most widespread complication of diabetes: diabetic wounds poses a significant clinical obstacle due to the intricate nature of wound healing in individuals with diabetes. Here a novel approach is proposed using easily applicable injectable gelatin/metal/tea polyphenol double nanonetworks, which effectively remodel the wound microenvironment and accelerates the healing process. The gelatin(Gel) crosslink with metal ions (Zr4+) through the amino acids, imparting advantageous mechanical properties like self‐healing, injectability, and adhesion. The nanonetwork's biological functions are further enhanced by incorporating the tea polyphenol metal nanonetwork through in situ doping of the epigallocatechin gallate (EGCG) with great antibacterial, self‐healing, antioxidant, and anticancer capabilities. The in vitro and in vivo tests show that this double nanonetworks hydrogel exhibits faster cell migration and favorable anti‐inflammatory and antioxidant properties and can greatly reshape the microenvironment of diabetic wounds and accelerate the wound healing rate. In addition, this hydrogel is completely degraded after subcutaneous injection for 7 days, with nondetectable cytotoxicity in H&E staining of major mice organs and the serum level of liver function indicators. Considering the above‐mentioned merits of this hydrogel, it is believed that the injectable gelatin/metal/tea polyphenol double nanonetworks have broad biomedical potential, especially in diabetic wound repair and tissue engineering.

Abstract Bacterial infection can impede the healing of chronic wounds, particularly diabetic wounds. The high‐sugar environment of diabetic wounds creates a favorable condition for bacterial growth, posing a challenge to wound healing. In clinical treatment, the irregular shape of the wound and the poor mechanical properties of traditional gel adjuvants make them susceptible to mechanical shear and compression, leading to morphological changes and fractures, and difficult to adapt to irregular wounds. Traditional gel adjuvants are prepared in advance, while in situ gel is formed at the site of administration after drug delivery in a liquid state, which can better fit the shape of the wound. Therefore, this study developed an in situ HA/GCA/Fe2+‐GOx gel using a photothermal‐enhanced Fenton reaction to promote the generation of hydroxyl radicals (·OH). The generation of ·OH has an antibacterial effect while promoting the formation of the gel, achieving a dual effect. The addition of double‐bonded adamantane (Ada) interacts with the host‐guest effect of graphene oxide and the double‐bond polymerization of HAMA gel, making the entire gel system more complete. At the same time, the storage modulus (G′) of the gel increased from 130 to 330 Pa, enhancing the mechanical properties of the gel. This enables the gel to have better injectability and self‐healing effects. The addition of GOx can consume glucose at the wound site, providing a good microenvironment for the repair of diabetic wounds. The gel has good biocompatibility and in a diabetic rat wound model infected with S. aureus, it can effectively kill bacteria at the wound site and promote wound repair. Meanwhile, the inflammation of wounds treated with HA/GCA/Fe2+‐GOx + NIR was lighter compared to untreated wounds. Therefore, this study provides a promising strategy for treating bacterial‐infected diabetic wounds.

Intervertebral disc degeneration (IVDD) is still a challenge and the efficient treatment approaches are still lacking, due to the high oxidative stress and inflammation and matrix degradation. The utilization of bioactive hydrogels as carriers for therapeutic factors offers a powerful means to enhance IVDD treatment. However, the therapeutic efficacy of existing hydrogels heavily relies on the loaded therapeutic drugs, resulting in reduced treatment efficiency. Herein, we report a dual-component polymer network hydrogel (FPFG) based on gelatin methacrylate (GelMA) and poly (ferulic acid)-F127- poly (ferulic acid) (FPF). The FPFG hydrogel exhibited injectability, antioxidative properties, good biocompatibility, and biodegradability. FPFG hydrogel could efficiently suppress the intracellular reactive oxygen species (ROS) and metallomatrix proteinase in nucleus pulposus (NP) cells, inhibit the expression of inflammatory factors in macrophages and enhance the extracellular matrix formation. The rat puncture model revealed that the FPFG hydrogel effectively restored disc height, maintained disc hydration, and preserved tissue structure. By exerting anti-inflammatory and antioxidant activities, the FPFG hydrogel successfully ameliorated the hostile microenvironment commonly found in degenerated disc tissue. These findings highlight the potential application of FPFG hydrogel in enhancing IVDD treatment.

Oral squamous cell carcinoma (OSCC) produces malignant tumours in the oral cavity and adjacent anatomical structures, ranking sixth among the 11 most common malignant tumours in the body. The poor surgical outcomes for OSCC have led to increasing interest in nanomedicines. Major challenges with concentration-dependent therapies include the effective and precise delivery of gases to the lesion and combination with other therapies to achieve precise treatment. Herein, novel Cu2Se nanosheets (Cu2Se NSs) were ingeniously synthesized and enveloped with a thermosensitive nitric oxide (NO) supplier (sodium nitroprusside dihydrate, SNP) within a sodium alginate (ALG) hydrogel matrix to effectively eradicate tumours by combining photothermal therapy (PTT) and gas therapy (GT). The Cu2Se NSs reduced the glutathione (GSH) present in high concentrations to glutathione disulfide (GSSG), effectively killing squamous cell carcinoma cells under 1064 nm laser irradiation. Moreover, the Cu2Se NS hydrogel wrapped with SNP exhibited good NIR-controlled NO release behaviour, thus realizing the combined application of PTT and GT. PTT along with NO release is expected to improve the antitumour effect and provide new solutions for treating OSCC.

It is often difficult to close and repair irregular wounds such as gums with traditional dressings that have a fixed shape, while injectable hydrogels that can be molded in situ offer tremendous advantages in treating complex, large wounds and can better seal or fill a variety of irregular wounds. While the majority of injectable hydrogels developed in current research have poor mechanical properties and biocompatibility and obstacles to clinical applications, this paper reports an injectable hydrogel that can be molded in situ with appropriate mechanical properties, excellent biocompatibility, and antibacterial activity. Under UV irradiation, a methacrylate-gelatin/poly-(vinyl alcohol) loaded with copper ion cross-linked tannic acid nanoparticle (GelMA/PVA-TA/Cu2+NPs) precursor solution could rapidly gel within 45 s and adhere stably to the wound tissue by topological adhesion and hydrogen bonding. Through hydrogen bonding and physical entanglement, TA/Cu2+NPs are anchored in the GelMA/PVA interpenetrating network to form the GelMA/PVA-TA/Cu2+NPs composite hydrogel. This injectable hydrogel, which can quickly achieve photocurable in situ molding, can not only achieve closure and repair of irregular wounds but also has appropriate swelling characteristics, absorbing tissue exudate and blocking bacteria, while providing a good moist environment for wounds and continuously promoting wound healing. Cytotoxicity tests and wound healing experiments have shown that GelMA/PVA-TA/Cu2+NPs injectable hydrogels have good biocompatibility and wound closure and repair ability and have promising applications in the treatment of irregularly wounded orifices. [ABSTRACT FROM AUTHOR]

The present study aimed at developing an injectable hydrogel based on acacia gum (AG) for wound healing acceleration. The hydrogels were synthetized through metal-ligand coordination mediated by Fe3+ and characterized in terms of gelation time, gel content, initial water content, swelling capacity, water retention ratio, and porosity. Moreover, FTIR, XRD and TGA analyses were performed for the hydrogels and allantoin (Alla) loaded ones. Furthermore, bioadhessiveness, and self-healing as well as antibacterial, toxicity and wound healing potentials of the hydrogels were evaluated. The hydrogels displayed fast gelation time, high swelling, porosity, and bioadhessiveness, as well as antioxidant, self-healing, antibacterial, blood clotting, and injectability properties. FTIR, XRD and TGA analyses confirmed hydrogel synthesis and drug loading. The Alla-loaded hydrogels accelerated wound healing by decreasing the inflammation and increasing the cell proliferation as well as collagen deposition. Hemocompatibility, cell cytotoxicity, and in vivo toxicity experiments were indicative of a high biocompatibility level for the hydrogels. Given the advantages of fast gelation, injectability and beneficial biological properties, the use of Alla-loaded hydrogels could be considered a new remedy for efficient wound healing. [ABSTRACT FROM AUTHOR]

