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A series of injectable polysaccharide hydrogels are prepared with oxidized dextran and diethylenetriamine‐modified carboxymethylcellulose (CMC) or hyaluronic acid (HA). Rheological evaluation reveals that CMC‐based hydrogels achieve storage moduli >1 kPa when prepared from 5 wt% solutions, while storage moduli >100 Pa are achievable from solutions with concentrations as low as 2 wt%. HA‐based hydrogels demonstrate smaller storage moduli but have swelling ratios more than four‐fold that of CMC systems at equal concentrations. The incorporation of N‐diazeniumdiolate nitric oxide (NO) donors into the hydrogels results in reduced hydrogel storage moduli as a function of NO donor concentration. The impact of the hydrogel architecture on NO‐release kinetics proves dependent on the identity of the NO donor. Hydrogel degradation over 14 d indicates that HA‐based hydrogels degrade more rapidly than CMC hydrogels and that the addition of NO to the hydrogels increases the rate at which they degrade. In vitro cytotoxicity of hydrogel extracts is minimal, with toxicity observed only at high NO‐donor concentrations for select cell lines. The diverse properties, versatility, and nontoxic characteristics of these injectable hydrogels should facilitate local delivery of nitric oxide for a range of biomedical applications. [ABSTRACT FROM AUTHOR]

[Display omitted] Hydrogels based on cellulose nanocrystals (CNC) have attracted great interest because of their sustainability, biocompatibility, mechanical strength and fibrillar structure. Gelation of colloidal particles can be induced by the introduction of polymers. Existing examples include gels based on CNC and derivatives of cellulose or poly(vinyl alcohol), however, gel structure and their application for extrusion printing were not shown. Hence, we rationalize formation of colloidal gels based on mixture of poly(N -isopropylacrylamide) (PNIPAM) and CNC and control their structure and mechanical properties by variation of components ratio. State diagram for colloidal system based on mixture of PNIPAM and CNC were established at 25 and 37 °C. Biocompatibility, fiber diameter and rheological properties of the gels were studied for different PNIPAM/CNC ratio. We show that depending on the ratio between PNIPAM and CNC, colloidal system could be in sol or gel state at 25 °C and at gel state or phase separated at 37 °C. Physically crosslinked hydrogels were thermosensitive and could reversibly change it transparency from translucent to opaque in biologically relevant temperature range. These colloidal hydrogels were biocompatible, had fibrillar structure and demonstrate shear-thinning behavior, which makes them a promising material for bioapplications related to extrusion printing. [ABSTRACT FROM AUTHOR]

Utilizing the immune system as a strategy for disease prevention and treatment is promising, especially with dendritic cells (DCs) playing a central role in adaptive immune responses. The unique properties of DCs drive interest in developing materials for cell-based therapy and immune modulation. Injectable systems require syringe-compatible scaffolds, while hydrogels, like alginate, known for their programmability and biocompatibility, offer a versatile platform for immune medicine enhancement through easy preparation and room-temperature cross-linking. In this study, we synthesized alginate balls loaded with DCs or cytosine–phosphorothioate–guanine deoxyribonucleotide (CpG DNA) microparticles, aiming for long-term immune cell culture with potential immune stimulation effects. Encapsulated DCs exhibited proliferation within the alginate balls for up to 7 days, and CpG MPs were uniformly dispersed, which can facilitate uptake by DCs. This was supported by the result that DCs effectively phagocytosed CpG microparticles in a 2D environment. After the uptake of CpG MPs, the alginate balls with CpG-MP-uptaken DCs were synthesized successfully. The injectable properties of the alginate balls were easily modulated by adjusting the syringe needle gauges. This innovative strategy holds substantial promise for advancing medical treatments, offering effective and comfortable solutions for controlled immune modulation.

The tissue engineering field is currently advancing towards minimally invasive procedures to reconstruct soft tissue defects. In this regard, injectable hydrogels are viewed as excellent scaffold candidates to support and promote the growth of encapsulated cells. Cross-linked gelatin methacryloyl (GelMA) gels have received substantial attention due to their extracellular matrix-mimicking properties. In particular, GelMA microgels were recently identified as interesting scaffold materials since the pores in between the microgel particles allow good cell movement and nutrient diffusion. The current work reports on a novel microgel preparation procedure in which a bulk GelMA hydrogel is ground into powder particles. These particles can be easily transformed into a microgel by swelling them in a suitable solvent. The rheological properties of the microgel are independent of the particle size and remain stable at body temperature, with only a minor reversible reduction in elastic modulus correlated to the unfolding of physical cross-links at elevated temperatures. Salts reduce the elastic modulus of the microgel network due to a deswelling of the particles, in addition to triple helix denaturation. The microgels are suited for clinical use, as proven by their excellent cytocompatibility. The latter is confirmed by the superior proliferation of encapsulated adipose tissue-derived stem cells in the microgel compared to the bulk hydrogel. Moreover, microgels made from the smallest particles are easily injected through a 20G needle, allowing a minimally invasive delivery. Hence, the current work reveals that powdered cross-linked GelMA is an excellent candidate to serve as an injectable hydrogel for adipose tissue engineering.

Submucosal injection material has shown protective effect against gastrointestinal injury during endoscopic surgery in clinic. However, the protective ability of existing submucosal injection material is strictly limited by their difficult injectability and short barrier time. Herein, we report a shear-thinning gellan gum hydrogel that simultaneously has easy injectability and long-lasting barrier function, together with good hemostatic property and biocompatibility. Shear-thinning property endows our gellan gum hydrogel with excellent endoscopic injection performance, and the injection pressure of our gellan gum hydrogel is much lower than that of the small molecule solution (50 wt% dextrose) when injected through the endoscopic needle. More importantly, our gellan gum hydrogel shows much stronger barrier retention ability than normal saline and sodium hyaluronate solution in the ex vivo and in vivo models. Furthermore, our epinephrine-containing gellan gum hydrogel has a satisfactory hemostatic effect in the mucosal lesion resection model of pig. These results indicate an appealing application prospect for gellan gum hydrogel utilizing as a submucosal injection material in endoscopic surgery.

Abstract 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. Graphical Abstract

Periodontitis is a multifactorial disease that involves the destruction of hard and soft tissues surrounding the tooth. Routine periodontal treatment includes mechanical debridement (surgical and non-surgical) and the systemic administration of antibiotics. In contrast, severe and chronic periodontitis involves aggressive tissue destruction and bone resorption, and the damage is usually irreversible. In these severe cases, bone grafts, the delivery of growth hormones, and guided tissue regeneration can all be used to stimulate periodontal regeneration. However, these approaches do not result in consistent and predictable treatment outcomes. As a result, advanced biomaterials have evolved as an adjunctive approach to improve clinical performance. These novel biomaterials are designed to either prolong the release of antibacterial agents or osteogenic molecules, or to act as immunomodulators to promote healing. The first half of this review briefly summarizes the key immune cells and their underlying cellular pathways implicated in periodontitis. Advanced biomaterials designed to promote periodontal regeneration will be highlighted in the second half. Finally, the limitations of the current experimental design and the challenges of translational science will be discussed.

