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Inspired by the commonly used creams in dermatology, the present study introduced a simple method to prepare a granular hydrogel that could be applied to the whole wound area via spread to promote wound healing. Gelatin microspheres were fabricated and densely stacked, followed by adsorbing dopamine and Zn2+ solution. Dopamine polymerised in-situ to form gelatin/polydopamine (PDA)/Zn2+ composite microspheres, which were self-assembled to form a granular hydrogel. Zn2+ accelerated dopamine polymerization. PDA formed Schiff base and hydrogen bond with gelatin, realizing the assembly among the composite microspheres. The granular hydrogel exhibited bulk feature, shear-thinning and self-healing properties, which was injectable and spreadable like creams. Zn2+ in hydrogel showed sustained and stable release within 7 d. The granular hydrogel was applied to wound and significantly promoted wound healing, shortening the healing time within 10 days. The present injectable granular hydrogel thus showed convenient and advanced features towards surgical wound treatment. [ABSTRACT FROM AUTHOR]

Polysaccharides-based injectable hydrogels are a unique group of biodegradable and biocompatible materials that have shown great potential in the different biomedical fields. The biomolecules or cells can be simply blended with the hydrogel precursors with a high loading capacity by homogenous mixing. The different physical and chemical crosslinking approaches for preparing polysaccharide-based injectable hydrogels are reviewed. Additionally, the review highlights the recent work using polysaccharides-based injectable hydrogels as stimuli-responsive delivery vehicles for the controlled release of different therapeutic agents and viscoelastic matrix for cell encapsulation. Moreover, the application of polysaccharides-based injectable hydrogel in regenerative medicine as tissue scaffold and wound healing dressing is covered. [ABSTRACT FROM AUTHOR]

The development of novel wound dressings with highly effective antibacterial and accelerating wound healing properties has become the focus of current research. In this study, a novel and injectable lactoferrin (LF)/lithium magnesium silicate hydrogel (LMSH) was first synthesized through a simple electrostatic interaction method. The physical and biological properties are systematically characterized. The results show that the synthesized LF/LMSH has good antibacterial properties and biocompatibility. More importantly, it can effectively promote wound healing in the rat full-thickness skin wound model after 14 days post-operation, and the healing rate can reach 99.1 %, which is much higher than that of other groups. Meanwhile, histochemical and immunofluorescent staining confirm that the prepared injectable LF/LMSH has good pro-collagen deposition, pro-angiogenic and anti-inflammatory properties. The healed wounds present a consistently thickened epidermis with more follicular and glandular structures, indicating the great potential of the prepared material for wound management. [ABSTRACT FROM AUTHOR]

Oxidative stress caused by the overexpression of reactive oxygen species (ROS) plays an important role in the pathogenesis of traumatic brain injury (TBI). Accumulation of ROS can lead to cell death, neurodegeneration, and neurological deficit. Therefore, the design and application of functional materials with ROS scavenging ability is of great significance for neural repair. Herein, an injectable and antioxidant hydrogel was developed for TBI treatment based on the Schiff base reaction of gallic acid-conjugated gelatin (GGA) and oxidized dextran (Odex). The resulting GGA/Odex hydrogel could effectively scavenge DPPH and ABTS radicals, as well as protect cells from the oxidative damage in vitro. Moreover, GGA/Odex hydrogel possessed well biocompatible features. In a moderate TBI mouse model, in situ implantation of GGA 6 Odex hydrogel efficiently facilitated neurogenesis and promoted the motor, learning and memory abilities. Also, this composite hydrogel suppressed oxidative stress and inflammation via the activation of Nrf2/HO-1 pathway and the regulating of inflammatory factors secretion and macrophage/microglia polarization. Therefore, this injectable and ROS-scavenging GGA 6 Odex hydrogel is a promising biomaterial for tissue regenerative medicine, including TBI and other tissue repair relevant to raised ROS circumstance. [Display omitted] [ABSTRACT FROM AUTHOR]

Uterine scar was one of the long-term complications cesarean section. In this study, an thermo-responsive injectable hydrogel loaded with human umbilical cord mesenchymal stem cells (UCMSCs) and asiaticoside microspheres (AMs) was used for uterine scar repair, which was prepared by optimizing the mixed ratio of aldehyde-functionalized Pluronic F127 (F127-CHO) and adipic dihydrazide-modified hyaluronic acid (AHA). The asiaticoside was loaded in Poly (DL-lactide- co -gycolide) (PLGA) by emulsion- diffusion-evaporation method. The hydrogel had appropriate pore size, good mechanical property, and slow release ability of asiaticoside. In vitro cell experiments demonstrated that F127-CHO/AHA/AMs could effectively promote stem cell adhesion and proliferation, promote angiogenesis, and provide a suitable microenvironment for cell survival. The F127-CHO/AHA/AMs/UCMSCs hydrogel was further used to repair uterine scar in female SD rats. The results showed that the prepared hydrogel could promote the proliferation of rat endometrial cells, promote the regeneration of glands, reduce the degree of endometrial fibrosis and restore the morphology of uterine cavity. The hydrogel could upregulate expression of Ki67 and IGF-1, downregulate TGF-β1 expression and promote M1-M2 transition of macrophages. This study confirmed that the prepared hydrogel could be used as an effective transplantation strategy, which could be expected to achieve clinical transformation of uterine scar repair. [ABSTRACT FROM AUTHOR]

Background: Cartilage defects pose a significant burden on medical treatment, leading to an urgent need to develop regenerative medicine approaches for cartilage repair, such as stem cell therapy. However, the direct injection of stem cells can result in insufficient delivery or inaccurate differentiation. Hence, it is necessary to choose appropriate stem cell delivery scaffolds with high biocompatibility, injectability and chondral differentiation induction ability for cartilage regeneration. Methods: In this study, the photocrosslinked gelatin methacrylate (GelMA) hydrogel with high cell affinity and plasticity was selected and strengthened by incorporating methacrylic anhydride-modified poly(amidoamine) (PAMAM-MA) to fabricate an adipose-derived stromal/stem cells (ASCs) delivery scaffold for cartilage repair. The physiochemical properties of the GelMA/PAMAM-MA hydrogel, including the internal structure, stability and mechanical properties, were tested. Then, ASCs were encapsulated into the hydrogels to determine the in vitro and in vivo chondrogenic differentiation induction abilities of the GelMA/PAMAM-MA hydrogel. Results: Compared with the GelMA hydrogel, the GelMA/PAMAM-MA hydrogel exhibited more uniform structure, stability and mechanical properties. Moreover, on the basis of good biocompatibility, the hybrid hydrogel was proven to exert a sufficient ability to promote cartilage regeneration by in vitro three-dimensional (3D) culture of rASCs and in vivo articular cartilage defect repair. Conclusions: The injectable photocrosslinked GelMA/PAMAM-MA hydrogel was proven to be a capable stem cell carrier for cartilage repair and provides new insight into the design strategy of stem cell delivery scaffolds. [ABSTRACT FROM AUTHOR]