Objective·To construct a self-healing injectable hyaluronic acid (HA)-based hydrogel (HAPD-Cu) and investigate the effects of different copper ions on the properties of the hydrogel and its vasogenic efficacy to evaluate its feasibility for clinical wound healing. Methods·Bisphosphonated hyaluronic acid (HAPD) was prepared via a blue-light mediated thiol-ene click reaction between thiolated hyaluronic acid (HASH) and acrylated bisphosphonate (Ac-PD) in the presence of photoinitiator 2959. Then, HAPD was further interacted with Cu2+ through metal coordination to prepare HAPD-Cu hydrogels with different Cu2+ concentrations, i.e. HAPD-Cu1, HAPD-Cu2, HAPD-Cu3 and HAPD-Cu4. The molecular structures of HASH, Ac-PD, HAPD and HAPD-Cu were verified with 1HNMR and FTIR. Microscopic morphology of HAPD-Cu was observed under SEM. The shearthinning and self-healing properties of HAPD-Cu were verified by rheometer. The Cu2+ release from HAPD-Cu was determined with ICP. Live-dead staining and CCK-8 assay were applied to evaluate the biocompatibility of HAPD-Cu. The in vitro vasculogenic activity of HAPD-Cu was determined by a tubule-forming assay with human umbilical vein vascular endothelial cells and the in vivo vasculogenic activity of HAPD-Cu was assessed by CD31 tissue staining. A rat wound defect model was established in vitro to evaluate its actual repair effect. Results·The preparation of the materials was demonstrated through chemical qualitative and quantitative analytical means. In vitro studies showed that all HAPD-Cu with a loose porous internal structure exhibited outstanding self-healing, injectability and degradability, with a one-week degradation cycle and abrupt release behavior, which can meet the needs of wound healing cycle. All HAPD-Cu showed good biocompatibility except HAPD-Cu4, due to its high Cu2+ concentrations. Moreover, its angiogenic effect in vitro or in vivo was enhanced with increasing Cu2+ concentrations within the permissible Cu2+ concentration range. In vitro wound model experiments also showed that the HAPD-Cu hydrogel significantly promoted wound healing compared with the control group. Conclusion·HAPD-Cu hydrogel constructed via the metal coordination shows excellent shape plasticity, allowing the filling of defective sites in a minimally invasive form, and the release of Cu2+ greatly facilitates the establishment of early vascular networks, with giant potential for use in the repair of clinically irregular wounds. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) has a high disability rate and poor treatment efficacy and severely affects the health and daily life of patients. Improving the local microenvironment after SCI is crucial for restoring the normal physiological function of the spinal cord. In this study, the injectable near-infrared (NIR) photothermal responsive drug-loaded multiwalled carbon nanotubes (DMWCNTs) containing hydrogel microspheres were prepared by microfluidic technology for SCI treatment. Specifically, paclitaxel (PTX) and vascular endothelial growth factor (VEGF) were loaded into dopamine-modified DMWCNTs, which were then further compounded into gellan gum (GG) by using microfluidic technology to obtain [PTX/VEGF]@DMWCNTs/GG microspheres. The physicochemical properties of the microspheres were characterized using various methods, including transmission electron microscopy (TEM), energy-dispersive X-ray (EDX) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, optical microscopy, and scanning electron microscopy (SEM). Results showed that microspheres with good injectability and controllable drug release were successfully prepared by using microfluidic technology. The presence of MWCNTs endowed the microspheres with photothermal responsiveness, which led to more drug release under NIR irradiation. The cytotoxicity test results showed that the microspheres had no obvious cytotoxicity and the drug-loaded MWCNTs containing hydrogel microspheres could promote the differentiation of neural stem cells (NSCs). Immunofluorescence results in rats with hemisectioned SCI showed that the microspheres promoted the differentiation of NSCs and the growth of neurons and inhibited the formation of astrocytes and glial scars at the lesion site. In conclusion, the injectable near-infrared photothermal responsive drug-loaded multiwalled carbon nanotube hydrogel microspheres prepared in this study exhibit a promoting effect on SCI repair and provide a strategy for developing transplantation materials for SCI treatment. [ABSTRACT FROM AUTHOR]

Modulating the inflammatory microenvironment can inhibit the process of inflammatory diseases (IDs). A tri‐cross‐linked inflammatory microenvironment‐responsive hydrogel with ideal mechanical properties achieves triggerable and sustained drug delivery and regulates the inflammatory microenvironment. Here, this study develops an inflammatory microenvironment‐responsive hydrogel (OD‐PP@SeNPs) composed of phenylboronic acid grafted polylysine (PP), oxidized dextran (OD), and selenium nanoparticles (SeNPs). The introduction of SeNPs as initiators and nano‐fillers into the hydrogel results in extra cross‐linking of the polymer network through hydrogen bonding. Based on Schiff base bonds, Phenylboronate ester bonds, and hydrogen bonds, a reactive oxygen species (ROS)/pH dual responsive hydrogel with a triple‐network is achieved. The hydrogel has injectable, self‐healing, adhesion, outstanding flexibility, suitable swelling capacity, optimal biodegradability, excellent stimuli‐responsive active substance release performance, and prominent biocompatibility. Most importantly, the hydrogel with ROS scavenging and pH‐regulating ability protects cells from oxidative stress and induces macrophages into M2 polarization to reduce inflammatory cytokines through PI3K/AKT/NF‐κB and MAPK pathways, exerting anti‐inflammatory effects and reshaping the inflammatory microenvironment, thereby effectively treating typical IDs, including S. aureus infected wound and rheumatoid arthritis in rats. In conclusion, this dynamically responsive injectable hydrogel with a triple‐network structure provides an effective strategy to treat IDs, holding great promise in clinical application. [ABSTRACT FROM AUTHOR]

Introduction: Cell transplantation with hydrogel-based carriers is one of the advanced therapeutics for challenging diseases, such as spinal cord injury. Electrically conductive hydrogel has received much attention for its effect on nerve outgrowth and differentiation. Besides, a load of neuroprotective substances, such as lithium chloride can promote the differentiation properties of the hydrogel. Methods: In this study, alginate/collagen/reduced graphene oxide hydrogel loaded with lithium chloride (AL/CO/rGO Li+) was prepared as an injectable cell delivery system for neural tissue regeneration. After determining the lithium-ion release profile, an MTT assay was performed to check neural viability. In the next step, real-time PCR was performed to evaluate the expression of cell adhesion and neurogenic markers. Results: Our results showed that the combination of collagen fibers and rGO with alginates increased cell viability and the gene expression of collagen-binding receptor subunits such as integrin a1, and ß1. Further, rGO contributed to the controlled release of lithium-ion hydrogel in terms of its plenty of negatively charged functional groups. The continuous culture of NSCs on AL/CO/rGO Li+ hydrogel increased neurogenic genes' expressions of nestin (5.9 fold), NF200 (36.8 fold), and synaptophysin (13.2 fold), as well as protein expression of NF200 and synaptophysin after about 14 days. Conclusion: The simultaneous ability of electrical conduction and lithium-ion release of AL/CO/rGO Li+ hydrogel could provide a favorable microenvironment for NSCs by improving their survival, maintaining cell morphology, and expressing the neural marker. It may be potentially used as a therapeutic approach for stem cell transplantation in a spinal cord injury. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a severe neurological injury caused by traffic accidents, trauma, or falls, which leads to significant loss of sensory, motor, and autonomous functions and seriously affects the patient's life quality. Although considerable progress has been made in mitigating secondary injury and promoting the regeneration/repair of SCI, the therapeutic effects need to be improved due to drug availability. Given their good biocompatibility, biodegradability, and low immunogenicity, injectable hydrogels can be used as delivery systems to achieve controlled release of drugs and other substances (cells and proteins, etc.), offering new hope for SCI repair. In this article, we summarized the types of injectable hydrogels, analyzed their application as delivery systems in SCI, and further discussed the mechanisms of hydrogels in the treatment of SCI, such as anti-inflammatory, antioxidant, anti-apoptosis, and pro-neurogenesis. Moreover, we highlighted the potential benefits of hydrogels in the treatment of SCI in combination with therapies, including the recent advances and achievements of these promising tools. Our review may offer new strategies for the development of SCI treatments based on injectable hydrogels as delivery systems. [ABSTRACT FROM AUTHOR]

Biopolymer-based injectable hydrogels with antibacterial activity have attracted considerable attention for biomedical applications. Herein, we report on an effective preparation of injectable double network hydrogel by adding zinc acetate (ZnOAc2) into an aqueous mixture of methylcellulose (MC) and chitosan (CS) at room temperature and then heating to T = 37 °C, in which the complexation of the CS with Zn2+ ion took place immediately and the MC underwent thermogelation at elevated temperature. The influence of both the CS and different salts (i.e., Zn(NO3)2, ZnCl2 and ZnOAc2) on the thermogelation of MC solution was investigated via inverted vial test and UV–Vis measurement. The results indicated that the thermogelation temperature of 1.0% w/v MC was about 60.8 °C, which decreased to 35.7 °C when mixed with 1.0% w/v CS and 0.3 mol/L sodium acetate. The mechanical properties of various hydrogels were evaluated via rheological analysis at different temperatures. A detailed study about the antibacterial activities of the resulting MC/CS hydrogels was carried out against both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli, confirming that the MC/CS double network hydrogel indeed exhibited excellent antibacterial activity when compared with pristine thermo-responsive MC hydrogel. At last, the injectability of the MC/CS hydrogel was also evaluated on a home-built double-syringe injection device. [ABSTRACT FROM AUTHOR]