Objectives: This study aimed to improve the performance and mode of administration of a glass-reinforced hydroxyapatite synthetic bone substitute, Bonelike by Biosckin® (BL®), by association with a dextrin-based hydrogel, DEXGEL, to achieve an injectable and moldable device named DEXGEL Bone. Methods: Twelve participants requiring pre-molar tooth extraction and implant placement were enrolled in this study. BL® granules (250–500 µm) were administered to 6 randomized participants whereas the other 6 received DEXGEL Bone. After 6 months, a bone biopsy of the grafted area was collected for histological and histomorphometric evaluation, prior to implant placement. The performance of DEXGEL Bone and BL® treatments on alveolar preservation were further analyzed by computed tomography and Hounsfield density analysis. Primary implant stability was analyzed by implant stability coefficient technique. Results: The healing of defects was free of any local or systemic complications. Both treatments showed good osseointegration with no signs of adverse reaction. DEXGEL Bone exhibited increased granule resorption (p = 0.029) accompanied by a tendency for more new bone ingrowth (although not statistically significant) compared to the BL® group. The addition of DEXGEL to BL® granules did not compromise bone volume or density, being even beneficial for implant primary stability (p = 0.017). Conclusions: The hydrogel-reinforced biomaterial exhibited an easier handling, a better defect filling, and benefits in implant stability. Clinical relevance: This study validates DEXGEL Bone safety and performance as an injectable carrier of granular bone substitutes for alveolar ridge preservation. Trial registration: European Databank on Medical Devices (EUDAMED) No. CIV-PT-18–01-02,705; Registo Nacional de Estudos Clínicos, RNEC, No. 30122. [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. [ABSTRACT FROM AUTHOR]

Despite the vast interest in utilizing rolling circle amplification (RCA)-based DNA networks for bioapplications, precise control of the mechanical and physicochemical properties is highly challenging. To address this concern, we aimed to develop ultrasoft self-supporting polymerized DNA networks (pDNets) of variable crystallinities to manipulate sequence-mediated drug release efficiency. A controlled ratio of the inorganic magnesium pyrophosphate (MgPPi) crystal to the organic polymeric DNA resulted in the synthesis of pDNets of various nanoporosities. The number of crystal microstructures influencing drug localization and release pattern and the tunable mechanical properties influencing injectability and structural stability under physiological conditions were investigated. The pDNets exhibited ultrasoft properties with Young's moduli of 0.06–0.54 Pa; approximately 9-fold differences in mechanical properties were obtained by varying the degree of crystallinity. With functional DNA sequences, the developed platforms showed pH stimuli-responsive drug release profiles of the dynamic DNA structures and aptamer-specific cell target adhesion efficiency. Analyses of controlled delivery of anticancer therapeutics in vitro and in vivo revealed crystallinity-dependent antitumor efficacy without side effects. This strategy provides an effective one-pot enzymatic polymerization methodology and a favorable microenvironment for a three-dimensional DNA network based on demand-localized drug delivery. Macroscale polymeric DNA networks with different crystallinities were synthesized using rolling circle amplification with varying DTT ratios for localized drug delivery. Functional DNA structures such as pH-responsive i-motif and cell-targeting aptamer were incorporated, and crystallinity-dependent effects such as injectable mechanical property, enzyme reaction and drug release kinetics, physiological stability, efficacy of dynamic DNA structure, and in vivo controlled drug delivery were investigated. [Display omitted] • DTT:MgCl 2 ratio control leads to crystallinity control of DNA networks during RCA. • Crystallinity-controlled DNA networks exhibited ultrasoft injectable properties. • Dynamic DNA structure formation is significantly influenced by the crystallinity. • Drug loading and release profiles were controlled by the MgPPi crystallinity. • In vitro and in vivo antitumor efficacy was dependent on the MgPPi crystallinity. [ABSTRACT FROM AUTHOR]

The typical symptoms of arthritis are inflammation and lubrication deficiency in joints, which increase wear of articular cartilage along with pain of patients. In the present study, one kind of novel macromolecular/microsphere-based injectable hydrogels (CMC-ODex NPs) with dual functionalities of drug release and lubrication, was fabricated via dynamic Schiff base crosslinking network between carboxymethyl chitosan (CMC) and oxidation dextran nanoparticles (ODex NPs). The CMC-ODex NPs hydrogels exhibited typical viscosity-thinning phenomenon at wide range of shear rates and obvious gel-sol transition feature at specific strain. As a result, CMC-ODex NPs hydrogels presented low friction coefficient at the sliding interface of bovine articular cartilages, resulting from the boundary lubrication of hydrogel and the rolling friction effect of ODex NPs. Furthermore, the anti-inflammatory drug (dexamethasone, DXM) encapsulated in ODex NPs exhibited sustainable drug release behavior during the dynamic shearing process, which making CMC-ODex NPs hydrogels possessed good and stable anti-inflammatory effect. CMC-ODex NPs hydrogels was prepared without utilizing any toxic agents, thus demonstrated excellent cytocompatibility. Our experimental results reveal the CMC-ODex NPs hydrogels is promising to be used as functional lubricant for inhibiting the development of arthritis. [Display omitted] • A novel injectable hydrogels (CMC-ODex NPs) with dual functionalities of drug release and water lubrication is prepared. • CMC-ODex NPs hydrogels was formed by applying dynamic Schiff base reaction between drugs-loaded ODex NPs and CMC. • The dynamic crosslinking network of CMC-ODex NPs hydrogels makes it present typical gel-sol transition behavior under shearing. • CMC-ODex NPs hydrogels exhibit good lubrication performance, sustained drug release and good biocompatibility. [ABSTRACT FROM AUTHOR]

Granular polymer hydrogels based on dynamic covalent bonds are attracting a great deal of interest for the design of injectable biomaterials. Such materials generally exhibit shear-thinning behavior and properties of self-healing/recovery after the extrusion that can be modulated through the interactions between gel microparticles. Herein, bulk macro-hydrogels based on thiolated-hyaluronic acid were produced by disulphide bond formation using oxygen as oxidant at physiological conditions and gelation kinetics were monitored. Three different thiol substitution degrees (SD%: 65%, 30% and 10%) were selected for hydrogel formation and fully characterized as to their stability in physiological medium and morphology. Then, extrusion fragmentation technique was applied to obtain hyaluronic acid microgels with dynamic disulphide bonds that were subsequently sterilized by autoclaving. The resulting granular hyaluronic hydrogels were able to form stable filaments when extruded through a syringe. Rheological characterization and cytotoxicity tests allowed to assess the potential of these materials as injectable biomaterials. The application of extrusion fragmentation for the formation of granular hyaluronic hydrogels and the understanding of the relation between the autoclaving processes and the resulting particle size and rheological properties should expand the development of injectable materials for biomedical applications. [ABSTRACT FROM AUTHOR]

Injectable self‐healing hydrogels have found broad applications in drug delivery, tissue engineering and controlled 3D cell culture. In this article, the coordination interaction between polymer‐bearing imidazole groups and Mg2+ ions "trapped" in Laponite, has been employed to develop an injectable self‐healing nanocomposite hydrogel. The properties and gelation mechanism of the hydrogel have been characterized and demonstrated by rheology, TEM, XRD, SEM, and NMR in particular. The hydrogel exhibits swift self‐healing performance without waiting for long time or elevated temperature. In particular, the present hydrogel can be applied in harsh alkaline environments, exhibiting a great advantage over traditional metal ion crosslinked hydrogels. The injectable self‐healing hydrogels based on the coordination interaction between Laponite and polymer have been rarely reported. Our research may make contributions not only to the design but also to the potential application of the hydrogels in a range of harsh alkaline environments, especially in enhanced oil recovery (EOR). [ABSTRACT FROM AUTHOR]