Previously, 5% w/v hyaluronic acid-tyramine (HA-TA) and dextran-tyramine (Dex-TA) enzymatically cross-linked hybrid hydrogels were demonstrated to provide a mechanically stable environment, maintain cell viability, and promote cartilaginous-specific matrix deposition in vitro. In this study, 5% w/v hybrid hydrogels were combined with human mesenchymal stem cells (hMSCs), bovine chondrocytes (bCHs), or a combination of both in a 4:1 ratio and subcutaneously implanted in the backs of male and female nude rats to assess the performance of cell-laden hydrogels in tissue formation. Subcutaneous implantation of these biomaterials showed signs of integration of the gels within the host tissue. Histological analysis showed residual fibrotic capsules four weeks after implantation. However, enhanced tissue invasion and some giant cell infiltration were observed in the HA-TA/Dex-TA hydrogels laden with either hMSCs or bCHs but not with the co-culture. Moreover, hMSC-bCH co-cultures showed beneficial interaction with the hydrogels, for instance, in enhanced cell proliferation and matrix deposition. In addition, we provide evidence that host gender has an impact on the performance of bCHs encapsulated in HA-TA/Dex-TA hydrogels. This study revealed that hydrogels laden with different types of cells result in distinct host responses. It can be concluded that 5% w/v hydrogels with a higher concentration of Dex-TA (≥50%) laden with bCH-hMSC co-cultures are adequate for injectable applications and in situ cell delivery in cartilage regeneration approaches. [ABSTRACT FROM AUTHOR]

Periprosthetic wear debris‐induced aseptic loosening brings great pain to patients undergoing total joint arthroplasty. Tumor necrosis factor α (TNF‐α) is a pivotal cytokine involved in wear debris‐induced aseptic inflammation and subsequent osteolysis. Herein, we developed an injectable hydrogel system containing etanercept (ETN), a TNF‐α antagonist, to inhibit wear debris‐induced osteolysis. A set of thermosensitive poly(lactide‐co‐glycolide)‐b‐poly(ethylene glycol)‐b‐poly(lactide‐co‐glycolide) (PLGA–PEG–PLGA) copolymers with comparable molecular weights but different LA/GA molar ratios were synthesized by us, and their aqueous solutions presented sol‐to‐gel transitions along with the elevation of temperature. The LA/GA ratio not only impacted the phase transition temperature but also controlled the degradation rate of gel in vivo. The hydrogel with an appropriate in vivo degradation rate was employed to load and deliver ETN, and the drug introduction did not influence on its thermo‐induced gelation behavior. The loaded ETN was released from the gel depot in vitro in a sustained manner for up to 30 days. In a mouse bone‐implanted air pouch model, a single injection of the hydrogel formulation and subsequent sustained release of active ETN efficiently neutralized TNF‐α, resulting in significant suppression of titanium particles‐induced aseptic inflammation and subsequent osteolysis, and the effect was pronouncedly superior to that of an ETN solution. [ABSTRACT FROM AUTHOR]

The irregular shape and depth of wounds could be the major hurdles in wound healing for the common three-dimensional foam, sheet, or film treatment design. The injectable hydrogel is a splendid alternate technique to enhance healing efficiency post-implantation via injectable or 3D-bioprinting technologies. The authentic combination of natural and synthetic polymers could potentially enhance the injectability and biocompatibility properties. Thus, the purpose of this study was to characterise a hybrid gelatin–PVA hydrogel crosslinked with genipin (GNP; natural crosslinker). In brief, gelatin (GE) and PVA were prepared in various concentrations (w/v): GE, GPVA3 (3% PVA), and GPVA5 (5% PVA), followed by a 0.1% (w/v) genipin (GNP) crosslink, to achieve polymerisation in three minutes. The physicochemical and biocompatibility properties were further evaluated. GPVA3_GNP and GPVA5_GNP with GNP demonstrated excellent physicochemical properties compared to GE_GNP and non-crosslinked hydrogels. GPVA5_GNP significantly displayed the optimum swelling ratio (621.1 ± 93.18%) and excellent hydrophilicity (38.51 ± 2.58°). In addition, GPVA5_GNP showed an optimum biodegradation rate (0.02 ± 0.005 mg/h) and the highest mechanical strength with the highest compression modulus (2.14 ± 0.06 MPa). In addition, the surface and cross-sectional view for scanning electron microscopy (SEM) displayed that all of the GPVA hydrogels have optimum average pore sizes (100–199 μm) with interconnected pores. There were no substantial changes in chemical analysis, including FTIR, XRD, and EDX, after PVA and GNP intervention. Furthermore, GPVA hydrogels influenced the cell biocompatibility, which successfully indicated >85% of cell viability. In conclusion, gelatin–PVA hydrogels crosslinked with GNP were proven to have excellent physicochemical, mechanical, and biocompatibility properties, as required for potential bioinks for chronic wound healing. [ABSTRACT FROM AUTHOR]

Clinical management of nonhealing ulcers requires advanced materials that can enhance wound closure rates without relying on the release of drugs or other growth factors to obviate systemic deleterious side effects. In our previous work, we synthesized an integrin-binding cell adhesive M NH2 {Fmoc-FFβAR(K)βA-NH 2 consisting of an RGD mimic, [R(K)], with an amide terminus}, M OH {Fmoc-FFβAR(K)βA-OH consisting of an RGD mimic, [R(K)], with acid terminus}, and M R (Fmoc-FFβARGDβA-NH 2 consisting of an RGD peptide, reference) with multifunctional activity. Here, we reported the synthesis, characterization, and performance of a reversed derivative, R-M NH2 (Fmoc-FFβA(K)RβA-NH 2 consisting of an RGD mimic, [K(R)], with an amide terminus) of an antimicrobial cell adhesive peptide, M NH2 . Both peptides (M NH2 and R-M NH2 ) were found to interact with αvβ3 integrin, as shown by docking studies; however, they differed in cell adhesive properties, hydrogel formation, and antimicrobial efficacy. Later, the wound healing ability of a series of RGD/RGD peptide mimics (M R , R-M NH2 , M NH2 , and M OH ) was studied in a methicillin-resistant Staphylococcus aureus (MRSA)-infected Balb/c mouse model. All studied peptides showed cell adhesion and wound healing properties; however, only the amide-terminal RGD peptide mimic, M NH2 , and its reversed derivative, R-M NH2 , showed antimicrobial activity in both in vitro and in vivo studies. Of these, M NH2 showed the highest integrin-mediated spreading, migration, and proliferation of dermal cells in vitro as well as in vivo . Therefore, the M NH2 peptide mimic represents a paradigm shift in the development of dermoconductive strategies to treat chronic wounds.

Osteoarthritis (OA) is a progressively developing condition primarily characterized by the deterioration of articular cartilage and the proliferation of bone, along with ongoing inflammation. Although the precise pathogenesis remains somewhat elusive, restoring the homeostatic balance of the intra-articular microenvironment is crucial for the management of OA. Intra-articular injection of medication is one of the most direct and effective treatment methods; however, most injectable drugs used for osteoarthritis treatment, due to their rapid breakdown, quick release, poor biological activity, and frequent injections, leading to increased risk of infection and suboptimal therapeutic outcomes. In this study, a lubricating and dual-responsive injectable hydrogel based on zeolitic imidazolate frameworks-8 (ZIF-8) impregnated with Quercetin (Que) is designed, which can facilitate OA treatment by remodeling the microenvironment. The prepared injectable nanocomposite hydrogel (MH/CCM@ZIF-8@Que) exhibits pH and reactive oxygen species (ROS) responsiveness, alongside a controllable release of bioactive substances to modulate the microenvironment of bone tissue, thereby mitigating synovitis and the degeneration of cartilage matrix, while simultaneously facilitating cartilage repair. This developed thermosensitive injectable hydrogel, which effectively balances lubrication with the controlled release of bioactive substances, represents a highly promising therapeutic approach for osteoarthritis., (© 2024 Wiley‐VCH GmbH.)