The current treatment for periodontitis is aimed at resolving gingival inflammation, whilst complete periodontal tissue regeneration is not predictable, and it represents a therapeutic challenge. Injectable biomaterials hold tremendous potential in dental tissue regeneration. This study aimed to investigate the ability of an injectable thermosensitive β-tricalcium phosphate (β-TCP) and chitosan-based hydrogel to carry cells and promote periodontal tissue regeneration. In this study, different concentrations of β-TCP-loaded chitosan hydrogels were prepared (0%, 2%, 4%, or 6% β-TCP, 10% β-glycerol phosphate, and 1.5% chitosan). The characteristics of the hydrogels were tested using rheology, a scanning electron microscope (SEM), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), degradation, and biological analyses. The new biomaterial showed a sol–gel transformation ability at body temperature and exhibited excellent chemical and physical characteristics, whilst the existence of β-TCP enhanced the structure and the properties of the hydrogels. The SEM confirmed the three-dimensional networks of the hydrogels, and the typical rheological properties of strong gel were observed. The EDX and XRD validated the successful incorporation of β-TCP, and similar patterns between different groups were found in terms of the FTIR spectra. The stable structure of the hydrogels under 100 °C was confirmed via DSC. Biological tests such as Alamar Blue assay and Live/Dead staining confirmed the remarkable biocompatibility of the hydrogels with pre-osteoblast MC3T3-E1 and human gingival fibroblast (HGF) cells for 14 days, and the results were validated with confocal imaging. This preliminary study shows great promise for the application of the β-TCP-loaded thermosensitive chitosan hydrogels as a scaffold in periodontal bone and soft tissue repair. [ABSTRACT FROM AUTHOR]

Bacterial infections and excessive inflammation can impede the healing of wounds. Hydrogels have emerged as a promising approach for dressing bacterial-infected injuries. However, some antibacterial hydrogels are complex, costly, and even require assistance with other instruments such as light, making them unsuitable for routine outdoor injuries. Here, we developed an in-situ generating hydrogel via hybridizing oxidized β -D-glucan with antimicrobial peptide C 8 G 2 through the Schiff base reaction. This hydrogel is easily accessible and actively contributes to the whole healing process of bacterial-infected wounds, demonstrating remarkable antibacterial activity and biological compatibility. The pH-sensitive reversible imine bond enables the hydrogel to self-heal and sustainably release the antibacterial peptide, thereby improving its bioavailability and reducing toxicity. Meanwhile, the immunoregulating β -D-glucan inhibits the release of inflammatory factors while promoting the release of anti-inflammatory factors. In methicillin-resistant Staphylococcus aureus (MRSA)-infected full-thickness skin wound models, the hybrid hydrogel showed superior antibacterial and anti-inflammatory activity, enhanced the M2 macrophage polarization, expedited wound closure, and regenerated epidermis tissue. These features make this hydrogel an appealing wound dressing for treating multi-drug-resistant bacteria-infected wounds. [Display omitted] • The BGA/C 8 G 2 injectable hydrogel can form rapidly in situ. • The hydrogel releases the antibacterial peptide in acidic bacterial infections. • The hydrogel can participate in the entire wound healing process. • The hydrogel accelerates MRSA-infected wound healing without additions. [ABSTRACT FROM AUTHOR]

Immunotherapy is an emerging antitumor modality with high specificity and persistence, but its application for resected tumor treatment is impeded by the low availability of tumor-specific antigens and strong immunosuppression in the wound margin. Here a nanoengineered hydrogel is developed for eliciting robust cooperative ferroptosis-immunotherapeutic effect on resected tumors. Specifically, β-cyclodextrin (β-CD) is first grafted onto oxidized sodium alginate (OSA) through Schiff base ligation, which could trap cRGD-modified redox-responsive Withaferin prodrugs (WA-cRGD) to obtain the hydrogel building blocks (Gel@WA-cRGD). Under Ca2+-mediated crosslinking, Gel@WA-cRGD rapidly forms physiologically stable hydrogels, of which the porous network is used to deliver programmed cell death ligand 1 antibodies (aPD-L1). After injection into the post-surgical wound cavity, the β-CD-entrapped WA-cRGD is detached by the local acidity and specifically internalized by residual tumor cells to trigger ferroptosis, thus releasing abundant damage-associated molecular patterns (DAMPs) and tumor-derived antigens for activating the antigen-presenting cell-mediated cross-presentation and downstream cytotoxic T cell (CTL)-mediated antitumor responses. Furthermore, aPD-L1 could block PD-1/PD-L1 interaction and enhance the effector function of CTLs to overcome tumor cell-mediated immunosuppression. This cooperative hydrogel-based antitumor strategy for ferroptosis-immunotherapy may serve as a generally-applicable approach for postoperative tumor management. To overcome the immunosuppressive microenvironment in resected solid tumors for enhanced patient survival, here we report a nanoengineered hydrogel incorporated supramolecular redox-activatable Withaferin prodrug and PD-L1 antibody, which could elicit robust cooperative ferroptosis-immunotherapeutic effect against residual tumor cells in the surgical bed to prevent tumor relapse, thus offering a generally-applicable approach for postoperative tumor management. [Display omitted] [ABSTRACT FROM AUTHOR]

Background Immunogenic cell death (ICD) induced by different cancer treatments has been widely evaluated to recruit immune cells and trigger the specific antitumor immunity. However, cancer associated fibroblasts (CAFs) can hinder the invasion of immune cells and polarize the recruited monocytes to M2-type macrophages, which greatly restrict the efficacy of immunotherapy (IT). Methods In this study, an injectable hydrogel induced by copper (Cu) has been designed to contain antibody of PD-L1 and nitric oxide (NO) donor. The therapeutic efficacy of hydrogel was studied in 4T1 cells and CAFs in vitro and 4T1 tumor-bearing mice in vivo. The immune effects on cytotoxic T lymphocytes, dendritic cells (DCs) and macrophages were analyzed by flow cytometry. Enzyme-linked immunosorbent assay, immunofluorescence and transcriptome analyses were also performed to evaluate the underlying mechanism. Results Due to the absorbance of Cu with the near-infrared laser irradiation, the injectable hydrogel exhibits persistent photothermal effect to kill cancer cells. In addition, the Cu of hydrogel shows the Fenton-like reaction to produce reactive oxygen species as chemodynamic therapy, thereby enhancing cancer treatment and amplifying ICD. More interestingly, we have found that the released NO can significantly increase depletion of CAFs and reduce the proportion of M2-type macrophages in vitro. Furthermore, due to the amplify of ICD, injectable hydrogel can effectively increase the infiltration of immune cells and reverse the immunosuppressive tumor microenvironment (TME) by regulating CAFs to enhance the therapeutic efficacy of anti-PD-L1 in vivo. Conclusions The ion induced self-assembled hydrogel with NO could enhance immunotherapy via amplifying ICD and regulating CAFs. It provides a novel strategy to provoke a robust antitumor immune response for clinical cancer immunotherapy. Graphical Abstract

Intervertebral disc (IVD) degeneration is a leading cause of back pain and precursor to more severe conditions, including disc herniation and spinal stenosis. While traditional growth factor therapies (e.g., TGFβ) are effective at transiently reversing degenerated disc by stimulation of matrix synthesis, it is increasingly accepted that bioscaffolds are required for sustained, complete IVD regeneration. Current scaffolds (e.g., metal/polymer composites, non-mammalian biopolymers) can be improved in one or more IVD regeneration demands: biodegradability, noninvasive injection, recapitulated healthy IVD biomechanics, predictable crosslinking, and matrix repair induction. To meet these demands, tetrazine-norbornene bioorthogonal ligation was combined with gelatin to create an injectable bioorthogonal hydrogel (BIOGEL). The liquid hydrogel precursors remain free-flowing across a wide range of temperatures and crosslink into a robust hydrogel after 5–10 min, allowing a human operator to easily inject the therapeutic constructs into degenerated IVD. Moreover, BIOGEL encapsulation of TGFβ potentiated histological repair (e.g., tissue architecture and matrix synthesis) and functional recovery (e.g., high water retention by promoting the matrix synthesis and reduced pain) in an in vivo rat IVD degeneration/nucleotomy model. This BIOGEL procedure readily integrates into existing nucleotomy procedures, indicating that clinical adoption should proceed with minimal difficulty. Since bioorthogonal crosslinking is essentially non-reactive towards biomolecules, our developed material platform can be extended to other payloads and degenerative injuries.

Abstract Background Cellular infiltration and angiogenesis into implanted biomaterial scaffolds are crucial for successful host tissue integration and tissue regeneration. Cellulose nanocrystal (CNC) is a nano-sized cellulose derivative, which can form an injectable physical gel with salts. Sulfate groups of sulfated CNC (CNC-S) can act as a binding domain to various growth factors and cytokines with a heparin-binding domain for sustained release of them. Vascular endothelial growth factor (VEGF) can promote the proliferation of endothelial cells and angiogenesis. In this study, VEGF-loaded CNC-S hydrogel was evaluated as an injectable scaffold that can induce cellular infiltration and angiogenesis. Methods CNC-S was hydrolyzed to get desulfated CNC (CNC-DS), which was used as a negative control group against CNC-S. Both CNC-S and CNC-DS hydrogels were prepared and compared in terms of biocompatibility and VEGF release. The hydrogels with or without VEGF loading were subcutaneously injected into mice to evaluate the biocompatibility, cellular infiltration, and angiogenesis induction of the hydrogels. Results Both hydrogels possessed similar stability and shear-thinning behavior to be applicable as injectable hydrogels. However, CNC-S hydrogel showed sustained release (until 8 weeks) of VEGF whereas CNC-DS showed a very fast release of VEGF with a large burst. Subcutaneously injected CNC-S hydrogel showed much enhanced cellular infiltration as well as better biocompatibility with milder foreign body response than CNC-DS hydrogel. Furthermore, VEGF-loaded CNC-S hydrogel induced significant angiogenesis inside the hydrogel whereas VEGF-loaded CNC-DS did not. Conclusion CNC-S possesses good properties as a biomaterial including injectability, biocompatibility, and allowing cellular infiltration and sustained release of growth factors. VEGF-loaded CNC-S hydrogel exhibited efficient angiogenesis inside the hydrogel. The sulfate group of CNC-S was a key for good biocompatibility and the biological activities of VEGF-loaded CNC hydrogel.