Enzymatically catalyzed cross-linking is a hydrogel fabrication method that generally is considered to have lower cytotoxicity than traditional chemical cross-linking methods. In order to optimize the properties of injectable hydrogels and expand their applications, an enzyme-catalyzed cross-linked injectable hydrogel was designed. The tyramine-modified gelatin (G-T) was formed into a stable injectable hydrogel by the combination of horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) catalysis. 1H NMR spectroscopy was used to demonstrate the successful modification of gelatin by tyramine. The surface morphology of the prepared hydrogels was characterized jointly by atomic force microscopy (AFM) and scanning electron microscopy (SEM). Rheological tests demonstrated the tunable mechanical strength, formation kinetics, shear thinning and good self-recovery properties of the hydrogels. In addition, the hydrogels can be formed into various shapes by injection. The hydrogel network structure is complex and interlaced, as such it is suitable to encapsulate drugs for controlled release. The drug release from the prepared hydrogels followed the Peppas–Sahlin model and belonged to Fickian diffusion. This study constructed injectable hydrogels through the enzyme-catalyzed cross-linking of modified gelatin and applied the hydrogels for drug release, which is expected to expand the application in biomedical fields. This work reports an enzyme-catalyzed cross-linking of injectable hydrogels. Tyramine-modified gelatin is used as the raw material, and horseradish peroxidase and H2O2 are added to catalyze the cross-linking to form an injectable hydrogel. The hydrogel can be used for drug release which will broaden the application of hydrogels in biomedical fields. [ABSTRACT FROM AUTHOR]

Conductive hydrogels are promising materials in bioelectronics that ensure a tissue-like soft modulus and re-enact the electrophysiological function of damaged tissues. However, recent approaches to fabricating conductive hydrogels have proved difficult: fixing of the conductive hydrogels on the target tissues hydrogels requires the aids from other medical glues because of their weak tissue-adhesiveness. In this study, an intrinsically conductive and tissue-adhesive granular hydrogel consisting of a PEDOT:PSS conducting polymer and an adhesive catechol-conjugated alginate polymer was fabricated via an electrohydrodynamic spraying method. Because alginate-based polymers can be crosslinked by calcium ions, alginate-catechol polymers mixed with PEDOT:PSS granular hydrogels (ACP) were easily fabricated. The fabricated ACP exhibited not only adhesive and shear-thinning properties but also conductivity similar to that of muscle tissue. Additionally, the granular structure makes the hydrogel injectable through a syringe, enabling on-tissue printing. This multifunctional granular hydrogel can be applied to soft and flexible electronics to connect humans and machines. [ABSTRACT FROM AUTHOR]

Overproduction of reactive oxygen species is one of the important reasons of non-healing wounds, such as diabetic wounds. Melatonin is well known as an antioxidant, while the poor solubility limits its use in many areas. In this study, the solubility of melatonin was improved by introducing γ-cyclodextrin to form the composite named MT-γ-CD through ultrasonic process. During this process, the molar ratio of melatonin and γ-cyclodextrin was 2:1, the temperature was set at 30 ℃, and the ultrasonic time was 40 min. The MT-γ-CD showed good antioxidant property in vitro with high free radical scavenging efficiency over 90%. Besides, an injectable self-healing hydrogel was prepared to load with MT-γ-CD to form the wound dressing, here, sodium carboxymethylated cellulose was oxidized to introduce aldehyde groups that could form Schiff base with amino groups in gelatin. This dressing with good biocompatibility could be injected into irregular wounds, suppress the level of reactive oxygen species, and accelerate wound healing of diabetic rats in vivo. Therefore, it has great potential to provide a new treatment strategy for diabetic wounds. [ABSTRACT FROM AUTHOR]

Silk fibroin is regarded as a promising biomaterial in various areas, including bone tissue regeneration. Herein, Laponite® (LAP), which can promote osteogenic differentiation, was introduced into regenerated silk fibroin (RSF) to prepare an RSF/LAP hybrid hydrogel. This thixotropic hydrogel is injectable during the operation process, which is favorable for repairing bone defects. Our previous work demonstrated that the RSF/LAP hydrogel greatly promoted the osteogenic differentiation of osteoblasts in vitro. In the present study, the RSF/LAP hydrogel was found to have excellent biocompatibility and significantly improved new bone formation in a standard rat calvarial defect model in vivo. Additionally, the underlying biological mechanism of the RSF/LAP hydrogel in promoting osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) was extensively explored. The results indicate that the RSF/LAP hydrogels provide suitable conditions for the adhesion and proliferation of BMSCs, showing good biocompatibility in vitro. With the increase in LAP content, the alkaline phosphatase (ALP) activity and mRNA and protein expression of the osteogenic markers of BMSCs improved significantly. Protein kinase B (AKT) pathway activation was found to be responsible for the inherent osteogenic properties of the RSF/LAP hybrid hydrogel. Therefore, the results shown in this study firmly suggest such an injectable RSF/LAP hydrogel with good biocompatibility (both in vitro and in vivo) would have good application prospects in the field of bone regeneration. [ABSTRACT FROM AUTHOR]

Currently, hydrogels are widely studied for wound dressings. However, wound healing is often hindered by bacterial infection. In this study, in situ cross-linked carboxymethyl chitosan (CMCS)/oxidized dextran (OD)/poly-γ-glutamic acid (γ-PGA) (COP) hydrogel was prepared for antimicrobial and hemostasis of diffuse wounds. In the COP hydrogel, γ-PGA was able to drain the surface moisture of the wound to enhance the surface adhesion. Moreover, γ-PGA could concentrate blood by absorbing plasma, and CMCS could electrostatically adsorb negative RBCs. The antibacterial properties of CMCS and OD endowed the COP hydrogel with certain antibacterial effects. In the inhibition zone experiment, an obvious inhibition zone appeared around the COP hydrogel. In vivo studies showed that the COP hydrogel significantly inhibited bacterial growth and promoted wound healing. In the rat tail diffuse hemorrhage wound model, the COP hydrogel showed superior hemostasis ability. Therefore, the multifunctional COP hydrogel is expected to find different applications in wound hemostasis and healing. [ABSTRACT FROM AUTHOR]

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 (PNIPAAmg-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. [ABSTRACT FROM AUTHOR]

Development of an injectable hemostatic for treating noncompressible or irregularly shaped bleeding wounds remains a pressing medical need. Herein, we report an injectable thermogelling chitosan/glycerophosphate formulation that enhances gel-forming capacity and wet tissue adherence by incorporation of dihydrocaffeic acid (DHCA). This was found to decrease gelation time by >2 times around 37 °C while increasing hydrogel internal network structure, with its tissue adhesive strength >2 times greater than that of the non-composite hydrogel or previously reported. The thermosensitive hydrogels significantly reduce whole blood coagulation time in vitro and both hemostasis time and blood loss in vivo using rat hepatic hemorrhage and tail amputation models. These improvements are biocompatible, without adversely affecting cell viability, blood components, biodegradability, or introducing notable inflammation, thus enabling injury healing. Moreover, our results displayed the potential of a facile approach to enhance thermogelling and bioadhesion of chitosan-based hydrogels via noncovalent supramolecular mechanisms. [ABSTRACT FROM AUTHOR]

With the development of minimally invasive orthopedics, injectable materials for bone repair are attracted more attention, especially for those wound with a small external mouth and sizeable internal cavity. In this work, the hydrogel with features of thermo-responsiveness, degradability and injectability was designed and fabricated. The hydrogel, named as FHCS, is composed of Pluronic F-127 (F127) loaded with carboxymethyl chitosan/sodium alginate nanoparticles (nCS) and nanohydroxyapatite (nHA). The hydrogel FHCS was non-toxic and good hemocompatible. It can enhance the ALP activity and extracellular matrix calcification of MC3T3-E1 due to the chitosan-based nanoparticle components (nCS). Moreover, FHCS-5 (containing 5 mg/mL nCS) showed relative high expression of osteogenic genes and protein markers. Osteal regeneration was observed treated by FHCS-5 hydrogel in a critical-size rat calvarial bone defect model. CT scanning showed that the whole defect was basically covered by new bone after FHCS-5 hydrogel. The results of H&E staining and Masson's trichrome staining on histological sections further confirmed that FHCS-5 hydrogel promoted new osteal formation and maturation, which up regulated the osteogenic related genes and proteins of ALP, OCN, OPN through BMP/Smad signaling pathway. Hence, this study suggests that FHCS-5 hydrogels have a promising application for non-loading bone regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