Surgical resection is still the main means for clinical treatments of breast cancer, but the postoperative immunosuppressive microenvironment and neoangiogenesis of the residual tumors easily lead to tumor metastasis and recurrence, which will further endanger patients' lives. The combination of antiangiogenic therapy and immunotherapy may promote the mutually reinforced cycle of immune reprogramming and vascular normalization to avoid tumor metastasis and recurrence. Herein, we prepared polydopamine nanoparticles for improving tissue adhesion and enriching tumor-associated antigens. This nanoregulator together with regorafenib (REG) was further incorporated into a hydrogel developed from grafting adipic acid dihydrazide onto 2,2,6,6-tetramethylpiperidine-1-oxyl radical oxidized chitin and oxidized hyaluronic acid, which was injectable at the cavity after subcutaneous tumor surgery with good mechanical properties and degradability. The system showed long-term release of REG. After combining with anti-PD-L1, the hydrogel applied to the surgical wound exhibited a reduction in tumor metastasis and recurrence. This effect was achieved by suppressing angiogenesis and enhancing antitumor immunity, characterized by increased levels of effector T lymphocytes and activation of dendritic cells within tumors, spleens, and draining lymph nodes. The injectable hydrogel offers a promising strategy for postoperative management aimed at preventing tumor metastasis and recurrence.

Pulpitis is inflammation of the dental pulp, often caused by bacterial infection from untreated cavities, leading to pain. The main challenge in treatment is eliminating infection while preserving tooth vitality. This study aims to address this challenge by developing a hydrogel for convenient insertion into the root canal system, securely attaching to dentin walls. An injectable hydrogel system is developed by chemically cross-linking natural polysaccharide pectin with gelatin (GPG) through reversible Schiff base reaction. The GPG system was then used to encapsulate and release drugs, such as ciprofloxacin (CIP) for infection prevention and deferoxamine (DFO) for promoting blood vessel proliferation and reducing inflammatory reactions. The GPGs absorbed significant amounts of CIP and DFO, enabling sustained release over a nearly ten-day period. When subcutaneously implanted, the GPGs formed stable gel depots, with only 50 % of the gels degrading after 3 weeks, indicating a sustained biodegradation pattern. Additionally, the GPG system demonstrated excellent antibacterial activity against both gram-negative and gram-positive bacteria. Results from in vitro scratch healing tests and in ovo chorioallantoic membrane chick model tests showed promising biocompatibility and promotion of vascular proliferation by the GPG. This study heralds a novel frontier in endodontic therapeutics, poised to potentially enable dental pulp regeneration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Discectomy serves as the primary therapeutic approach for lumbar disc herniation, but the annular fibrosus defects after discectomy may lead to recurrence of disc herniation. Despite recent advances in bioinspired adhesives to seal the AF defect, the growing popularity of endoscopic discectomy has put forward high requirements for the tissue bioadhesives with rapid injectability, easy operation, and robust tissue adhesion in underwater environments. Herein, a rapidly in situ forming injectable tetra-PEG bioadhesive (ISG) comprising of FDA-approved tetra-armed poly (ethylene glycol) amine (tetra-PEG-NH 2 ) and tetra-armed poly (ethylene glycol) succinimidyl glutarate (tetra-PEG-SG) for the sutureless closure of AF defects, is reported. Relying on quick ammonolysis reaction between N-hydroxysuccinimide (NHS)-ester of tetra-PEG-SG polymer and amine groups of tetra-PEG-NH 2 polymer and tissue proteins, the uniform networks are formed within seconds with easy injection, efficient waterproofness, instant tissue adhesion, and durable compliance. The goat lumbar discectomy model was used to assess the effect of ISG hydrogels in vivo. The results reveal that the resultant ISG bioadhesive can effectively maintain the disc height, fuse with the host tissue, ameliorate IVD degeneration, and retain the initial biomechanics. Together, this study provides an efficient strategy of in situ injectable glue for the minimally invasive treatment of AF defects., (© 2024 Wiley‐VCH GmbH.)

Wound infections caused by microorganisms often give rise to extensive inflammation and vascular damage that compromise the wound healing process. Designing approaches to more effectively controlling wound infections and accelerating this healing process are urgently needed. This study was designed with the goal of synthesizing an injectable, double cross-linked hydrogel suitable for use when treating infected wounds. After initially synthesizing methacrylated polylysine (PLMA) through polylysine grafting with methacrylic anhydride, CGRP and PLMA were incorporated into a PEG hydrogel network through reactions between NHS-activated carboxyl esters and amino groups (NH₂). PLMA was also employed to enhance the self-crosslinking activity, culminating in the production of PEG/PLMA/CGRP double cross-linked hydrogels. After injection these hydrogels were capable of undergoing rapid molding such that they were able to conform to the irregularly shaped wound contours. This PEG/PLMA/CGRP formulation was capable of mimicking nerve ending-mediated CGRP secretion to control wound healing, while also exhibiting robust antioxidant, anti-inflammatory, and pro-angiogenic properties. In addition, PEG/PLMA/CGRP hydrogels in vitro showed robust resistance to S. aureus and E. coli. In a rat model of S. aureus-mediated wound infection, this hydrogel markedly promoted wound healing. PEG/PLMA/CGRP hydrogels are thus an effective tool for use in the context of infected wound healing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Piezoelectric, conductive, and injectable hydrogel (SPG hydrogel) is constructed to rapidly close wounds, efficiently harvest biomechanical energy from animal motion, and generate electrical stimulation for electrotherapy of wound healing. 3-amino-4-methoxybenzoic acid (AMB) monomer was polymerized and grafted onto the gelatin, which was further crosslinked using EDC/NHS and embedded with strontium titanate nanoparticles (80.5 wt%), forming SPG hydrogel. This SPG hydrogel had high tissue adhesion ability, and could generate the output voltage (maximum output voltage 1 V) and current (maximum output current 0.5 nA) upon mechanical bending, promoting NIH-3T3 cell migration and proliferation. Upon application to the mice wound model, the SPG hydrogel rapidly closed the skin wound, smoothed the wound's appearance, reduced the remaining wound size, and increased epidermal thickness, demonstrating remarkable wound healing capabilities. This study suggests that the body motion-promoted electrotherapy offers a promising strategy for wound healing. STATEMENT OF SIGNIFICANCE: Piezoelectric nanomaterials are often incorporated into hydrogels to create piezoelectric hydrogels for wound healing. However, piezoelectric nanomaterials tend to agglomerate within the hydrogel matrix, and the hydrogel's low conductivity hinders efficient electron transfer. Together, both factors significantly reduce the piezoelectric effect. In this study, we developed an SPG hydrogel to improve the homogeneity and conductivity of the piezoelectric hydrogel. We first designed a conductive PG hydrogel and then immoblized piezoelectric STO nanoparticles within its matrix through coordination chemistry. Upon mechanical deformation, the uniformly distributed STO nanoparticles can generate electricity, which can efficiently transfer through the conductive matrix to the hydrogel's surface. This design shows great potential for wound healing applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Up to now, the clinical treatment of spinal cord injury (SCI) to recover the locomotion function, sensory function, and autonomic function of patients is a global medical challenge. In this study, based on the excellent effects of Tetramethylpyrazine (TMP) on regulating pathological micro-environment, we designed a new injectable conductive hydrogel consists of water-soluble polypyrrole (Ppy), agar, and TMP. The TMP@PA hydrogel has excellent physicochemical properties, bio-safety, and drug release ability, which can be injected into lesions in situ without secondary injury for SCI. Our in vivo and in vitro experiments have demonstrated that the TMP@PA hydrogel can not only fill the spinal cord cavity to reconstruct the electrical conduction pathway but also release TMP continuously to inhibit ferroptosis by regulating nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy regulated by Yes-Associated Protein (YAP) to promote SCI repair. Collectively, TMP@PA hydrogel may be an effective tissue engineering scaffold to treat SCI with highly promising clinical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Injectable thermoresponsive hydrogels (thermogels), valued for their conformability and minimal invasiveness, are increasingly used as in situ forming implants for drug delivery and as regenerative scaffolds. These gels exhibit sol-to-gel phase transitions at body temperature. As localized depots and scaffolds, these gels determine the chemical and mechanical environments and could dramatically influence the release kinetics of drugs or the fate of cells. Current synthetic approaches for thermogels, however, often limit the ability to fully exploit interactions between the thermogel matrix and the encapsulated agent. In this study, we introduce a modular synthetic platform for creating a library of functionalized polyurethane thermogels that enables customization of gelation properties and intermolecular interactions. These thermogels can exhibit a wide range of stiffness, offer complementary ionic interactions, and enhance hydrophobic interactions and hydrogen bonding. By leveraging these tunable interactions between the thermogelling scaffold, functional groups, and encapsulated agents, we achieved sustained and controlled release, from days to over 6 months, for both low and high molecular weight drug analogs. Release profiles varied from monophasic to biphasic and triphasic depending on the compatibility between the thermogel properties and the encapsulated agents. The design rules identified here support the development of drug-specific formulations, facilitating precise, sustained, and modulated release tailored to therapeutic needs. Beyond providing an adaptable strategy for customizable injectable drug depots, this synthetic strategy lays the groundwork for future iterations of multi stimuli-responsive thermogels with enhanced bioactivity, advancing the potential for customizable, biointeractive therapeutic systems.