The treatment adherence of narcotics-addicted individuals with reduced incidences of relapse can be enhanced by a sustained drug release formulation of antinarcotics. So far, different drug formulations have been reported with sustained drug release periods of 28 and 35 days. To further enhance this duration, different formulations of injectable hydrogels (IHs) have been developed by combining low molecular weight (LMW) and high molecular weight (HMW) chitosan (CS) with guar gum (GG) and crosslinking them by sodium bi phosphate dibasic. The structural, morphological, and physicochemical properties of LMW-CS IH, and HMW-CS IH were evaluated using Fourier transform infrared spectroscopy (FT-IR), thermo-gravimetric analysis (TGA), scanning electron microscopy (SEM), and rheological, swelling, and biodegradation analysis. The HMW-CS IH showed high crosslinking, increased thermal stability, high mechanical strength, elevated swelling, and low biodegradation. The antinarcotic drugs naltrexone (NTX) and disulfiram (DSF) were loaded separately into the HMW-CS IH and LMW-CS IH. The release of NTX and DSF was investigated in phosphate buffer saline (PBS) and ethanol (0.3%, 0.4%, and 0.5%) over a 56-day period using an UV spectrophotometer. The drug release data were tested in zero-order, first-order, and Korsemeyer–Peppas mathematical models. In PBS, all prepared formulations followed non-Fickian drug release, while in ethanol, only NTX HMW-CS IH followed non-Fickian release in all three different concentrations of ethanol.

Rotator cuff tears are a prevalent musculoskeletal problem that affect many individuals and may result in substantial social and health-related expenses. Moreover, the muscular fat infiltration and dystrophy associated with rotator cuff tears have been persistent challenges in rotator cuff surgical repair and postoperative rehabilitation. In this study, an in situ-formed injectable sodium alginate (SA) and bioglass (BG) hydrogel consisting of poly (lactic-co-glycolic acid) (PLGA) microspheres containing metformin (SA/BG-PLGA-Met) was developed for the prevention of muscular fat infiltration and dystrophy. Metformin and silicon ions were slowly released by the combined hydrogel, resulting in long-term biological effects. Moreover, the hydrogel displayed excellent degradability and biocompatibility. Extracts of SA/BG-PLGA-Met inhibited the adipogenesis of 3T3-L1 cells and stimulated the myogenic differentiation of C2C12 cells in vitro. In a mouse model of rotator cuff degeneration, the SA/BG-PLGA-Met hydrogel inhibited fat infiltration and dystrophy of the supraspinatus muscle. Overall, the SA/BG-PLGA-Met hydrogel, as a novel biomaterial, has great clinical potential for preventing rotator cuff muscle fat infiltration and atrophy.

Reactive oxygen burst in articular chondrocytes is a major contributor to osteoarthritis progression. Although selenium is indispensable role in the antioxidant process, the narrow therapeutic window, delicate toxicity margins, and lack of an efficient delivery system have hindered its translation to clinical applications. Herein, transcriptomic and biochemical analyses revealed that osteoarthritis was associated with selenium metabolic abnormality. A novel injectable hydrogel to deliver selenium nanoparticles (SeNPs) was proposed to intervene selenoprotein expression for osteoarthritis treatment. The hydrogels based on oxidized hyaluronic acid (OHA) cross-linked with hyaluronic acid-adipic acid dihydrazide (HA-ADH) was formulated to load SeNPs through a Schiff base reaction. The hydrogels were further incorporated with SeNPs, which exhibited minimal toxicity, mechanical properties, self-healing capability, and sustained drug release. Encapsulated with SeNPs, the hydrogels facilitated cartilage repair through synergetic effects of scavenging reactive oxygen species (ROS) and depressing apoptosis. Mechanistically, the hydrogel restored redox homeostasis by targeting glutathione peroxidase-1 (GPX1). Therapeutic outcomes of the SeNPs-laden hydrogel were demonstrated in an osteoarthritis rat model created by destabilization of the medial meniscus, including cartilage protection, subchondral bone sclerosis improvement, inflammation attenuation, and pain relief were demonstrated. These results highlight therapeutic potential of OHA/HA-ADH@SeNPs hydrogels, providing fundamental insights into remedying selenium imbalance for osteoarthritis biomaterial development.

Bone defects have long been a major healthcare issue because of the difficulties in regenerating bone mass volume and the high cost of treatment. G protein-coupled receptor kinase 2 interacting protein 1 (GIT1) has been proven to play an important role both in vascular development and in bone fracture healing. In this study, a type of thermoresponsive injectable hydrogel from oligoethylene glycol-based dendronized chitosan (G1-CS) was loaded with GIT1-plasmids (G1-CS/GIT1), and used to fill unicortical bone defects. RT-PCR analysis confirmed that G1-CS/GIT1 enhanced DNA transfection in MSCs both in vitro and in vivo. From the results of micro-CT, RT-PCR and histological analysis, it can be concluded that G1-CS/GIT1 accelerated the bone healing rate and increased the amount of neovascularization around the bone defects. In addition, an adeno-associated virus (AAV)-GIT1 was constructed to transfect mesenchymal stem cells. The results of capillary tube formation assay, immunofluorescence staining and western blot analysis proved that high expression of GIT1 induces mesenchymal stem cells to differentiate into endothelial cells. RT-PCR analysis and capillary tube formation assay confirmed that the Notch signaling pathway was activated in the differentiation process. Overall, we developed an efficient strategy through combination of injectable hydrogel and G1T1 for bone tissue engineering.

Gene therapy has shown remarkable effectiveness in the management of disease like cancer and inflammation as a revolutionary therapeutic. Nonetheless, therapeutic drug target discovery, efficient gene delivery, and gene delivery vehicles continue to be significant obstacles. Due to their effective gene transport capabilities and low immunogenicity, supramolecular polymers have garnered significant interest. Herein, ABHD5 is identified as a potential therapeutic target since it is dysregulated in hepatocellular carcinoma (HCC). Interestingly, the downregulation of ABHD5 could induce programmed death-ligand 1 (PD-L1) expression in liver cancer, which may contribute to the immunosuppression. To overcome the immunosuppression caused by PD-L1, an injectable hydrogel is designed to achieve efficient abhydrolase domain containing 5 (ABHD5) gene delivery via the host-guest interaction with branched polyethyleneimine-g-poly (ethylene glycol), poly (ethylene oxide) and poly (propylene oxide) block copolymers and α-CD (PPA/CD), demonstrating the capability for sustained gene release. The co-assembly hydrogel demonstrates good biocompatibility and enhanced gene transfection efficiency, efficiently triggering tumor cell apoptosis. Overall, the results of this study suggest that ABHD5 is a potential therapeutic target, and that a host-guest-based supramolecular hydrogel could serve as a promising platform for the inhibition of HCC.

Abstract Modulating the inflammatory microenvironment can inhibit the process of inflammatory diseases (IDs). A tri‐cross‐linked inflammatory microenvironment‐responsive hydrogel with ideal mechanical properties achieves triggerable and sustained drug delivery and regulates the inflammatory microenvironment. Here, this study develops an inflammatory microenvironment‐responsive hydrogel (OD‐PP@SeNPs) composed of phenylboronic acid grafted polylysine (PP), oxidized dextran (OD), and selenium nanoparticles (SeNPs). The introduction of SeNPs as initiators and nano‐fillers into the hydrogel results in extra cross‐linking of the polymer network through hydrogen bonding. Based on Schiff base bonds, Phenylboronate ester bonds, and hydrogen bonds, a reactive oxygen species (ROS)/pH dual responsive hydrogel with a triple‐network is achieved. The hydrogel has injectable, self‐healing, adhesion, outstanding flexibility, suitable swelling capacity, optimal biodegradability, excellent stimuli‐responsive active substance release performance, and prominent biocompatibility. Most importantly, the hydrogel with ROS scavenging and pH‐regulating ability protects cells from oxidative stress and induces macrophages into M2 polarization to reduce inflammatory cytokines through PI3K/AKT/NF‐κB and MAPK pathways, exerting anti‐inflammatory effects and reshaping the inflammatory microenvironment, thereby effectively treating typical IDs, including S. aureus infected wound and rheumatoid arthritis in rats. In conclusion, this dynamically responsive injectable hydrogel with a triple‐network structure provides an effective strategy to treat IDs, holding great promise in clinical application.