A drawback in the development of treatments that can reach the retina is the presence of barriers in the eye that restrain compounds from reaching the target. Intravitreal injections hold promise for retinal delivery, but the natural defenses in the vitreous can rapidly degrade or eliminate therapeutic molecules. Injectable hydrogel implants, which act as a reservoir, can allow for long-term drug delivery with a single injection into the eye, but still suffer due to the fast clearance of the released drugs when traversing the vitreous and random diffusion that leads to lower pharmaceutic efficacy. A combination with HA-covered nanoparticles, which can be released from the gel and more readily pass through the vitreous to increase the delivery of therapeutic agents to the retina, represents an advanced and elegant way to overcome some of the limitations in eye drug delivery. In this article, we developed hybrid PLGA-Dotap NPs that, due to their hyaluronic acid coating, can improve in vivo distribution throughout the vitreous and delivery to retinal cells. Moreover, a hydrogel implant was developed to act as a depot for the hybrid NPs to better control and slow their release. These results are a first step to improve the treatment of retinal diseases by protecting and transporting the therapeutic treatment across the vitreous and to improve treatment options by creating a depot system for long-term treatments. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hydrogel is a three-dimensional structure that has the potential to absorb and retain water within the mesh of its porous network structure. Currently hydrogels made from natural biopolymers are preferred in the discipline of biomedical applications because of their blood compatibility, adhesion of platelets and protein binding, ease of administration and delivery of ingredients to the place of action. OBJECTIVE: The aim of this work was to prepare a hydrogel from natural biopolymers and evaluate its blood compatibility, swelling nature, prolonged degradation and morphological features in order to further recommend its clinical use. METHODS: To prepare hydrogels, different combinations of gelatin, dialyzed SF, curcumin and N, N methylene bisacrylamide (MBA) were evenly mixed on a magnetic stirrer. After an hour of the gelation process it was kept in a refrigerator at 4 °C. For the characterization and biocompatibility studies of hydrogel, the swelling test and biodegradation analysis, SEM, FTIR, in vitro coagulation tests, total serum albumin and cholesterol level analysis were applied. RESULTS: Injectable hydrogels were successfully made with significantly correlated combinations of polymers. The analysis of physiochemical biocompatibility studies and morphological characterization were done effectively. CONCLUSION: The results of the study indicate that hydrogels made from natural biopolymers are a potential source and suitable matrices with excellent biocompatible nature acting as a useful device in delivering drugs. [ABSTRACT FROM AUTHOR]

The management of wound infection remains the major challenges in real-time diagnosis, effective bacterial elimination and rapid wound healing. Herein, we developed injectable theranostic hydrogels to achieve long-term visual imaging of infected wounds and possible infection recurrence and to launch an on-demand bactericidal effect without using any antibiotics. Antimicrobial peptide ε-polylysine (ePL)-derived hydrogels were prepared through the copolymerization of methacrylated ePL (mPL) and the conjugates with tetrakis(4-carboxyphenyl) porphyrin (mPL-TCPP) and phenol red (mPL-Pr). Light illumination of mPL-TCPP produces reactive oxidative species (ROS) to initiate free radical crosslinking into PL@Pr-TCPP hydrogels without using any additional photoinitiators and concurrently exhibits antibacterial photodynamic therapy (PDT). PL@Pr-TCPP hydrogels experience quick color changes from yellow to orange and finally to red when pH values change from 5.0 to 9.0. The actual pH and related bacterial levels in the wounds could be read from G/B signal ratios of hydrogel colors captured by a smart phone. The conjugation of phenol red and TCPP into hydrogels affords a robust bacterial infection diagnosis and persistent bactericidal effect after cycled light illumination. The bacterial capture by ePL hydrogels strengthens PDT effect through alleviating the short lifetime and action distance of ROS. On a Staphylococcus aureus -infected abscess model, light illumination of the pregel solutions achieves in situ formation of hydrogel dressings. The synergistic bactericidal performance significantly relieves inflammatory status, accelerates collagen deposition, and promotes neovascularization, leading to full recovery of the infected wounds with regeneration of skin accessories. PL@Pr-TCPP hydrogels on the wound bed show color changes upon the recurrence of bacterial infection, which could also be totally eliminated after light illumination. Therefore, this study demonstrates a feasible strategy to develop theranostic hydrogel dressings for life-cycle diagnosis and on-demand treatment of wound infections. Over 30% of skin and soft tissue infections become chronic even after appropriate antibacterial treatment, and recurrent infections are commonly reported after initial infection. Challenges remain in the development of theranostic wound dressings having the capability of point-of-care diagnosis, life-cycle monitoring and on-demand elimination of bacterial infection. Herein, light-triggered gelation is used to develop theranostic hydrogels for reversible naked-eye diagnosis and on-demand photodynamic therapy of wound infections. Light illumination plays a "one-stone-two-birds" role, i.e., photodynamically produced reactive oxidative species enable bactericidal effect without using any antibiotics, and the generated free radicals initiate crosslinking of hydrogels without using any additional photoinitiators. Bacterial infection-activated color changes of hydrogels could be captured with a smart phone for on-site and persistent monitoring of bacterial infection and wound healing process. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Diabetic wound (DW) is the most devastating complication resulting in significant mortality and morbidity in diabetic patients. The objective of the current study was to formulate Epidermal Growth Factor loaded Chitosan nanoparticle impregnated with thermos-responsive injectable hydrogel with protease inhibitor. EGF, shown in all stages of wound healing from inflammation to proliferation and remodelling, combined with Doxycycline, a well-known anti-inflammatory and anti-bacterial drug, could be a better strategy in diabetic wound healing. However, EGF's low stability makes it difficult to use. Methodology: The nanoparticles were prepared using the ionic gelation method. The prepared nanoparticles were evaluated for particle size, zeta potential, entrapment efficiency, and SEM studies. Further, the optimized nanoparticle batch was loaded into hydrogel with a protease inhibitor. The hydrogel was evaluated for morphology, protease degradation, in vitro drug release, anti-bacterial activity, cell migration, in vitro cell biocompatibility, and in vivo wound healing studies. Results and Conclusion: The particle size analysis of nanoparticles revealed the size (203 ± 1.236 nm), Zeta potential (+28.5 ± 1.0 mV), and entrapment efficiency of 83.430 ± 1.8%, respectively. The hydrogel showed good porous morphology, injectability, thermo-responsive, biocompatibility, and controlled drug release. In vitro anti-bacterial studies revealed the potential anti-bacterial activity of doxycycline against various microbes. In vivo data indicated that combining EGF and DOX considerably reduced inflammation time-dependent than single-agent treatment. Furthermore, histological studies corroborated these findings. After topical application of hydrogel, histopathology studies revealed significant collagen synthesis and a fully regenerated epithelial layer and advancement in all three stages (proliferation, remodelling, and maturation), which are required to improve the diabetic wound healing process by any dressing. These findings demonstrated that hydrogel promoted cutaneous wound healing in STZ-induced rats by suppressing inflammation at the wound site. Furthermore, histological studies corroborated these findings. After topical application of hydrogel, histopathology studies revealed significant collagen synthesis, a fully regenerated epithelial layer, and advancement in all three stages (proliferation, remodelling, and maturation), which are required to improve the diabetic wound healing process by any dressing. These findings demonstrated that hydrogel promoted cutaneous wound healing in STZ-induced rats by suppressing inflammation at the wound site. [ABSTRACT FROM AUTHOR]