Endometritis, a prevalent obstetric condition primarily caused by Escherichia coli ( E. coli) and Staphylococcus aureus ( S. aureus ), significantly threatens the reproductive performance of female animals. In this study, thermosensitive injectable chitosan (CS)/β-glycerophosphate (β-GP) hydrogels loaded with berberine (BBR) and carvacrol (CAR) were prepared for endometritis treatment. In vitro , BBR/CAR-CS/β-GP hydrogels exhibited rapid gelation within 5 min at 37 °C, excellent injectability, and more than 90% degradation within 30 days under enzymatic action. The dual drug-loaded system also exhibited controlled release of BBR and CAR and demonstrated the antimicrobial activity against E. coli and S. aureus . In vivo , uterine injection of BBR/CAR-CS/β-GP hydrogels alleviated infection-induced injuries and reduced the bacterial load in infected uterine tissues. In summary, these findings highlight the potential of BBR/CAR-CS/β-GP hydrogels as innovative carriers for drug delivery targeting endometritis.

Damaged cartilage tissue has a limited ability to self-heal due to its avascular nature and low cellularity. To effectively engineer cartilage tissue, innovative techniques such as injectable and interactive hydrogels using a minimally invasive approach are required to mimic the natural properties of cartilage. In this study, an injectable hydrogel containing magnetic iron oxide nanoparticles (MNPs) has been rationally designed to induce chondrogenic differentiation in bone marrow mesenchymal stem cells (BMSCs) using an external magnetic field application. The effect of the incorporation of MNPs with the surface functional group of either carboxyl or amine on the properties of the hydrogels (denoted as HS and HA samples, respectively) has been investigated, and compared to control hydrogel without MNPs (denoted as H). The hydrogels demonstrated thermomagnetic-responsive and shear-thinning behavior. Incorporating MNPs in the hydrogel combination resulted in the formation of a more robust network with increased compressive modulus (by 2 and 2.5 times), cell viability (by 24 % and 7 %), swelling ratio (by 97 % and 42 %) for HS and HA, respectively, as well as better cell adhesion. Also, incorporating MNPs resulted in decreased elastic modulus (by 28 and 5 times), biodegradation rate (by 5 % and 9 %), and viscosity (by 4 and 20 times) for HS and HA, respectively. The results of glycosaminoglycans (GAG) staining indicated the synergistic effect of MNP incorporation and magnetic field application in improving chondrogenic differentiation of BMSCs in vitro. The research findings could lead to the development of superior injectable hydrogels and bioinks for tissue engineering applications., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024. Published by Elsevier B.V.)

In this study, we synthesized mesoporous polydopamine nanoparticles (MPDA NPs) using an emulsion-induced interface assembly strategy and loaded epigallocatechin gallate (EGCG) into MPDA NPs via electrostatic attraction to form EGCG@MPDA NPs. In the post myocardial infarction (MI) environment, these interventions specifically aimed to eliminate reactive oxygen species (ROS) and facilitate the repair of MI. We further combined them with a thermosensitive chitosan (CS) hydrogel to construct an injectable composite hydrogel (EGCG@MPDA/CS hydrogel). Utilizing in vitro experiments, the EGCG@MPDA/CS hydrogel exhibited excellent ROS-scavenging ability of H9C2 cells under the oxidative stress environment and also could inhibit their apoptosis. The EGCG@MPDA/CS hydrogel significantly promoted left ventricular ejection fraction (LVEF) in infarcted rat models post injection for 28 days compared to the PBS group (51.25 ± 1.73% vs 29.31 ± 0.78%, P < 0.05). In comparison to the PBS group, histological analysis revealed a substantial increase in left ventricular (LV) wall thickness in the EGCG@MPDA/CS hydrogel group (from 0.58 ± 0.03 to 1.39 ± 1.11 mm, P < 0.05). This work presents a novel approach to enhance MI repair by employing the EGCG@MPDA/CS hydrogel. This hydrogel effectively reduces local oxidative stress by ROS and stimulates the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway.