Intervertebral disc (IVD) degeneration occurred with the increasing age or accidents has puzzled peoples in daily life. To seal IVD defect by injectable hydrogels is a promising method for slowing down IVD degeneration. Herein, we reported a rapidly in situ forming injectable chitosan/PEG hydrogel (CSMA-PEGDA-L) through integrating photo-crosslink of methacrylate chitosan (CSMA) with Schiff base reaction between CSMA and aldehyde polyethylene glycol (PEGDA). The CSMA-PEGDA-L possessed a stronger compressive strength than the photo-crosslinked CSMA-L hydrogel and Schiff-base-crosslinked CSMA-PEGDA hydrogel. This chitosan/PEG hydrogel showed low cytotoxicity from incubation experiments of nucleus pulpous cells. When implanted on the punctured IVD of rat's tail, the CSMA-PEGDA-L hydrogel could well retard the progression of IVD degeneration through physical plugging, powerfully proven by radiological and histological evaluations. This work demonstrated the strategy of in situ injectable glue may be a potential solution for prevention of IVD degeneration.

Hydrogels based on dynamic covalent bonds have unique properties and are competent in many biomedical fields. However, critical issues such as biocompatibility, mechanical properties, and stimulus responsiveness are required to be solved. It is also expected to develop a simple preparation method with mild conditions. Based on these objectives, chitosan (CS), sodium alginate (SA) and 2‐formylphenylboronic acid (2‐FPBA) are used to prepare the dynamic covalent bond hydrogels within minutes neither chemical medications nor severe conditions. Benefiting from the imine borate and boronic ester bonds both formed in the hydrogels, the hydrogels are stable, injectable, and of efficient self‐healing properties. The damage‐recovery process can be repeated for more than 6 cycles. The microstructure of the hydrogels recoded by atomic force microscopy (AFM) is consistent with the mechanical properties and both of them could be affected by the concentrations of SA and 2‐FPBA. Moreover, the dynamic hydrogels are responsive to pH values and oxidative environment. When the model drug 5‐fluorouracil (5‐FU) is loaded in the dynamic hydrogels, the release profiles are sustainable and present significant differences with various stimuli. These dynamic covalent bond hydrogels have a promising prospect in tissue engineering and drug delivery. [ABSTRACT FROM AUTHOR]

Injectable hydrogels offer numerous advantages in various areas, which include tissue engineering and drug delivery because of their unique properties such as tunability, excellent carrier properties, and biocompatibility. These hydrogels can be administered with minimal invasiveness. In this study, we synthesized an injectable hydrogel by rehydrating lyophilized mixtures of guar adamantane (Guar-ADI) and poly-β-cyclodextrin (p-βCD) in a solution of phosphate-buffered saline (PBS) maintained at pH 7.4. The hydrogel was formed via host-guest interaction between modified guar (Guar-ADI), obtained by reacting guar gum with 1-adamantyl isocyanate (ADI) and p-βCD. Comprehensive characterization of all synthesized materials, including the hydrogel, was performed using nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), thermogravimetric analysis (TGA), and rheology. The in vitro drug release study demonstrated the hydrogel's efficacy in controlled drug delivery, exemplified by the release of bovine serum albumin (BSA) and anastrozole, both of which followed first-order kinetics. Furthermore, the hydrogel displayed excellent biocompatibility and served as an ideal scaffold for promoting the growth of mouse osteoblastic MC3T3 cells as evidenced by the in vitro biocompatibility study. [ABSTRACT FROM AUTHOR]

This study highlights the development of smart stimuli-responsive carrier for controlled drug release system. Novel cytocompatible and injectable carriers were synthesized using chitosan and poly(vinyl alcohol) with different amounts of 3-aminopropyl(diethoxy)methylsilane (3-APDEMS). The characterizations of the prepared samples were accomplished via FTIR, SEM, TGA, mechanical properties, swelling, biodegradation, antimicrobial activity, antioxidant activity, anti-inflammatory activity, cytotoxicity and drug release profile. FTIR analysis was performed to approve the siloxane linkages among the integrated constituents. SEM images demonstrated the morphology, while TGA showed the highest thermal stability (593 °C offset temperature) for hydrogel with 150 μL APDEMS concentration. The antimicrobial response of hydrogels toward Bacillus cereus and E.coli was noticeable. The antioxidant activity and anti-inflammatory activity were performed to check the behavior of the MCP series against the free radical generating substance and inflammation response, respectively. All stimuli-responsive crosslinked carriers appeared cytocompatible for plated 3T3 fibroblast cells as inspected by continuous increase in the viability of cells from 24 to 48 h and 72 h post initial seeding in all samples. The swelling behavior in buffer solution (at different pH) confirmed these carriers as pH-responsive. These carriers at optimum amount of 3-APDEMS showed 99.5% drug release in phosphate buffer saline solution at 7.4 pH. [ABSTRACT FROM AUTHOR]

The application of hydrogels in bone repair is limited due to their low mechanical strength. Simulating bone extracellular matrix, methylacrylylated gelatin (GelMA)/methylacrylylated hyaluronic acid (HAMA)/nano-hydroxyapatite(nHap) composite hydrogels were prepared by combining the double network strategy and composite of nHap in this study. The precursor solutions of the composite hydrogels were injectable due to their shear thinning property. The compressive elastic modulus of the composite hydrogel was significantly enhanced, the fracture strength of the composite hydrogel nearly reached 1 MPa, and the composite hydrogel retained its high water content at above 88%. The composite hydrogels possess good compatibility with BMSCS and have the potential to be used as injectable hydrogels for bone defect treatment. [ABSTRACT FROM AUTHOR]

Bone defect is still a challenging problem in orthopedic practice. Injectable bone substitutes that can fill different geometry of bone defect and improve biological environment for bone regeneration are attracting attention. Herein, silk fibroin (SF) is noticeable polymer regarding its biocompatible and biodegradable properties. Thus, the calcium phosphate particles incorporated in silk fibroin/methylcellulose (CAPs‐SF/MC) and only methylcellulose (CAPs‐MC) hydrogels are developed and compared their physicochemical properties. Both CAPs‐hydrogels solutions can be administered with a low injectability force of ~6 N, and they require ~40‐min to change to hydrogel at physiological temperature (37°C). The CAPs are evenly distributed throughout the hydrogel matrix and are capable transformed to bioactive hydroxyapatite at pH 7.4. The CAPs in CAPs‐SF/MC have a smaller size than those in CAPs‐MC. Moreover, CAPs‐SF/MC exhibit gradual degradation, as prediction of the degradation mechanism by the Peppas‐Sahlin model and show a greater ability to sustain CAPs release. CAPs‐SF/MC has good biocompatibility with less cytotoxicity in a dose‐dependent manner on mouse preosteoblast cell line (MC3T3‐E1) when compared to CAPs‐MC. CAPs‐SF/MC hydrogels also have better possibility for promoting cell proliferation and differentiation. In conclusion SF incorporated into composite injectable hydrogel potentially improve biological characteristics and may provide clinical advantages. [ABSTRACT FROM AUTHOR]

To prevent local tumor recurrence caused by possible residual cancer cells after surgery, avoid toxicity of systemic chemotherapy and protect the fragile immune system of postsurgical patients, an increasing amount of attention has been paid to local anti–cancer drug delivery systems. In this paper, golden buckwheat was first applied to prevent post–operative tumor recurrence, which is a Chinese herb and possesses anti–tumor activity. Golden buckwheat extract–loaded gellan gum injectable hydrogels were fabricated via Ca2+ crosslinking for localized chemotherapy. Blank and/or drug–loaded hydrogels were characterized via FT–IR, TG, SEM, density functional theory, drug release and rheology studies to explore the interaction among gellan gum, Ca2+ and golden buckwheat extract (GBE). Blank hydrogels were non–toxic to NIH3T3 cells. Of significance, GBE and GBE–loaded hydrogel inhibited the proliferation of tumor cells (up to 90% inhibition rate in HepG2 cells). In vitro hemolysis assay showed that blank hydrogel and GBE–loaded hydrogel had good blood compatibility. When GBE–loaded hydrogel was applied to the incompletely resected tumor of mice bearing B16 tumor xenografts, it showed inhibition of tumor growth in vivo and induced the apoptosis of tumor cells. Taken together, gellan gum injectable hydrogel containing GBE is a potential local anticancer drug delivery system for the prevention of postsurgical tumor recurrence. [ABSTRACT FROM AUTHOR]

The use of anti-inflammatory strategies has the potential to be a definitive treatment for ventricular remodeling post myocardial infarction (MI). The regulation of macrophage phenotypes by anti-inflammatory agents contributes to the alleviation of myocardial fibrosis. However, their poor retention rates severely affect treatment efficacy. Here, we propose a supramolecular compound, NapFFY, to co-assemble with IL-10 and SN50 as a novel anti-inflammatory SN50/IL - 10/NapFFY hydrogel with cardioprotective properties. Results from the in vitro and in vivo experiments in murine cell line and rats, respectively, demonstrated that the SN50/IL-10/NapFFY hydrogel exhibits an ideal and sustained release of IL-10 and SN50. Intramyocardial injection of the SN50/IL-10/NapFFY hydrogel in a rat model of MI significantly inhibited the expression of proinflammatory cytokines. It promoted the polarization of M2 macrophages, which reduced cardiomyocyte apoptosis and improved vascularization at the border zones. Specifically, the SN50/IL-10/NapFFY hydrogel significantly improved heart function and ameliorated ventricular remodeling 28 days post MI. We envision that the SN50/IL-10/NapFFY hydrogel could serve as a new anti-inflammatory agent for the clinical treatment of MI in future studies. Anti-inflammation is an ideal strategy for the treatment of ventricular remodeling post myocardial infarction (MI). SN50 and IL-10 have been shown to have diverse roles in antiinflammatory process, respectively. However, direct intravenous administration or intramyocardial injection of SN50 or IL-10 is not a viable option given its poor half-life in vivo. This study aimed to evaluate the synergistic cardioprotective effects of a supramolecular hydrogel loaded with an NF-κB inhibitor (SN50) and IL-10. Animal experiments showed that the SN50/IL-10/NapFFY hydrogels ameliorated the inflammatory microenvironment, and improved cardiac function to the infarct area in a rat model of MI. We anticipate that SN50/IL10NapFFY hydrogel could be used clinically to treat MI in the near future. [Display omitted] [ABSTRACT FROM AUTHOR]