In orthopedic practice, accommodating irregular defects caused by trauma or surgery with traditional preformed bone graft substitutes is often challenging. As a result, injectable hydrogels with seed cells have garnered significant interest in bone repair due to their adaptability and minimally invasive properties. However, they cannot simultaneously achieve injectability and mechanical properties, providing a biophysical and biochemical environment for cell support. In this study, a novel injectable hydrogel system (OA hydrogel) loaded with aspirin and bone mesenchymal stem cells (BMSCs) was developed to enhance osteogenesis and immune regulation in small irregular bone defects. OA hydrogels possessed self-healing and shear-thinning properties due to dynamic/covalent hydrazone bonds between aldehyde-modified hyaluronic acid methacrylate (ADH-HAMA) and oxidized hyaluronic acid (OHA). By photopolymerization of the enclosed HAMA, the OADC hydrogel was further reinforced, making it more suitable for cell proliferation. In vitro , composite hydrogels improved the osteogenic differentiation of BMSCs. Additionally, it promoted the M2 polarization of human monocytic leukemia (THP-1) cells. In vivo , the synergistic effect of acetylsalicylic acid (ASA) and BMSCs encapsulated within the OADC hydrogel promoted new bone formation in rat calvaria through increased recruitment and polarization of M2 macrophages. These findings underscore the significant promise of hydrogels for bone tissue engineering applications. [ABSTRACT FROM AUTHOR]

Although biological scaffolds containing bone morphogenetic protein-2 (BMP-2) have been widely used for osteogenic therapy, achieving stable and controlled release of BMP-2 remains a challenge. Herein, a novel BMP-2 sustained-release system composed of carboxymethyl chitosan (CMCS)/polyethylene glycol (PEG)/heparin sulfate (HS) (CMCS/PEG/HS) was constructed with a Schiff base reaction, yielding an injectable hydrogel for the release of BMP-2 in a controlled manner. For the CMCS/PEG/HS/BMP-2 hydrogel, the HS component had a negatively charged structure, which can bind to positively charged growth factors and prevent early hydrolytic metabolism of growth factors, thus achieving sustainable release of BMP-2. Notably, the release of BMP-2 in hydrogels was dependent mainly on degradation of the hydrogel matrix rather than simple diffusion. Generally, the CMCS/PEG/HS/BMP-2 hydrogel scaffold demonstrated excellent recoverability, good injectability, excellent biocompatibility and high adaptability, as well as efficient self-healing features to occupy irregularly shaped bone marrow cavities. The in vitro results revealed that the CMCS/PEG/HS/BMP-2 hydrogel promoted the osteogenic differentiation of MC3T3-E1 cells. Furthermore, the in vivo results suggest that the hydrogel has promising osteogenic effects that promote bone regeneration in a skull bone defect model. The injectable hydrogel scaffold shows great promise for bone treatment in the future. [ABSTRACT FROM AUTHOR]

The rising prevalence of global antibiotic resistance evokes the urgent requirement to explore the alternative antimicrobial candidates. It is of great significance to overcome these serious threats of multidrug-resistant bacterial infections and difficult-to-heal cutaneous wounds to human health. Herein, we proposed a rapidly in situ forming innovative antibiotic-free hydrogel dressing with excellent biocompatibility, easy injectability, strong tissue adhesion and superior antibacterial activity against drug-resistant bacteria. An octa-armed poly(ethylene glycol) amine (Octa-PEG-NH 2) was quickly crosslinked with a green industrial microbicide tetrakis (hydroxymethyl) phosphonium chloride (THPC) to form an antibacterial hydrogel (OPTH) by simple mixing without any other initiators or crosslinkers. A significant broad-spectrum antibacterial efficacy was demonstrated against Gram-positive Staphylococcus aureus (S. aureus), Gram-negative Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA). Significantly, benefiting from its flexible injectability and reliable tissue adhesion, the excellent antibacterial performances were further evidenced by employing human-induced pluripotent stem cell (iPSC)-derived skin organoids in a 3D culture system and rat animal wound models in vivo with MRSA infection, thus allowing for reepithelization promotion and wound healing. Collectively, the findings not only propose a facile gelatinization strategy for readily accessible antibiotic-free hydrogel dressings for effective MRSA therapy but also hold great clinical translation potential in obliterating multi-pathogenic bacteria and accelerating wound healing. An antibiotic-free hydrogel dressing with easy injectability, excellent biocompatibility and strong tissue adhesion displays superior broad-spectrum antibacterial efficacy and promoting wound healing. [Display omitted] [ABSTRACT FROM AUTHOR]

Breast cancer is a malignant tumor that poses a significant threat to women's health and single therapy fails to play a good oncological therapeutic effect. Synergistic treatment with multiple strategies may make up for the deficiencies and has gained widespread attention. In this study, sulfhydryl-modified hyaluronic acid (HA-SH) was covalently crosslinked with polydopamine (PDA) via a Michael addition reaction to develop an injectable hydrogel, in which PDA can be used not only as a matrix but also as a photothermal agent. After HSA and paclitaxel were spontaneously organized into nanoparticles via hydrophobic interaction, hyaluronic acid with low molecular weight was covalently linked to HSA, thus conferring effectively delivery. This photothermal injectable hydrogel incorporates PTX@HSA-HA nanoparticles, thereby initiating a thermochemotherapeutic response to target malignancy. Our results demonstrated that this injectable hydrogel possesses consistent drug delivery capability in a murine breast cancer model, collaborating with photothermal therapy to effectively suppress tumor growth, represented by low expression of Ki-67 and increasing apoptosis. Photothermal therapy (PTT) can effectively stimulate immune response by increasing IL-6 and TNF-α. Notably, the treatment did not elicit any indications of toxicity. This injectable hydrogel holds significant promise as a multifaceted therapeutic agent that integrates photothermal and chemotherapeutic modalities. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Injectable bioadhesives with sealing and anti-fouling properties for anti-adhesion were engineered. • Sealing property interrupts the adhesion cascade resulted from the leakage of severe wounds. • Anti-fouling property further prevents the accumulation of inflammatory cells and fibroblasts. • The bioadhesives exhibited strong resistance of foreign body reaction. • The bioadhesives effectively prevented tissue adhesion in rat cecum-sidewall adhesion and rabbit laminectomy models. Postoperative adhesion is a common complication that follows various types of surgeries, causing patients suffering and increasing healthcare costs. Current anti-adhesion barriers fail to provide satisfactory therapeutic outcomes mainly due to their weak retention, inability to prevent fluid leakage, and potential foreign body reactions. In the present study, we fabricated a serine-modified bioadhesive (SESAgel) with improved sealing and anti-fouling properties for postoperative adhesion prevention. The resulting SESAgel exhibited good injectability and in-situ adhesion ability, forming a stable membranous anti-adhesion barrier on the wound surface. Innovatively, it possessed efficient sealing properties, effectively stopping the leakage of tissue fluid and blood, which triggers tissue adhesion formation in the early stage. On this basis, the anti-fouling property derived from the serine in this physical barrier can further prevent the accumulation of inflammatory cells and foreign body reactions, thereby minimizing tissue adhesion. Two animal models were used to demonstrate that SESAgel effectively inhibited postoperative adhesion in different surgeries. With its natural design and good biocompatibility, SESAgel is a promising anti-adhesion biomaterial for clinical translation and practice. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) infections pose great challenges to skin wound care due to the severe drug resistance developed in the clinic. There is an urgent need to exploit next-generation bactericidal therapeutics that are both antibiotic-free and multifunctional for enhanced wound healing. Herein, we designed a Ca2+-crosslinked alginate hydrogel (EcNSIN@Alg) containing two naturally derived bioactive components, probiotics Escherichia coli Nissle1917 (EcN) and Squid ink nanoparticles (SIN), to treat MRSA-infected wounds. The injectable composite hydrogel displayed excellent biocompatibility, photothermal antibacterial activity, and reactive oxygen species (ROS) scavenging property. Importantly, the probiotic EcN can enhance the photothermal SIN to promote immune regulatory activities, shifting pro-inflammatory macrophages (M1) to anti-inflammatory macrophages (M2). In an MRSA-infected abscess model, EcNSIN@Alg can reduce the expression level of wound inflammatory factors and ROS, increase the number of anti-inflammatory macrophages, accelerate collagen deposition and promote wound healing. This work offers a new perspective on developing safe, antibiotic-free, multifunctional bactericides using fully bioderived materials, with potential applications in clinical practice. • An injectable alginate hydrogel containing probiotics and Squid ink was designed. • The hydrogel displayed excellent photothermal antibacterial property. • The hydrogel showed antioxidant, enhanced proliferating, and immune regulating properties. • The hydrogel could treat MRSA infected wounds in multiple stages. [ABSTRACT FROM AUTHOR]