Chemotherapy is the cornerstone of triple-negative breast cancer. The poor effectiveness and severe neuropathic pain caused by it have a significant impact on the immune system. Studies confirmed that immune cells in the tumor microenvironment (TME), have critical roles in tumor immune regulation and prognosis. In this study, it is revealed that the painless administration of Esketamine, combined with Cisplatin (DDP), can exert an anti-tumor effect, which is further boosted by the hydrogel delivery system. It is also discovered that Esketamine combined with DDP co-loaded in Poloxamer Hydrogel (PDEH) induces local immunity by increasing mature Dendritic Cells (mDCs) and activated T cells in PDEH group while the regulatory T cells (Tregs) known as CD4 + CD25 + FoxP3 + decreased significantly. Finally, , CD8 + and CD4 + T cells in the spleen exhibited a significant increase, suggesting a lasting immune impact of PDEH. This study proposes that Esketamine can serve as a painless immune modulator, enhancing an anti-tumor effect while co-loaded in poloxamer hydrogel with DDP. Along with improving immune cells in the microenvironment, it can potentially alleviate anxiety and depression. With its outstanding bio-safety profile, it offers promising new possibilities for painless clinical therapy., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Bacterial-infected wounds could cause delayed wound healing due to increased inflammation, especially wounds infected by drug-resistant bacteria remain a major clinical problem. However, traditional treatment strategies were gradually losing efficacy, such as the abuse of antibiotics leading to enhanced bacterial resistance. Therefore, there was an urgent need to develop an antibiotic-free multifunctional dressing for bacterially infected wound healing. This study demonstrated the preparation of a multifunctional injectable hydrogel and evaluated its efficacy in treating acute and infected wounds. The hydrogel was prepared by a one-step mixing method, and cross-linked by natural deep eutectic solvent (DES), polyvinyl alcohol (PVA), chitosan (CS), tannic acid (TA), and Cu 2+ through non-covalent interactions (hydrogen bonds and metal coordination bonds). PVA/CS/DES/CuTA 500 hydrogel has multiple functional properties, including injectability, tissue adhesion, biocompatibility, hemostasis, broad-spectrum antibacterial, anti-inflammatory, and angiogenesis. Most importantly, in the MRSA -infected skin wound model, PVA/CS/DES/CuTA 500 hydrogel could ultimately accelerate infected wound healing by killing bacteria, activating M2 polarization, inhibiting inflammation, and promoting angiogenesis. In summary, the PVA/CS/DES/CuTA 500 hydrogel showed great potential as a wound dressing for bacterial infected wounds treatment in the clinic., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Uncontrolled bleeding from incompressible or irregularly shaped wounds is a major factor in the death of people in the battlefield or surgery process. Ideal rapid hemostatic materials should have the performance of rapid hemostasis and at the same time can be applied to a variety of complex wound trauma types, in addition, excellent antimicrobial properties, adhesion, biocompatibility, degradation, and the non-toxicity of degradation products are also necessary, but there are fewer hemostatic materials that meet these requirements. Herein, we prepared an injectable hemostatic hydrogel based on the natural products sodium alginate (SA) and carboxymethyl chitosan (CMC). Oxidized sodium alginate (OSA) was prepared by the oxidation reaction of NaIO 4 with SA, and OSA with aldehyde group was mixed with CMC with amino group to rapidly form an in situ injectable hemostatic hydrogel (OSA/CMC) by the Schiff base reaction. OSA/CMC hydrogel exhibited excellent antimicrobial and adhesion properties by the Schiff base reaction. In addition, OSA/CMC hydrogel directly activate the endogenous coagulation pathway through the synergistic effect of OSA, CMC to enhance the hemostatic effect. The results of in vivo hemostasis study showed that OSA/CMC hydrogel significantly accelerated hemostasis and reduced blood loss in liver hemorrhage model and tail amputation model. Therefore, OSA/CMC hydrogel is expected to be a potential material in the direction of rapid clinical hemostasis due to its good adhesion properties, antimicrobial properties, biocompatibility, blood compatibility, and efficient rapid hemostasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Colorectal cancer (CRC) recurrence post-surgery remains a major challenge. While Chimeric Antigen Receptor (CAR)-engineered natural killer (NK) cells hold immense therapeutic potential, their intratumoral infiltration ability remains limited, hampering efficacy. Building upon prior research suggesting that chemokines like C-X-C motif chemokine ligand 9 (CXCL9) and C-X-C motif chemokine ligand 10 (CXCL10) recruit CAR-NK cells, we hypothesized that tumor cell m6A methylation, regulated by Methyltransferase-like 3 (METTL3), influences chemokine secretion. This study aims to elucidate the underlying mechanisms and improve METTL3 inhibition efficiency. We designed an adhesive hemostasis hydrogel loaded with STM2457, a METTL3 inhibitor, aimed at sustained release in the acidic tumor microenvironment. In vitro, the hydrogel promoted CAR-NK cell recruitment and tumor killing via sustained METTL3 inhibition. The hydrogel's Schiff base bonds further enabled intestinal adhesion and hemostasis in an incomplete tumor resection model of CRC. Combining the hydrogel with CAR-NK cell therapy significantly reduced CRC recurrence in vivo. Overall, our study reveals the crucial role of METTL3 in CRC recurrence and proposes a promising, multimodal strategy using STM2457-loaded hydrogel and CAR-NK cells for enhanced therapeutic efficacy., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

Clinical oncology is currently experiencing a technology bottleneck due to the expeditious evolution of therapy defiance in tumors. Although drugs used in chemotherapy work for a sort of cell death with potential clinical application, the effectiveness of chemotherapy-inducing drugs is subject to several endogenous conditions when used alone, necessitating the urgent need for controlled mechanisms. A tumor-targeted drug delivery therapy using Li-Al (M + /M 3+ )-based layered double hydroxide (LDHs) family has been proposed with the general chemical formula [M + 1- x M 3+ x (OH)] 2 x + [(A m- ) 2 x / m . n , which is fully biodegradable and works in connection with the therapeutic interaction between LDH nanocarriers and anticancerous doxorubicin (DOX). Compositional variation of Li and Al in LDHs has been used as a nanoplatform, which provides a functional balance between circulation lifetime, drug loading capacity, encapsulation efficiency, and tumor-specific uptake to act as self-regulatory therapeutic cargo to be released intracellularly. First-principle analyses based on DFT have been employed to investigate the interaction of bonding and electronic structure of LDH with DOX and assess its capability and potential for a superior drug carrier. Following the internalization into cancer cells, nanoformulations are carried to the nucleus via lysosomes, and the mechanistic pathways have been revealed. Additionally, in vitro along with in vivo therapeutic assessments on melanoma-bearing mice show a dimensional effect of nanoformulation for better biocompatibility and excellent synergetic anticancer activity. Further, the severe toxic consequences associated with traditional chemotherapy have been eradicated by using injectable hydrogel placed just beneath the tumor site, and regulated release of the drug has been confirmed through protein expression applying various markers. However, Li-Al-based LDH nanocarriers open up new design options for multifunctional nanomedicine, which has intriguing potential for use in cancer treatment through sustained drug delivery.2 O)] 2 x - , which is fully biodegradable and works in connection with the therapeutic interaction between LDH nanocarriers and anticancerous doxorubicin (DOX). Compositional variation of Li and Al in LDHs has been used as a nanoplatform, which provides a functional balance between circulation lifetime, drug loading capacity, encapsulation efficiency, and tumor-specific uptake to act as self-regulatory therapeutic cargo to be released intracellularly. First-principle analyses based on DFT have been employed to investigate the interaction of bonding and electronic structure of LDH with DOX and assess its capability and potential for a superior drug carrier. Following the internalization into cancer cells, nanoformulations are carried to the nucleus via lysosomes, and the mechanistic pathways have been revealed. Additionally, in vitro along with in vivo therapeutic assessments on melanoma-bearing mice show a dimensional effect of nanoformulation for better biocompatibility and excellent synergetic anticancer activity. Further, the severe toxic consequences associated with traditional chemotherapy have been eradicated by using injectable hydrogel placed just beneath the tumor site, and regulated release of the drug has been confirmed through protein expression applying various markers. However, Li-Al-based LDH nanocarriers open up new design options for multifunctional nanomedicine, which has intriguing potential for use in cancer treatment through sustained drug delivery.

Local recurrence of osteosarcoma and wound healing after excision surgery are major challenges in clinical research. The present anti-tumor treatments could inhibit normal tissues, resulting in difficulties in surgical wound healing. In this study, we constructed an injectable hydrogel as a platform to co-deliver MnO 2 nanoparticles and ferrocene Fc, termed as (MnO 2 /Fc)@PLGA for osteosarcoma treatment and wound healing after excision. By simple local injection, the hydrogel could form a protective barrier on the surgical wound after osteosarcoma excision, which could promote wound healing and steady release of MnO 2 /Fc nanoparticles. The released MnO 2 /Fc might undergo the Fenton reaction through Mn 2+ /Fe 2+ to inhibit osteosarcoma cells with chemodynamic therapy (CDT). Furthermore, MnO 2 could catalyze endogenous H 2 O 2 to produce O 2 , which eliminates the adverse effects of H 2 O 2 and remodels the hypoxic state in the local lesions. The increased O 2 facilitated surgical wound healing and anti-tumor effects by regulating the hypoxia inducible factor-1 functions. In conclusion, (MnO 2 /Fc)@PLGA hydrogel could effectively prevent local recurrence of osteosarcoma and promote wound healing after excision surgery, thereby providing a novel strategy for tumor treatment and tissue repair., Competing Interests: No conflict of interest exits in the submission of this manuscript., (© 2024 The Authors.)