Periodontal diseases significantly impact about half of the global population, and their treatment often encompasses relieving symptoms as well as regenerating the destroyed tissues. Revolutionary research in the management of periodontal disease includes biomaterials, a boon to re-generative dentistry owing to their excellent biological properties: non-toxicity, anti-inflammatory, biocompatibility, biodegradability, and adhesion. This study aimed to fabricate an injectable fucoidan containing chitosan hydrogel and prove its effectiveness in periodontal bone regeneration. The injectable hydrogel was prepared using the sol-gel method and was subjected to various physical, chemical, and biological characterizations to understand its efficacy in formation of new bone. The effectiveness of the developed hydrogel was assessed in periodontal bony defects to study the soft and hard tissue changes. A total of 40 periodontitis patients with bony defects were recruited and randomized into two groups to receive fucoidan-chitosan hydrogel and concentrated growth factor, respectively. Customized acrylic stents were used to guide the hydrogel placement into the defect site. Post-surgical changes in clinical parameters were assessed at 3, 6, and 9 months to appreciate the soft and hard tissue changes using repeated measures analysis of variance and Bonferroni's post hoc test. Significance was kept at 5%. The porosity, water uptake of the prepared hydrogel showed good efficacy, with particle size of the fucoidan containing chitosan hydrogel of 6.000 nm. The MG-63 osteoblasts cell line revealed biocompatibility, biodegradability and showed slow and sustained drug release, increased cell proliferation, and enhanced alkaline phosphatase secretion. Mineralization assay was greatest in the fucoidan containing chitosan hydrogel. Clinically, it exhibited significantly lower probing depth values and a higher mean improvement in clinical attachment level as compared to the concentrated growth factor (CGF) group at the end of 3 and 6 months (p < 0.05). The mean of the defect fills in the fucoidan containing chitosan group was 1.20 at the end of 9 months (p < 0.001) as compared with defect fills observed in the CGF group. The presence of fucoidan in the hydrogel significantly contributed to bone regeneration in humans, thus strengthening its potential in tissue engineering. Fucoidan-chitosan will be a promising biomaterial for bone tissue regeneration. [ABSTRACT FROM AUTHOR]

Injectable polymers offer great benefits compared to other types of implants; however, they tend to suffer from increased mechanical wear and may need a replacement implant to restore these mechanical properties. The purpose of this experiment is to investigate an injectable hydrogel's self-healing ability to augment itself to a previously molded implant. This was accomplished by performing a tensile strength test to examine potential diminishing mechanical properties with increasing time, as well as dye penetration tests to examine the formation of interfacial bonds between healed areas of hydrogels. There were several time points in between injections that were explored, from 0 min between injections all the way up to 48 h in between injections. The tests showed no statistical differences of the increased injection times compared to the single injection for the tensile test. However, our results showed an increase of mechanical breaks at self-healed joints, as well as a linear regression test showed a decrease in dye diffusion rate as time between injections increase. These results show that the hydrogel has strong self-healing abilities, and as time between injections increase, they mechanical properties will slowly decrease. Based on this, the tests can be applied to other injectable implants and a noninvasive solution to a worn-down implant, as well as show scientific backing to a possibly unique and beneficial self-healing property.

Injectable hydrogel is suitable for the repair of lacunar bone deficiency. This study fabricated an injectable, self-adaptive silk fibroin/mesoporous bioglass/sodium alginate (SMS) composite hydrogel system. With controllable and adjustable physical and chemical properties, the SMS hydrogel could be easily optimized adaptively to different clinical applications. The SMS hydrogel effectively showed great injectability and shapeability, allowing defect filling with no gap. Moreover, the SMS hydrogel displayed self-adaptability in mechanical reinforcement and degradation, responsive to the concentration of Ca2+ and inflammatory-like pH value in the microenvironment of bone deficiency, respectively. In vitro biological studies indicated that SMS hydrogel could promote osteogenic differentiation of bone marrow mesenchymal stem cells by activation of the MAPK signaling pathway. The SMS hydrogel also could improve migration and tube formation of human umbilical vein endothelial cells. Investigations of the crosstalk between osteoblasts and macrophages confirmed that SMS hydrogel could regulate macrophage polarization from M1 to M2, which could create a specific favorable environment to induce new bone formation and angiogenesis. Meanwhile, SMS hydrogel was proved to be antibacterial, especially for gram-negative bacteria. Furthermore, in vivo study indicated that SMS could be easily applied for maxillary sinus elevation, inducing sufficient new bone formation. Thus, it is convincing that SMS hydrogel could be potent in a simple, minimally invasive and efficient treatment for the repair of lacunar bone deficiency.

Myocardial infarction (MI) leads to massive cardiomyocyte death and deposition of collagen fibers. This fibrous tissue disrupts electrical signaling in the myocardium, leading to cardiac systolic and diastolic dysfunction, as well as arrhythmias. Conductive hydrogels are a promising therapeutic strategy for MI. Here, we prepared a highly water-soluble conductive material (GP) by grafting polypyrrole (PPy) onto non-conductive gelatin. This component was added to the gel system formed by the Schiff base reaction between oxidized xanthan gum (OXG) and gelatin to construct an injectable conductive hydrogel. The prepared self-healing OGGP3 (3 wt% GP) hydrogel had good biocompatibility, elastic modulus, and electrical conductivity that matched the natural heart. The prepared biomaterials were injected into the rat myocardial scar tissue 2 days after MI. We found that the cardiac function of the rats treated with OGGP3 was improved, making it more difficult to induce arrhythmias. The electrical resistivity of myocardial fibrous tissue was reduced, and the conduction velocity of myocardial tissue was increased. Histological analysis showed reduced infarct size, increased left ventricular wall thickness, increased vessel density, and decreased inflammatory response in the infarcted area. Our findings clearly demonstrate that the OGGP3 hydrogel attenuates ventricular remodeling and inhibits infarct dilation, thus showing its potential for the treatment of MI.

Introduction: Biocompatible and biodegradable scaffolds based on natural polymers such as gelatin and chitosan (CS) provide suitable microenvironments in dental tissue engineering. In the present study, we report on the synthesis of injectable thermosensitive hydrogel (PNIPAAm-g-CS copolymer/gelatin hybrid hydrogel) for osteogenic differentiation of human dental pulp stem cells (hDPSCs). Methods: The CS-g-PNIPAAm was synthesized using the reaction of carboxyl terminated PNIPAAm with CS, which was then mixed with various amounts of gelatin solution in the presence of genipin as a chemical crosslinker to gain a homogenous solution. The chemical composition and microstructures of the fabricated hydrogels were confirmed by FT-IR and SEM analysis, respectively. To evaluate the mechanical properties (e.g., storage and loss modulus of the gels), the rheological analysis was considered. Calcium deposition and ALP activity of DPSCs were carried out using alizarin red staining and ALP test. While the live/dead assay was performed to study its toxicity, the real-time PCR was conducted to investigate the osteogenic differentiation of hDPSCs cultured on prepared hydrogels. Results: The hydrogels with higher gelatin incorporation showed a slightly looser network compared to the other ones. The hydrogel with less gelatin indicates a rather higher value of G', indicating a higher elasticity due to more crosslinking reaction of amine groups of CS via a covalent bond with genipin. All the hydrogels contained viable cells with negligible dead cells, indicating the high biocompatibility of the prepared hydrogels for hDPSCs. The quantitative results of alizarin red staining displayed a significant rise in calcium deposition in hDPSCs cultured on prepared hydrogels after 21 days. Further, hDPSCs cultured on hydrogel with more gelatin displayed the most ALP activity. The expression of late osteogenic genes such as OCN and BMP-2 were respectively 6 and 4 times higher on the hydrogel with more gelatin than the control group after 21 days. Conclusion: The prepared PNIPAAm-g-CS copolymer/gelatin hybrid hydrogel presented great features (e.g., porous structure, suitable rheological behavior, and improved cell viability), and resulted in osteogenic differentiation necessary for dental tissue engineering.