Skin wound dressings are commonly utilized for the treatment of skin injuries, as they effectively facilitate wound healing and possess anti-inflammatory and antibacterial properties. However, conventional dressings fail to inhibit ROS production and promote vascularization, leading to delayed wound healing. Here, we developed injectable self-crosslinking hydrogels through thiolated hyaluronic acid (HASH/rhCOLIII) with enhancing the ROS inhibitory capacity while preserving the cell adhesion ability of hyaluronic acid. Additionally, recombinant humanized collagen type III (rhCOLIII) is incorporated via electrostatic adsorption to further enhance mechanical strength and angiogenesis properties of the hydrogel. The HASH/rhCOLIII demonstrated excellent biocompatibility, remarkable ROS scavenging ability, as well as hemostatic and angiogenic properties. Cell experiment results show that HASH/rhCOLIII has excellent biocompatibility and can significantly promote angiogenesis. Animal experiments results showed that HASH/rhCOLIII exhibits anti-inflammatory effects, significantly accelerating wound healing in a full-thickness skin defect model. These findings highlight that HASH/rhCOLIII hydrogel holds great promise as an advanced dressing for effective wound healing. [ABSTRACT FROM AUTHOR]

[Display omitted] • PDA reinforced injectable hydrogel was prepared by hydrazone bonds formation. • The hydrogel had the dual properties for both adsorption and catalytic purposes. • The hydrogel showed high adsorption capacity of Cu2+, Pb2+ and Cd2+. • Microscopic understanding of water adsorption systems was investigated. • The adsorbed Cu2+ could be reduced to make the hydrogel with catalytic ability. By in situ generation of hydrazone bonds, a composite hydrogel that combines poly(N-isopropylacrylamide) and carboxymethyl cellulose and is reinforced with PDA nanoparticles was successfully prepared for injectable use, and was employed to treat metal ions in aqueous solutions. The composite hydrogels presented desirable compressive strength and anti-fatigue performance. The adsorption capacities of Cu2+, Pb2+ and Cd2+ reached high values of 193.8, 168.8 and 112.6 mg/g, respectively, in a single-ion adsorption system, due to the plentiful adsorptive sites on the hydrogels. The adsorption kinetics followed the Pseudo-second-order model, while the adsorption isotherm adhered to the Langmuir model. Besides, the hydrogels showed slightly higher selectivity for Cu2+ in an adsorption system involving multiple ions, and exhibited good reusability, enabling it to be employed repeatedly as a recyclable adsorbent. The analysis of the mechanism indicated that ion exchange, electrostatic interaction, chemical adsorption and coordination effect might occurred between metal ions and functional groups in hydrogel matrix and PDA nanopartiles. Moreover, the Cu2+-adsorbed hydrogels could act as a scaffold for the on-site generation of Cu nanoparticles. With the Cu nanoparticles, the hydrogels showed catalytic activity of ∼ 80 % conversion of 4-nitrophenol (1 mmol) to 4-aminophenol in 30 min, validating the dual functional properties for both adsorption and catalytic purposes in the treatment of wastewater. [ABSTRACT FROM AUTHOR]

[Display omitted] • HA-PDRN crosslinked hydrogels were fabricated by the covalently connecting the carboxyl groups of HA to amino groups of PDRN. • HA-PDRN crosslinked hydrogel demonstrated good viscoelasticity, appearance, hydration, degradation, injection, and biocompatibility. • Compared to the HA crosslinked hydrogel, HA-PDRN crosslinked hydrogel was more biocompatible and produced more collagen. • Injectable HA-PDRN crosslinked hydrogel offers considerable promise for use as a dermal filler. Injectable hydrogels, commonly utilized as dermal fillers, show great potential for increasing tissue volume and correcting wrinkles. HA (hyaluronic acid), extensively used in dermal fillers, requires considerable modifications to meet commercial demands for effectiveness and functionality. PDRN (polydeoxyribonucleotides), DNA extracted from salmon sperm cells, offer several therapeutic benefits, including anti-inflammatory and collagen stimulation. This work presents a new crosslinked hydrogel based on HA and PDRN. HA-PDRN crosslinked hydrogels were fabricated via covalent interactions between the carboxyl groups of HA and amino groups of PDRN, resulting in desirable properties such as viscoelasticity, appearance, hydration, degradation, injectability, and biocompatibility. In vivo studies on mice revealed that these hydrogels maintain volume for over 24 weeks, with reduced inflammation and enhanced collagen synthesis, as well as exhibiting durability, safety, and supportability. [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.

Inflammatory responses of nucleus pulposus (NP) can induce imbalanced anabolism and catabolism of extracellular matrix, and the cytosolic dsDNA accumulation and STING–NF–κB pathway activation found in NP inflammation are considered as fairly important cause of intervertebral disc (IVD) degeneration. Herein, we constructed a siSTING delivery hydrogel of aldehyde hyaluronic acid (HA-CHO) and poly(amidoamine) PAMAM/siRNA complex to intervene the abnormal STING signal for IVD degeneration treatment, where the formation of dynamic Schiff base bonds in the system (siSTING@HPgel) was able to overcome the shortcomings such as low cellular uptake, short half-life, and rapid degradation of siRNA-based strategy. PAMAM not only formed complexes with siRNA to promote siRNA transfection, but also served as dynamic crosslinker to construct hydrogel, and the injectable and self-healing hydrogel efficiently and steadily silenced STING expression in NP cells. Finally, the siSTING@HPgel significantly eased IVD inflammation and slowed IVD degeneration by prolonging STING knockdown in puncture-induced IVD degeneration rat model, revealing that STING pathway was a therapeutic target for IVD degeneration and such novel hydrogel had great potential for being applied to many other diseases for gene delivery.