Elevation of early-stage gastrointestinal cancer using submucosal injection materials (SIMs) and postoperative wound care with adhesive materials are crucial for preventing complications arising from endoscopic submucosal dissection (ESD). Several types of SIMs have been developed; however, they often provide insufficient tissue elevation and fail to adequately adhere to the defect following the removal of early-stage gastrointestinal cancer. In this study, we present the development of injectable Cat-PBA-ApGltn hydrogels, which are based on catechol group-modified Alaska pollock gelatin (Cat-ApGltn) and phenylboronic acid-modified Alaska pollock gelatin (PBA-ApGltn), serving as multifunctional SIMs. A Cat-ApGltn/PBA-ApGltn mixed solution formed a hydrogel within 3 seconds. The resulting Cat-PBA-ApGltn hydrogels were easily injected manually through a 23 G needle due to their shear-thinning properties. Additionally, 10 w/v% Cat-PBA-ApGltn hydrogels demonstrated a 2.3-fold increase in mucosal elevation (7.2 ± 0.4 mm) compared with a commercially available SIM (3.1 ± 0.7 mm). The 10 w/v% Cat-PBA-ApGltn hydrogel, when adhered to porcine gastric submucosa, exhibited a burst strength 7 times greater than the average human intragastric pressure. Furthermore, the Cat-PBA-ApGltn hydrogels demonstrated biodegradability without inducing severe inflammation upon implantation in rat subcutaneous tissue. These Cat-PBA-ApGltn hydrogels hold promise as multifunctional SIMs, boasting injectability, excellent elevation, adhesion capabilities, and biodegradability., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Glioblastoma (GBM) recurrence leads to high mortality, which remains a major concern in clinical therapy. Herein, an injectable triptolide (TP)-preloaded hydrogel (TP@DNH) accompanied by a postoperative injection strategy is developed to prevent the recurrence of GBM. With a potential inhibitor of the NRF2/SLC7A11/GPX4 axis, it is demonstrated that TP can deactivate glutathione peroxidase 4 (GPX4) from the source of glutathione (GSH) biosynthesis, thereby activating ferroptosis in GBM cells by blocking the neutralization of intracellular lipid peroxide (LPO). Based on acid-sensitive Fe 3+ /tannic acid (TA) metal-phenolic networks (MPNs), the TP@DNH hydrogel can induce the effective generation of reactive oxygen species (ROS) through Fe 3+ /TA-mediated Fenton reaction and achieve controllable release of TP in resected GBM cavity. Due to ROS generation and GPX4 deactivation, postoperative injection of TP@DNH can achieve high-level ferroptosis through dual-pathway LPO accumulation, remarkably suppressing the growth of recurrent GBM and prolonging the overall survival in orthotopic GBM relapse mouse model. This work provides an alternative paradigm for regulating ferroptosis in the postoperative treatment of GBM., (© 2024 Wiley‐VCH GmbH.)

Wound infections pose a significant challenge in healthcare, and traditional antibiotic treatments often result in the development of resistant pathogens. Addressing this gap, ProGel is introduced, a living hydrogel created by entrapping probiotic Lactobacillus plantarum as a therapeutic component within a gelatin matrix. With a double-syringe system, ProGel can be easily mixed and applied, conforming swiftly to any wound shape and forming hydrogel in situ. It also demonstrates robust mechanical and self-healing properties owing to the Schiff-base bonds. ProGel sustains more than 80% viability of the entrapped L. plantarum while restricting their escape from the hydrogel. After a week of storage, more than 70% viability of the entrapped L. plantarum is preserved. Importantly, ProGel exhibits broad-spectrum antimicrobial efficacy against pathogens commonly associated with wound infections, i.e., Pseudomonas aeruginosa (7Log reduction), Staphylococcus aureus (3-7Log reduction), and Candida albicans (40-70% reduction). Moreover, its cytocompatibility is affirmed through coculture with human dermal fibroblasts. The effectiveness of ProGel is further highlighted in more clinically relevant tests on human skin wound models infected with P. aeruginosa and S. aureus, where it successfully prevents the biofilm formation of these pathogens. This study showcases an injectable living hydrogel system for the management of complex wound infections., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Introduction: The objective of this study is to investigate the effect of gelatin microspheres incorporating growth factors on the therapeutic efficacy in cell transplantation. The strength of this study is to combine gelatin hydrogel microspheres incorporating basic fibroblast growth factor and platelet growth factor mixture (GM/GF) with bioabsorbable injectable hydrogels (iGel) for transplantation of adipose-derived stem cells (ASCs). Methods: The rats ASCs suspended in various solutions were transplanted in masseter muscle. Rats were euthanized 2, 7, 14 days after injection for measurement of the number of ASCs retention in the muscle and morphological evaluation of muscle fibers and the inflammation of the injected tissue by histologic and immunofluorescent stain. Results: Following the injection into the skeletal muscle, the GM/GF allowed the growth factors to release at the injection site over one week. When ASCs were transplanted into skeletal muscle using iGel incorporating GM/GF (iGel+GM/GF), the number of cells grafted was significantly high compared with other control groups. Moreover, for the groups to which GM/GF was added, the cells transplanted survived, and the Myo-D expression of a myoblast marker was observed at the region of cells transplanted. Conclusions: The growth factors released for a long time likely enhance the proliferative and differentiative capacity of cells. The simple combination with iGel and GM/GF allowed ASCs to enhance their survival at the injected site and consequently achieve improved therapeutic efficacy in cell transplantation.

Triple-negative breast cancer (TNBC) patients are considered intractable, as this disease has few effective treatments and a very poor prognosis even in its early stages. Here, intratumoral therapy with resveratrol (Res), which has anticancer and metastasis inhibitory effects, was proposed for the effective treatment of TNBC. An injectable Res-loaded click-crosslinked hyaluronic acid (Res-Cx-HA) hydrogel was designed and intratumorally injected to generate a Res-Cx-HA depot inside the tumor. The Res-Cx-HA formulation exhibited good injectability into the tumor tissue, quick depot formation inside the tumor, and the depot remained inside the injected tumor for extended periods. In vivo formed Res-Cx-HA depots sustained Res inside the tumor for extended periods. More importantly, the bioavailability and therapeutic efficacy of Res remained almost exclusively within the tumor and not in other organs. Intratumoral injection of Res-Cx-HA in animal models resulted in significant negative tumor growth rates (i.e., the tumor volume decreased over time) coupled with large apoptotic cells and limited angiogenesis in tumors. Therefore, Res-Cx-HA intratumoral injection is a promising way to treat TNBC patients with high efficacy and minimal adverse effects.

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.

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.

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.

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.