Rapid maxillary expansion (RME), as a common treatment for craniomaxillofacial deformity, faces the challenge of high relapse rates and unsatisfactory therapeutic effects. In this study, a standardized Sprague-Dawley (SD) rat RME model was first established with a modified expander as well as retainer design and optimized anterior maxillary expanding force of 100 g which exerted the most synchronized mobility of mid-palatal suture and incisors. Via the standardized model, the high relapse rate was proven to be attributed to insufficient osteogenesis in expanded suture, requiring long-term retainer wearing in clinical situations. To reduce the relapse rate, mesoporous bioactive glass/fibrin glue (MBG/FG) composite hydrogels were developed for an in situ minimal invasive injection that enhance osteogenesis in the expanded palate. The component of 1 wt% MBG was adopted for enhanced mechanical strength, matched degradation rate and ion dissolution, excellent in vitro biocompatibility and osteoinductivity. Effects of 1%MBG/FG composite hydrogel on osteogenesis in expanded mid-palatal sutures with/without retention were evaluated in the standardized model. The results demonstrated that injection of 1%MBG/FG composite hydrogel significantly promoted bone formation within the expanded mid-palatal suture, inhibited osteoclastogenesis and benefited the balance of bone remodeling towards osteogenesis. Combination of retainer and injectable biomaterial was demonstrated as a promising treatment to reduce relapse rate and enhance osteogenesis after RME. The model establishment and the composite hydrogel development in this article might provide new insight to other craniomaxillofacial deformity treatment and design of bone-repairing biomaterials with higher regenerative efficiency.

All-in-one treatments represent a paradigm shift in future medicine. For example, inflammatory bowel disease (IBD) is mainly diagnosed by endoscopy, which could be applied for not only on-site monitoring but also the intestinal lesion-targeted spray of injectable hydrogels. Furthermore, molecular conjugation to the hydrogels would program both lesion-specific adhesion and drug-free therapy. This study validated this concept of all-in-one treatment by first utilizing a well-known injectable hydrogel that underwent efficient solution-to-gel transition and nanomicelle formation as a translatable component. These properties enabled spraying of the hydrogel onto the intestinal walls during endoscopy. Next, peptide conjugation to the hydrogel guided endoscopic monitoring of IBD progress upon adhesive gelation with subsequent moisturization of inflammatory lesions, specifically by nanomicelles. The peptide was designed to mimic the major component that mediates intestinal interaction with Bacillus subtilis flagellin during IBD initiation. Hence, the peptide-guided efficient adhesion of the hydrogel nanomicelles onto Toll-like receptor 5 (TLR5) as the main target of flagellin binding and Notch-1. The peptide binding potently suppressed inflammatory signaling without drug loading, where TLR5 and Notch-1 operated collaboratively through downstream actions of tumor necrosis factor-alpha. The results were produced using a human colorectal cell line, clinical IBD patient cells, gut-on-a-chip, a mouse IBD model, and pig experiments to validate the translational utility.

Irregular defects generated by trauma or surgery in orthopaedics practice were usually difficult to be fitted by the preformed traditional bone graft substitute. Therefore, the injectable hydrogels have attracted an increasing interest for bone repair because of their fittability and mini-invasivity. However, the uncontrollable spreading or mechanical failures during its manipulation remain a problem to be solved. Moreover, in order to achieve vascularized bone regeneration, alternatives of osteogenic and angiogenic growth factors should be adopted to avoid the problem of immunogenicity and high cost.In this study, a novel injectable self-healing hydrogel system (GMO hydrogel) loaded with KP and QK peptides had been developed for enhancing vascularized regeneration of small irregular bone defect. The dynamic imine bonds between gelatin methacryloyl and oxidized dextran provided the GMO hydrogel with self-healing and shear-thinning abilities, which led to an excellent injectability and fittability. By photopolymerization of the enclosed GelMA, GMO hydrogel was further strengthened and thus more suitable for bone regeneration. Besides, the osteogenic peptide KP and angiogenic peptide QK were tethered to GMO hydrogel by Schiff base reaction, leading to desired releasing profiles. In vitro, this composite hydrogel could significantly improve the osteogenic differentiation of BMSCs and angiogenesis ability of HUVECs. In vivo, KP and QK in the GMO hydrogel demonstrated a significant synergistic effect in promoting new bone formation in rat calvaria. Overall, the KP and QK loaded GMO hydrogel was injectable and self-healing, which can be served as an efficient approach for vascularized bone regeneration via a minimally invasive approach.

Spinal cord injury (SCI) often causes severe functional impairment of body, which leads to a huge burden to the patient and the whole society. Many strategies, especially biomaterials, have been employed for SCI repair. Among various biomaterials, injectable hydrogels have attracted much attention because of their ability to load functional components and be injected into the lesioned area without surgeries. In this review, we summarize the recent progress in injectable hydrogels for SCI repair. We firstly introduce the pathophysiology of SCI, which reveals the mechanism of clinical manifestations and determines the therapeutic schedule. Then, we describe the original sources of polymers and the crosslinking manners in forming hydrogels. After that, we focus on the in vivo therapeutic strategies and effects of injectable hydrogels. Finally, the recent challenges and future outlook of injectable hydrogel for SCI repair are concluded and discussed. We believe this review can be helpful and inspire the further development of injectable hydrogels for SCI repair.

BACKGROUND: Injectable hydrogel has a broad application prospect and unique therapeutic plasticity in the treatment of severe spinal cord injury. OBJECTIVE: To review the research progress of injectable hydrogels in spinal cord injury. METHODS: PubMed, Web of Science, Embase, CNKI, Wanfang, VIP, and China Biomedical Literature Database were searched. The key words were “spinal cord injury, spinal fracture, injectable hydrogel” in Chinese and “spinal cord trauma, myelopathy, traumatic, injuries, spinal cord, spinal cord injury, spinal cord transection, spinal cord laceration, post-traumatic myelopathy, spinal cord contusion, injectable hydrogel” in English. The related studies of injectable hydrogel in the treatment of spinal cord injury were screened. RESULTS AND CONCLUSION: Injectable hydrogel can be injected in animal and cell experiments to repair spinal cord injury. Injectable hydrogel has the characteristics of fewer traumas and can fit irregular defects. Injectable hydrogel with electrical conductivity and temperature sensitivity has a good repair function for spinal cord injury in terms of physical and chemical properties. Injectable hydrogel with stem cells or neurotrophic factors is beneficial to nerve regeneration and repair of local microenvironment of spinal cord injury. Injectable composite hydrogels have a bright future in clinical application. [ABSTRACT FROM AUTHOR]

Injectable hydrogels can be applied to treat damaged meniscus in minimally invasive conditions. Generally, injectable hydrogels can be prepared from various polymers such as polycaprolactone (PCL) and poly (N-isopropylacrylamide) (PNIPAAm). Poly (ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer-diacrylate (PEO-PPO-PEO-DA) is an interesting polymer due to its biodegradability and can be prepared as water-insoluble injectable hydrogel after curing with UV light at low intensity. However, mechanical and cell adhesion properties are not optimal for these hydrogels. For the improved mechanical performance of the injectable hydrogel, cellulose nanofiber (CNF) extracted from cassava pulp was used as a reinforcing filler in this study. In addition, gelatin methacrylate (GelMA), the denatured form of collagen was used to enhance cell adhesion. PEO-PPO-PEO-DA/CNF/GelMA injectable hydrogels were prepared with 2-hydroxy-1-(4-(hydroxy ethoxy) phenyl)-2-methyl-1-propanone as a photoinitiator and then cured with UV light, 365 nm at 6 mW/cm2. Physicochemical characteristics of the hydrogels and hydrogels with CNF were studied in detail including morphology characterization, pore size diameter, porosity, mechanical properties, water uptake, and swelling. In addition, cell viability was also studied. CNF-reinforced injectable hydrogels were successfully prepared after curing with UV light within 10 min with a thickness of 2 mm. CNF significantly improved the mechanical characteristics of injectable hydrogels. The incorporation of GelMA into the injectable hydrogels improved the viability of human cartilage stem/progenitor cells. At optimum formulation, 12%PEO-PPO-PEO-DA/0.5%CNF/3%GelMA injectable hydrogels significantly promoted cell viability (>80%) and also showed good physicochemical properties, which met tissue engineering requirements. In summary, this work shows that these novel injectable hydrogels have the potential for meniscus tissue engineering. [ABSTRACT FROM AUTHOR]