Background/Objective: Intervertebral disc (IVD) degeneration (IVDD) that greatly affected by regional biomechanical environment is a major cause of low back pain. Injectable hydrogels have been commonly studied for treatment of IVDD due to their capability of mimicking extracellular matrix structure to support cellular behavior and clinical prospects in minimally invasive treatment. However, most hydrogels suffer from complicated chemistry, potential uncertainty and toxicity from in-situ gelation, and mismatch with IVD mechanical environment that limit their therapeutic effects or clinical translation in IVDD or intervertebral disc defect repair. For IVD lesion repair, the study aims to develop a novel hydrogel with shear-thinning enabled injectability, high bio-safety, and mechanical properties adaptable to the IVD environment, using a simple chemistry and method. And therapeutic efficacy of the novel hydrogel in the treatment of IVDD or intervertebral disc defect will be revealed. Methods: A glycerol cross-linked PVA gel (GPG) was synthesized based on multiple H-bonds formation between glycerol molecules and PVA chains. The rheological and mechanical properties were tested. The swelling ratio was measured. The micro-architecture was observed through scanning and transmission electron microscopes. Nucleus pulposus (NP) cells were cultured in GPG-coated plates or silicone chambers treated under hydrostatic or dynamic loading in vitro, and examined for proliferation, vitality, apoptosis, expression of catabolic and anabolic markers. GPG was injected in needle puncture (IDD) or NP discectomy (NPD) models in vivo, and examined through magnetic resonance imaging, micro-computed tomography scanning and histological staining. Results: GPG had a highly porous structure consisting of interconnected pores. Meanwhile, the GPG had NP-like viscoelastic property, and was able to withstand the cyclic deformation while exhibiting a prominent energy-dissipating capability. In vitro cell tests demonstrated that, the hydrogel significantly down-regulated the expression of catabolic markers, maintained the level of anabolic markers, preserved cell proliferation and vitality, reduced apoptotic rate of NP cells under pathologically hydrostatic and dynamic loading environments compared to cells cultured on untreated plate or silicone chamber. In vivo animal studies revealed that injection of GPG efficiently maintained NP structural integrity, IVD height and relative water content in IDD models, and stimulated the fibrous repair in NPD models. Conclusion: This study showed that GPG, with high injectability, NP-like viscoelastic characteristics, good energy-dissipating properties and swelling capacities, preserved NP cells vitality against pathological loading, and had therapeutic effects on IVD repair in IDD and NPD models. The translational potential of this article: Effective clinical strategy for treatment of intervertebral disc degeneration (IVDD) is still lacking. This study demonstrates that injection of a hydrogel with nucleus pulposus-matched viscoelastic property could remarkably prevent the IVDD progress. Prepared with simple chemistry and procedure, the cell/drug-free GPG with high bio-safety and shear-thinning enabled injectability bears great translational potential for the clinical treatment of IVDD via a minimally invasive approach.

Cardiovascular diseases such as myocardial infarction (MI) are among the major causes of death worldwide. Although intramyocardial injection of hydrogels can effectively enhance the ventricular wall, this approach is limited because of its restriction to the poor vascularization in the infarcted myocardium. Here, we reported a new type of hydrogel composed of alginate (ALG) and hyaluronic acid (HA) with lyophilized platelet-rich fibrin (Ly-PRF) for releasing abundant growth factors to realize their respective functions. The results of in vitro studies demonstrated favorable mechanical property and release ability of ALG-HA with Ly-PRF. When injected into the infarcted myocardium, this composite hydrogel preserved heart function and the Ly-PRF within the hydrogel promoted angiogenesis and increased vascular density in both infarcted and border zone, which rescued the ischemic myocardium. These beneficial effects were also accompanied by macrophage polarization and regulation of myocardial fibrosis. Moreover, the autologous origin of Ly-PRF with ALG-HA hydrogel offers myriad advantages including safety profile, easiness to obtain and cost-effectiveness. Overall, this study demonstrated the versatile therapeutic effects of a novel composite hydrogel ALG-HA with Ly-PRF, which optimizes a promising vascularized substitution strategy for improving cardiac function after MI.

Abstract 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.

Features of black phosphorous (BP) nano sheets such as enhancing mineralization and reducing cytotoxicity in bone regeneration field have been reported. Thermo-responsive FHE hydrogel (mainly composed of oxidized hyaluronic acid (OHA), poly-ε-L-lysine (ε-EPL) and F127) also showed a desired outcome in skin regeneration due to its stability and antibacterial benefits. This study investigated the application of BP-FHE hydrogel in anterior cruciate ligament reconstruction (ACLR) both in in vitro and in vivo, and addressed its effects on tendon and bone healing. This BP-FHE hydrogel is expected to bring the benefits of both components (thermo-sensitivity, induced osteogenesis and easy delivery) to optimize the clinical application of ACLR and enhance the recovery. Our in vitro results confirmed the potential role of BP-FHE via significantly increased rBMSC attachment, proliferation and osteogenic differentiation with ARS and PCR analysis. Moreover, In vivo results indicated that BP-FHE hydrogels can successfully optimize the recovery of ACLR through enhancing osteogenesis and improving the integration of tendon and bone interface. Further results of Biomechanical testing and Micro-CT analysis [bone tunnel area (mm2) and bone volume/total volume (%)] demonstrated that BP can indeed accelerate bone ingrowth. Additionally, histological staining (H&E, Masson and Safranin O/fast green) and immunohistochemical analysis (COL I, COL III and BMP-2) strongly supported the ability of BP to promote tendon-bone healing after ACLR in murine animal models.

Immunotherapy is a revolutionary and promising approach to cancer treatment. However, traditional cancer immunotherapy often has the disadvantages of limited immune response rate, poor targeting, and low treatment index due to systemic administration. Hydrogels are drug carriers with many advantages. They can be loaded and transported with immunotherapeutic agents, chemical anticancer drugs, radiopharmaceuticals, photothermal agents, photosensitizers, and other therapeutic agents to achieve controlled release of drugs, extend the retention time of drugs, and thus successfully trigger anti-tumor effects and maintain long-term therapeutic effects after administration. This paper reviews recent advances in injectable hydrogel-based cancer immunotherapy, including immunotherapy alone, immunotherapy with combination chemotherapy, radiotherapy, phototherapy, and DNA hydrogel-based immunotherapy. Finally, we review the potential and limitations of injectable hydrogels in cancer immunotherapy.

Wound repair remains a huge clinical challenge, which can cause bleeding, infection, and patient death. In our current research, a bioactive, injectable, multifunctional composite hydrogel doped with nanospheres was prepared with antibacterial and angiogenesis-promoting functions for the treatment of wounds. Amino groups in ε-polylysine (ε-EPL) undergo dynamic Schiff base reaction cross-linking with oxidized hyaluronic acid (OHA), and F127 exhibits unique temperature sensitivity to form an injectable thermosensitive hydrogel (FHE10), which can form a hydrogel to cover the wound at body temperature. Nanospheres (PNs) prepared using poly (glyceryl-sebacate-acrylate) (PGSA) were loaded into hydrogels (FHE10) for promoting wound repair. The prepared FHE10 exhibited rapid gelation, good injectable abilities, and showed resistance to the flourish of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). In vitro investigations showed that FHE10 had good hemocompatibility and cytocompatibility. FHE10@PNs exhibited good proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) and human foreskin fibroblasts (HFF-1). Furthermore, FHE10@PNs significantly promoted reepithelialization and collagen deposition as well as micro-vascularization compared with the use of FHE10 or PNs alone, thereby accelerating the repair of wounds. In general, this study demonstrated that the multifunctional injectable composite hydrogel showed great potential in wound treatment.