BACKGROUND: Injectable sodium alginate hydrogel can repair bone defects by non-invasive or minimally invasive methods, but the mechanical properties are poor and polyethylene glycol-based hydrogel has elasticity. The composite of materials is expected to improve the mechanical properties and cellular biocompatibility of hydrogel scaffolds. OBJECTIVE: To investigate the physical and chemical properties of glucolactone-sodium alginate/β-tricalcium phosphate-polyethylene glycol hydrogel and its effect on the proliferation and differentiation of murine bone marrow mesenchymal stem cells. METHODS: Gluconolactone as cross-linking agent was set to prepare glucolactone-sodium alginate/β-tricalcium phosphate-polyethylene glycol hydrogel (concentrations of cross-linking agent were 5, 10, and 20 g/L, respectively, which were marked as groups A, B, and C) and glucolactone-sodium alginate/ β-tricalcium phosphate hydrogel (concentration of cross-linking agent was 10 g/L, which was marked as group D). The morphology, mechanical properties, and gelation time of hydrogels in the four groups were characterized. Rat bone marrow mesenchymal stem cells were co-cultured with four groups of hydrogels. The proliferation of cells was detected by CCK-8 assay. Cell survival was observed by Live/Dead fluorescence staining. Osteogenic differentiation was detected by immunocytochemical staining of type I collagen. RESULTS AND CONCLUSION: (1) The filamentous structure similar to adhesion was observed by scanning electron microscope in the groups A, B and C. The pore size distribution of group A was uneven. The pore size of group B was uniform and the porosity was high. The group C had high porosity but different pore sizes. The group D had uneven pore size distribution and low porosity. (2) Physicochemical properties: The compressive stress in group B was higher than that in group D (P < 0.05). With the increase of gluconolactone concentration, the compressive stress of hydrogel in groups A, B and C increased (P < 0.05). The macroscopic performance of hydrogel after 50% compression showed that there were larger cracks in group D and only smaller cracks in group B after compression. The gelation time of groups A, B and C shortened with the increase of gluconolactone concentration, and the gelation time of group B was slightly longer than that of group D (P < 0.05). (3) CCK-8 assay showed that the cell proliferation rate of groups A and B was higher than that of group C (P < 0.05), and that of group B was higher than that of group D (P < 0.05). Live/Dead staining showed that the cell survival rate of each group was higher, but the number of dead cells was more in group C than that in the other three groups. (4) Immunocytochemical staining showed that the cells in groups A, B, and D were polygonal, and the cells in group C were partially round. The green fluorescence intensity in group B was higher than that in the other three groups, and the morphology of the cytoskeleton and microfilaments and the number of cells were also better than those in the other three groups. (5) The results show that the glucolactone-sodium alginate/β-tricalcium phosphate-polyethylene glycol hydrogel has perfect mechanical properties and stability; hydrogel prepared with 10 g/L gluconolactone can effectively promote the proliferation and differentiation of murine bone marrow mesenchymal stem cells. [ABSTRACT FROM AUTHOR]

Various immunotherapeutic agents that can elicit antitumor immune responses have recently been developed with the potential for improved efficacy in treating cancer. However, insufficient delivery efficiency at the tumor site, along with severe side effects after systemic administration of these anticancer agents, have hindered their therapeutic application in cancer immunotherapy. Hydrogels that can be directly injected into tumor sites have been developed to help modulate or elicit antitumor responses. Based on the biocompatibility, degradability, and controllable mechanochemical properties of these injectable hydrogels, various types of immunotherapeutic agents, such as hydrophobic anticancer drugs, cytokines, antigens, and adjuvants, have been easily and effectively encapsulated, resulting in the successful elicitation of antitumor immune responses and the retention of long-term immunotherapeutic efficacy following administration. This review summarizes recent advances in combination immunotherapy involving injectable hydrogel-based chemoimmunotherapy, photoimmunotherapy, and radioimmunotherapy. Finally, we briefly discuss the current limitations and future perspectives on injectable hydrogels for the effective combination immunotherapy of tumors. [ABSTRACT FROM AUTHOR]

Hypoxia is a huge barrier for the development of photodynamic therapy (PDT). Chemodynamic therapy (CDT) could provide a possible solution to this dilemma. In this work, a controlled Schiff-base reaction was conducted between amido groups on the surface of carbon dots (CDs) and aldehyde groups on aldehyde-modified cellulose nanocrystals (mCNCs) as well as aldehyde-mCNCs decorated with Fe3O4 nanoparticles. In this process, the mCNCs not only prevent the agglomeration of Fe3O4 but also form hydrogels with CDs. The CDs act as both photothermal agent and photosensitizer. The hypoxia could be effectively relieved through the Fenton reaction due to the addition of Fe3O4, and the ·OH produced in the reaction further induces CDT and enhances tumor therapy efficiency. The therapy performance was further verified through in vitro cell experiments and in vivo animal experiments. This convenient method provides inspirations for the design and preparation of advanced biomaterials with multiple functions for cancer therapy. [ABSTRACT FROM AUTHOR]

This study develops a multi-functional hydrogel with a dual injection system based on the adhesive and self-healing properties of the byssus excretion found in mussels. Through precisely controlling the composite cross-linking hydrophobic association (HA) structure composed of A and B solutions, a high-strength, temperature-sensitive injectable hydrogel can be obtained, and it has good self-healing properties. The main composition of A solution contains the surfactant SDS, which can form amphiphilic micelles, the strength increasing component stearyl methacrylate (C18), and NIPAAm, which provides thermo-sensitivity. Solution B contains dopamine acrylate (DAA), which has self-healing properties, and ferric chloride (FeCl3), which is a connecting agent. The rheological behavior shows that when the temperature is increased from 25 °C to 32 °C, the gel can be completed in seven minutes to form a composite hydrogel of NIPAAm-DAA-HA. When NMR identification was conducted on composite DAA, it was found that when comparing DAA and dopamine hydrochloride there were new peaks with specific characteristics, which confirm that this study successfully prepared DAA; swelling tests found that swelling could surpass a rate of 100%, and a higher ratio of crosslinking agent decreased the amount of moisture absorbed; the results of the compression test showed that the addition of hydrophobic micelles C18 effectively enhanced the mechanical properties of hydrogel, allowing it to withstand increased external stress; the adhesiveness results show that an increase in the catechol-Fe3+ concentration of the NIPAAm-DAA-HA hydrogel results in an increased adhesiveness of 0.0081 kg/cm2 on pig skin; the self-healing tests show that after taking damage, NIPAAm-DAA-HA hydrogel can be reactivated with catechol-Fe3+ and self-heal at a rate of up to 70% after 24 h; antibacterial tests show that hydrogel has good bacterial resistance to against E. coli, staphylococcus epidermidis, and bacillus cereus; through in vitro transdermal absorption, it can be seen that the release ability of drugs within the hydrogel can reach up to 8.87 μg/cm2. The NIPAAm-DAA-HA hydrogel prepared by this study performed excellently in both adhesion and self-healing tests. The thermo-sensitive and antibacterial properties can be applied to the treatment of deep wounds and address some of the flaws of traditional wound dressings. [ABSTRACT FROM AUTHOR]

The temporomandibular joint (TMJ) is commonly affected during fundamental oral activities, reducing the quality of life. Herein, we synthesized a heparin‐conjugated poloxamer hydrogel (HEP) as a thermo‐responsive injectable hydrogel for the treatment of TMJ disorders. While the gelation temperature of synthesized HEP (25% [w/v]) was 29.8–30.0°C, there was a slight difference between loss and storage modulus. HEP decreased the friction of the TMJ, thus requires less energy during load‐bearing jaw movement in comparison to POL. Moreover, the oscillation test dependent on strain ranges from 0.01% to 1000% validated that POL and HEP3 hydrogels showed a similar critical strain of about 5.6%. The total elastic recovery percentage of HEP3 (53.50%) was higher than POL (45.55%), indicating a better recovery of the deformed hydrogel structure. Along with the suitable viscoelastic properties for temporomandibular cavity, both hydrogels increased the proliferation of fibroblasts (L929) and chondrocytes (ATDC5) (cell viabilities were above 100%). However, newly synthesized HEP induced differentiated cell proliferation of chondrogenic cells at increasing concentrations up to 0.0156 mg/mL (p < 0.0001) compared to POL and the control group. The promising rheological properties and effects on chondrogenic cell proliferation of injectable heparin‐conjugated hydrogel make them candidates for intra‐articular injections used for the treatment of TMJ. [ABSTRACT FROM AUTHOR]