Extracellular matrix (ECM) provides various types of direct interactions with cells and a dynamic environment, which can be remodeled through different assembly/degradation mechanisms to adapt to different biological processes. Herein, through introducing polyphosphate-modified hyaluronic acid and bioactive glass (BG) nano-fibril into a self-assembled hydrogel system with peptide-polymer conjugate, we can realize many new ECM-like functions in a synthetic polymer network. The hydrogel network formation is mediated by coacervation, followed by a gradual transition of peptide structure from α-helix to β-sheet. The ECM-like hydrogels can be degraded through a number of orthogonal mechanisms, including treatments with protease, hyaluronidase, alkaline phosphatase, and calcium ion. As 2D coating, the ECM-like hydrogels can be used to modify the planar surface to promote the adhesion of mesenchymal stromal cells, or to coat the cell surface in a layer-by-layer fashion to shield the interaction with the substrate. As ECM-like hydrogels for 3D cell culture, the system is compatible with injection and cell encapsulation. Upon incorporating fragmented electrospun bioactive glass nano-fibril into the hydrogels, the synergetic effects of soft hydrogel and stiff reinforcement nanofibers on recapitulating ECM functions result in reduced cell circularity in 3D. Finally, by injecting the ECM-like hydrogels into mice, gradual degradations over a time period of one month and high biocompatibility have been shown in vivo. The contribution of complex network dynamics and hierarchical structures to cell-biomatrix interaction can be investigated multi-dimensionally, as many mechanisms are orthogonal to each other and can be regulated individually. A list of native ECM features has attracted the most interest and attention in the research of synthetic biomaterials. In this research, we have described a simple ECM-like hydrogel system in which the complex and elegant functions of native ECM can be recapitulated in a chemically defined synthetic system. The ECM-like hydrogel systems were developed to avoid undesired features of biological substances (e.g., ethical concerns, batch-to-batch variation, immunogenicity, and potential risk of contamination), as well as gaining new functions to facilitate bioengineering applications (e.g., 3D cell culture, injection, and high stability). To this end, we have developed an ECM-like hydrogel system and provide evidence that this purely synthetic biomaterial is a promising candidate for cell bioengineering applications. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Injectable hydrogels are important in situ forming implants for tissue regeneration at damaged sites. Understanding the behavior of these systems in a complex in vivo environment remains a challenge. Ultrathin films as 2D model systems are expected to provide fundamental insights into formation and (bio)degradation at material-liquid interfaces, and are also applicable as bioresponsive coatings. Hydrogel ultrathin films are prepared by covalently cross-linking four-arm PEG macromers with maleimide end-groups (PEG4MAL) at alkaline pH using two different types of dithiol-bearing cross-linkers – thio-depsipeptide (TDP) or 3,6-Dioxa-1,8-octanedithiol (DODT). This thiol-Michael addition "click" reaction is carried out at the air-water interface using the Langmuir technique. Morphological observation in real time is carried out by Brewster angle microscopy (BAM) and in coatings using atomic force microscopy (AFM). Stability against enzymatic and oxidative degradation is evaluated in the same setup. Non-cross-linked PEG or PEG incubated with cross-linkers at slightly acidic pH desorbs from the interface over time. Cross-linking of PEG at alkaline pH renders 2D hydrogel networks (thickness <1 nm) that are stable against desorption. They are easily transferrable onto solid mica surfaces, forming homogenous coatings as revealed by AFM. The type of dithiol cross-linker used to form the branching centers influences the degradability of these 2D hydrogel networks in the presence of lipase, peroxides, or bases. For example, enzymatic degradation of the 2D hydrogel networks can be switched "on" or "off" depending on the cleavable sites in the cross-linkers. [ABSTRACT FROM AUTHOR]

Wound treatment is largely influenced by pre-existing hypoxic microenvironments and biofilms, which can severely diminish the efficacy of phototherapy, suggesting the importance of multifunctional nanoplatforms for synergistic treatment of wound infections. Here, we developed a multifunctional injectable hydrogel (PSPG hydrogel) by loading photothermal sensitive sodium nitroprusside (SNP) into Pt-modified porphyrin metal organic framework (PCN) and in situ modification of gold particles to form a near-infrared (NIR) light-triggered all-in-one phototherapeutic nanoplatform. The Pt-modified nanoplatform exhibits a remarkable catalase-like behavior and promotes the continuous decomposition of endogenous H 2 O 2 into O 2 , thereby enhancing the photodynamic therapy (PDT) effect under hypoxia. Under dual NIR irradiation, PSPG hydrogel can not only produce hyperthermia (η=89.21%) but also generate reactive oxygen species and trigger NO release, contributing jointly to removal of biofilms and disruption of the cell membranes of methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli). In vivo experiments demonstrated a 99.9% reduction in bacterial burden on wounds. Additionally, PSPG hydrogel can accelerate MRSA-infected and Pseudomonas aeruginosa -infected (P. aeruginosa -infected) wound healing by promoting angiogenesis, collagen deposition, and suppressing inflammatory responses. Furthermore, in vitro and in vivo experiments revealed that PSPG hydrogel has good cytocompatibility. Overall, we proposed an antimicrobial strategy to eliminate bacteria through the synergistic effects of gas-photodynamic-photothermal killing, alleviating hypoxia in the bacterial infection microenvironment, and inhibiting biofilms, offering a new way against antimicrobial resistance and biofilm-associated infections. The NIR light-triggered multifunctional injectable hydrogel nanoplatform (PSPG hydrogel) based on Pt-decorated gold nanoparticles with sodium nitroprusside (SNP)-loading porphyrin metal organic framework (PCN) as inner templates can efficiently perform photothermal conversion (η=89.21%) to trigger NO release from SNP, while continuously regulating the hypoxic microenvironment at the bacterial infection site through Pt-induced self-oxygenation, achieving efficient sterilization and removal of biofilm by synergistic PDT and PTT phototherapy. In vivo and in vitro experiments demonstrated that the PSPG hydrogel has significant anti-biofilm, antibacterial, and inflammatory regulatory functions. This study proposed an antimicrobial strategy to eliminate bacteria through the synergistic effects of gas-photodynamic-photothermal killing, alleviating hypoxia in the bacterial infection microenvironment, and inhibiting biofilms. [Display omitted] [ABSTRACT FROM AUTHOR]

Routine wound management faces significant challenges including rebleeding and bacterial infection that affect millions of people each year. However, conventional wound dressings (e.g., gauze, bandage) are limited to simply cover the injured surfaces and rarely show special functionality to promote the wound recovery. Currently, injectable hydrogels have been widely designed as multifunctional wound dressings to manage the hemostatic and wound healing process. Nevertheless, the integration of multiple functions through simple composition and easy construction is still difficult and hardly achieved. Herein, we reported a bioinspired multifunctional injectable hydrogel (CQCS@gel) consisted of only two components, catechol-functionalized quaternized chitosan (CQCS) and dibenzaldehyde-terminated poly(ethylene glycol) (DB-PEG 2000). The building blocks endowed CQCS@gel with tissue-adhesive, antibacterial, antioxidant, self-healing and pH-responsive properties. Based on the in vivo hemostatic study, quick hemostasis for acute tissue injuries such as liver and carotid wounds was realized owing to the rapid gelation rate and strong tissue-adhesiveness of CQCS@gel. Moreover, CQCS@gel remarkably boosted the chronic recovery process of MRSA-infected cutaneous wounds by promoting collagen deposition, hair follicles regeneration and angiogenesis. Overall, this multifunctional injectable hydrogel shows potentials as a universal wound dressing in clinical applications, enabling both hemostasis and infected wound management. This is the first report showing the multifunctional injectable hydrogel (CQCS@gel) consisted of catechol-functionalized quaternized chitosan and dibenzaldehyde-terminated poly(ethylene glycol). The incorporation of quaternary ammonium groups imparted the CQCS@gel with outstanding contact-active bacterial killing efficiency and the catechol moieties enhanced its tissue adhesive and antioxidant properties. Moreover, the reversible imine crosslinks endowed the CQCS@gel with self-healing and pH-responsive drug release capabilities. These multiple functions were integrated into a single injectable hydrogel system with easy availability and low cost. In vitro and in vivo results showed that the newly designed hydrogel was biocompatible, realized successful sealing hemostasis under multiple bleeding scenarios and enabled accelerated healing of infected skin wounds. [Display omitted] [ABSTRACT FROM AUTHOR]

Aim: The study aimed to develop a bicomponent bioactive hydrogel formed in situ and enriched with an extract of platelet‐rich fibrin (PRFe) and to assess its potential for use in pulp‐dentine complex tissue engineering via cell homing. Methodology: A bicomponent hydrogel based on photo‐activated naturally derived polymers, methacrylated chitosan (ChitMA) and methacrylated collagen (ColMA), plus PRFe was fabricated. The optimized formulation of PRFe‐loaded bicomponent hydrogel was determined by analysing the mechanical strength, swelling ratio and cell viability simultaneously. The physical, mechanical, rheological and morphological properties of the optimal hydrogel with and without PRFe were determined. Additionally, MTT, phalloidin/DAPI and live/dead assays were carried out to compare the viability, cytoskeletal morphology and migration ability of stem cells from the apical papilla (SCAP) within the developed hydrogels with and without PRFe, respectively. To further investigate the effect of PRFe on the differentiation of encapsulated SCAP, alizarin red S staining, RT‐PCR analysis and immunohistochemical detection were performed. Statistical significance was established at p <.05. Results: The optimized formulation of PRFe‐loaded bicomponent hydrogel can be rapidly photocrosslinked using available dental light curing units. Compared to bicomponent hydrogels without PRFe, the PRFe‐loaded hydrogel exhibited greater viscoelasticity and higher cytocompatibility to SCAP. Moreover, it promoted cell proliferation and migration in vitro. It also supported the odontogenic differentiation of SCAP as evidenced by its promotion of biomineralization and upregulating the gene expression for ALP, COL I, DSPP and DMP1 as well as facilitated angiogenesis by enhancing VEGFA gene expression. Conclusions: The new PRFe‐loaded ChitMA/ColMA hydrogel developed within this study fulfils the criteria of injectability, cytocompatibility, chemoattractivity and bioactivity to promote odontogenic differentiation, which are fundamental requirements for scaffolds used in pulp‐dentine complex regeneration via cell‐homing approaches. [ABSTRACT FROM AUTHOR]