For the purpose of developing a 3D vehicle for the delivery of hepatocytes in cell therapy, the improved system of crosslinker and new gelling agent combinations consisting of glycerophosphate and sodium hydrogen carbonate have been employed to produce injectable, thermoresponsive hydrogels based on chitosan and silk fibroin. Adjusting the polymer-to-gelling agent ratio and utilizing a chemical crosslinker developed hydrogel scaffolds with optimal gelling time and pH. Applying sodium hydrogen carbonate neutralizes chitosan while keeping its thermoresponsive characteristics and decreases glycerophosphate from 60% to 30%. Genipin boosts the mechanical properties of hydrogel without affecting the gel time. Due to their stable microstructure and lower amine availability, genipin-containing materials have a low swelling ratio, around six compared to eight for those without genipin. Hydrogels that are crosslinked degrade about half as fast as those that are not. The slowerr degradation of Silk fibroin compared to chitosan makes it an efficient degradation inhibitor in silk-containing formulations. All of the optimized samples showed less than 5% hemolytic activity, indicating that they lacked hemolytic characteristics. The acceptable cell viability in crosslinked hydrogels ranges from 72% to 91% due to the decreasing total salt concentration, which protects cells from hyperosmolality. The pH of hydrogels and their interstitial pores kept most encapsulated cells alive and functioning for 24 h. Urea levels are higher in the encapsulation condition compared to HepG2 cultivated alone, and this may be due to cell-matrix interactions that boost liver-specific activity. Urea synthesis in genipin crosslinked hydrogels increased dramatically from day 1 (about 4 mg dl−1) to day 3 (approximately 6 mg dl−1), suggesting the enormous potential of these hydrogels for cell milieu preparation. All mentioned findings represent that the optimized system may be a promising candidate for liver regeneration.

Endoscopic submucosal dissection (ESD) is one of the most effective approaches for the minimally invasive treatment of early gastrointestinal cancers. Submucosal injections help safely and successfully remove lesions during ESD by elevating the mucosa and separating the submucosal muscle layer. Herein, we report dynamic injectable sodium alginate hydrogels (ISAHs) with shear-thinning for ESD surgery, which were easily fabricated by the sulfhydryl group of GSH-modified sodium alginate (SA-GSH) reacting with the aldehyde group of oxidized sodium alginate (OSA) at room temperature. ISAHs have advantageous self-healing abilities and antioxidant activity. Additionally, according to an in vitro test on porcine colorectal submucosal lifting, the submucosal elevation heights created by ISAHs were 13 % -18 % greater than those created by commercial ESD solutions (0.4 w / v % sodium hyaluronate). These properties and biocompatibility were confirmed in vitro and in vivo experiments. ISAHs will hopefully become a novel submucosal injectable hydrogel to assist ESD surgery. • ISAHs are shear-thinning and can be injected by an endoscopic injection needle. • ISAH have desirable self-healing properties and can effectively elevate lesions. • ISAHs with good antioxidant activity have the potential to reduce the inflammation. • ISAHs have more sustained submucosal lift than the commercial ESD solution. [ABSTRACT FROM AUTHOR]

Cutaneous wound management remains a major concern due to uncontrolled inflammation and bacterial infection in clinical care. A desirable hydrogel dressing with antibacterial and antioxidative properties can drive wound healing by inhibiting infection and inflammation. Herein, a multifunctional hydrogel based on polylysine- graft -cysteine (EPL-SH)/oxidized dextran (ODex) was fabricated for promoting skin tissue regeneration. The engineered hydrogel possessed versatile properties including tunable gelation time (60–300 s), typical rheological behavior, suitable swelling and degradation progress, injectable and self-healing ability. The unique hydrogels also displayed promising tissue adhesiveness, high cell affinity, excellent antioxidant and antimicrobial activity. Furthermore, the in vivo full-thickness skin defect experiment demonstrated the simple-to-implement injectable hydrogels could significantly promoting wound healing by improving the collagen deposition and angiogenesis. The manufacture of our multifunctional hydrogels dressing affords a new strategy for improving efficacy of cutaneous wound treatment. [Display omitted] • The oxidized dextran and thiolated ε-poly- l -lysine and were successfully synthesized. • A multi-functional injectable self-healing Dex/EPL hydrogel dressing was designed. • The hydrogel exhibited good antibacterial and free radical scavenging capacity. • The hydrogel has better efficacy on promoting wound repair than commercial dressing. [ABSTRACT FROM AUTHOR]

Hydrogels have been used as scaffolds for biomineralization in tissue engineering and regenerative medicine for the repair and treatment of many tissue types. In the present work, we studied an amino acid-based material that is attached to protecting groups and self-assembles into biocompatible and stable nanostructures that are suitable for tissue engineering applications. Specifically, the doubly protected aspartic residue (Asp) with fluorenyl methoxycarbonyl (Fmoc) protecting groups have been shown to lead to the formation of well-ordered fibrous structures. Many amino acids and small peptides which are modified with protecting groups display relatively fast self-assembly and exhibit remarkable physicochemical properties leading to three-dimensional (3D) networks, the trapping of solvent molecules, and forming hydrogels. In this study, the self-assembling fibrous structures are targeted toward calcium binding and act as nucleation points for the binding of the available phosphate groups. The cell viability, proliferation, and osteogenic differentiation of pre-osteoblastic cells cultured on the formed hydrogel under various conditions demonstrate that hydrogel formation in CaCl2 and CaCl2-Na2HPO4 solutions lead to calcium ion binding onto the hydrogels and enrichment with phosphate groups, respectively, rendering these mechanically stable hydrogels osteoinductive scaffolds for bone tissue engineering. [ABSTRACT FROM AUTHOR]

Traditional hydrogels have drawbacks such as surgical implantation, large wound surfaces, and uncontrollable drug release during tumor treatment. In this paper, targeted nanomedicine has been combined with injectable hydrogel for photothermal–chemotherapy combination therapy. First, targeted nanomedicine (ICG—MTX) was fabricated by combining near-infrared (NIR) photothermal reagents (ICG) and chemotherapy drugs (MTX). The ICG—MTX was then mixed with the hydrogel precursor and radical initiator to obtain an injectable hydrogel precursor solution. Under the irradiation of NIR light, the precursor solution could release alkyl radicals, which promote the transition of the precursor solution from a liquid to a colloidal state. As a result, the nanomedicine could effectively remain at the site of the tumor and continue to be released from the hydrogel. Due to the targeted nature of MTX, the released ICG—MTX could target tumor cells and improve the accuracy of photothermal–chemo combination therapy. The results indicated that the injectable nanomedicine–hydrogel system has a favorable therapeutic effect on tumors. [ABSTRACT FROM AUTHOR]

For the delivery of anticancer drugs, an injectable in situ hydrogel with thermal responsiveness and prolonged drug release capabilities shows considerable potential. Here, we present a series of thermosensitive in situ hydrogels that serve as drug delivery systems for the treatment of liver cancer. These hydrogels were created by utilizing the polydimethylsiloxane (PDMS) oligomer, polyethylene glycol (PEG) and polypropylene glycol (PPG)'s chemical cross-linking capabilities. Doxorubicin (DOX) was encapsulated in a hydrogel with a hydrophobic core and hydrophilic shell to enhance DOX solubility. Studies into the behavior of in situ produced hydrogels at the microscopic and macroscopic levels revealed that the copolymer solution exhibits a progressive shift from sol to gel as the temperature rises. The hydrogels' chemical composition, thermal properties, rheological characteristics, gelation period, and DOX release behavior were all reported. Subcutaneous injection in mice was used to confirm the injectability. Through the in vitro release of DOX in a PBS solution that mimics the tumor microenvironment, the hydrogel's sustained drug release behavior was confirmed. Additionally, using human hepatocellular hepatoma, the anticancer efficacy of thermogel (DEP-2@DOX) was assessed (HepG2). The carrier polymer material DEP-2 was tested for cytotoxicity using HepG2 cells and its excellent cytocompatibility was confirmed. In conclusion, these thermally responsive injectable hydrogels are prominent potential candidates as drug delivery vehicles for the treatment of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]