Although combination chemoimmunotherapy shows promising clinical results for cancer treatment, this approach is largely restricted by variable objective response rate and severe systemic adverse effects of immunotherapeutic antibody and chemotherapeutic drugs. Therefore, an in situ-formed therapeutic silk-chitosan composite scaffold is fabricated in this study to allow local release of the chemotherapeutic drug doxorubicin (DOX) and JQ1 (small molecular inhibitor used for the extraterminal protein BRD4 and bromodomain) with control release kinetics. DOX-JQ1@Gel contains a pH-degradable group that releases therapeutics in a weak acidic tumor microenvironment. The released DOX could directly kill tumor cells or lead to immunogenic cell death, thereby triggering the response of antitumor immunity. Meanwhile, chemotherapy-triggered antigen release and JQ1-mediated PD-L1 checkpoint blockade cumulatively contribute to trigger the response of antitumor immunity. Finally, the DOX-JQ1@Gel is locally injected to evaluate its synergistic cancer therapeutic effect, which is expected to improve objective response rate of immunotherapy and minimize systemic side effects. [ABSTRACT FROM AUTHOR]

Thermosensitive nanoparticles with phase transition abilities have been considered as suitable materials in biomedical fields, especially drug delivery systems. Moreover, electroactive injectable hydrogels supporting bone regeneration of the elderly will highly be desired in bone tissue engineering applications. Herein, thermosensitive nanoparticles were fabricated using chitosan/poly(N-isopropyl acrylamide) for simvastatin acid delivery. The nanoparticles were incorporated into electroactive injectable hydrogels based on aniline pentamer/silk fibroin/polyacrylamide containing vitamin C. The nanoparticles had thermosensitive properties as simvastatin acid had higher release rates at 37 than 23 °C without significant burst release. The hydrogels also revealed an appropriate gelation time, stable mechanical and rheological characteristics, high water absorbency, and proper biodegradability. In vitro studies indicated that the hydrogel was biocompatible and nontoxic, especially those containing drugs. Implantation of the hydrogels containing both simvastatin acid and vitamin C into the critical calvarial bone defect of the aged rat also demonstrated significant enhancement of bone healing after 4 and 8 weeks post-implantation. We found that the electroactive injectable hydrogels containing thermosensitive nanoparticles exhibited great potential for treating bone defects in the elderly rats [ABSTRACT FROM AUTHOR]

Autologous tumor cell vaccine is an individualized tumor treatment strategy to elicit tumor‐specific immune responses. However, it is difficult to exert efficacy in "cold" tumors, which lack tumor‐infiltrating T cells and are not sensitive to immunotherapy. Here, a dendritic cells (DCs) activation hydrogel is constructed based on bifunctional fusion membrane nanoparticles (FM‐NPs) composed of autologous tumor cell membranes and Mycobacterium phlei membrane extracts. The FM‐NPs not only provide tumor antigens but also can activate DCs. Afterward, the FM‐NPs are loaded in an injectable alginate hydrogel together with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). GM‐CSF releases rapidly and recruits DCs to hydrogel, while FM‐NPs retain in hydrogel to continuously interconnected with DCs, enriching mature DCs loaded with tumor antigens. In the 4T1 mouse breast tumor model, this hydrogel promotes the maturation of DCs in tumor‐draining lymph nodes and induces sufficient effector memory T cells that migrate to the tumor microenvironment. This successfully converts the "cold" tumors to "hot", thus exerting a significant antitumor effect synergized with the PD‐1 antibody. It is also verified the inhibitory effect of FM‐NPs using human gastric cancer organoids. Altogether, these findings demonstrate the application potential for the bifunctional fusion membrane‐based hydrogel as an autologous tumor vaccine by activating DCs. [ABSTRACT FROM AUTHOR]

The efficacy of myocardial regeneration strategies for myocardial infarction (MI) is significantly compromised by the complex structure and microenvironment of the myocardium. Although tissue engineering strategies based on cell therapy and/or pro-angiogenesis can somewhat improve cardiac function, the lack of proper myocardial materials that can withstand sustained deformability and adaptable mechanical properties severely affects myocardial wall integrity, systolic-diastolic cycles, and regeneration. Herein, we developed an integrated single "all-in-one" in situ dual crosslinking conductive hydrogel with favorable treatment properties termed as MaHA/B-G-SH/Fe3+ by ionic interactions and chemical covalency based on modified hyaluronic acid (HA), gelatin (G), and Fe3+. The resulting dual crosslinking dynamic hydrogel not only provides self-healing and mechanical properties adapted to the myocardial systolic-diastolic cycle with simultaneous electrical signal transmission to fibrous islands and normal tissue, but also leads to significant increase of the myocardial wall thickness very close to that of normal myocardium upon one single injection with complete degradation within 28 days. Notably, the hydrogel covalently conjugated with a tailored peptide sequence of GGR-KLT and encapsulated with bone mesenchymal stem cells (BMSCs) was further used for in situ injection in a rat MI model, which exhibited (i) efficient inhibition of excessive matrix degradation dependent on early MMP-2 expression, (ii) triggered on-demand release of KLT for at least 14 days and significant promotion of angiogenesis, and (iii) synergistic BMSCs considerably enhanced myocardial regeneration within 28 days. Taken together, the dual crosslinking conductive hydrogel-mediated synergistic peptide and cell therapy provides comprehensive recovery and regeneration of the structure and function of the injured myocardium, thus demonstrating great potential for clinical translations. [Display omitted] • The dual cross-linked hydrogel has the ability to support myocardial systole-diastole. • The GGR exhibited inhibition of excessive degradation of the ECM by early MMPs. • The GGR-KLT exhibited on-demand release of KLT for promoted angiogenesis. • The hydrogel-mediated integrated therapy provides efficient regeneration for MI. [ABSTRACT FROM AUTHOR]

Uncontrolled bleeding from incompressible or irregularly shaped wounds is a major factor in the death of people in the battlefield or surgery process. Ideal rapid hemostatic materials should have the performance of rapid hemostasis and at the same time can be applied to a variety of complex wound trauma types, in addition, excellent antimicrobial properties, adhesion, biocompatibility, degradation, and the non-toxicity of degradation products are also necessary, but there are fewer hemostatic materials that meet these requirements. Herein, we prepared an injectable hemostatic hydrogel based on the natural products sodium alginate (SA) and carboxymethyl chitosan (CMC). Oxidized sodium alginate (OSA) was prepared by the oxidation reaction of NaIO 4 with SA, and OSA with aldehyde group was mixed with CMC with amino group to rapidly form an in situ injectable hemostatic hydrogel (OSA/CMC) by the Schiff base reaction. OSA/CMC hydrogel exhibited excellent antimicrobial and adhesion properties by the Schiff base reaction. In addition, OSA/CMC hydrogel directly activate the endogenous coagulation pathway through the synergistic effect of OSA, CMC to enhance the hemostatic effect. The results of in vivo hemostasis study showed that OSA/CMC hydrogel significantly accelerated hemostasis and reduced blood loss in liver hemorrhage model and tail amputation model. Therefore, OSA/CMC hydrogel is expected to be a potential material in the direction of rapid clinical hemostasis due to its good adhesion properties, antimicrobial properties, biocompatibility, blood compatibility, and efficient rapid hemostasis. • OSA/CMC hydrogel can be injected on irregular or incompressible wounds to rapidly form hemostatic hydrogel. • OSA/CMC hydrogel activates endogenous coagulation pathway by the synergistic action of OSA and CMC to rapid hemostasis. • OSA/CMC hydrogel shows excellent antimicrobial properties by the synergistic action of OSA and CMC. • OSA/CMC hydrogel shows excellent adhesion properties by OSA. [ABSTRACT FROM AUTHOR]