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Injectable hydrogels for cancer immunotherapy are effective for both active and passive approaches. Tumor‐infiltrating lymphocyte (TIL) immunoshaping can change the tumor microenvironment to favor tumor cell elimination. The primary objective of immunoshaping is to reduce regulatory T‐cells (Tregs), which can enhance the effectiveness of ex vivo immune cell therapy in solid tumors. A shear‐thinning injectable hydrogel that consists of gelatin and Laponite (Gel‐Lap) is used in this study. By optimizing the formulation, their immunotherapeutic and anti‐tumor properties are examined. Gemcitabine (GEM), an anti‐metabolite cancer chemotherapy agent, is loaded into a Gel‐Lap hydrogel (immunogel). The study compares the effects of immunogel on 4T1 inoculated breast cancer animal models. Results show that immunogel increases survival rates and significantly inhibits metastasis. The Treg cell population reduction is observed up to 70% in TILs and splenocyte population in line with CD8+ T‐cells population increment in inguinal lymph nodes near the tumor region; the CD8+ T‐cells function may be mediated through overexpression of eomesodermin (EOMES) as cytotoxic T lymphocyte (CTL) activation transcription factor. The human 3D cell culture model confirmed results in animal data demonstrating T‐cell migration through the hydrogel and anticancer efficacy. Local delivery of GEM using our silicate‐based hydrogel holds promise for editing tumor microenvironment in favor of systemic immune responses. [ABSTRACT FROM AUTHOR]

In recent years, injectable hydrogels and cardiac patches have provided a promising approach to improve cardiac regeneration and function after myocardial infarction, however, the crucial designing factors of these biomaterials have been less reviewed. Therefore, in this review, we speculate on the prominent design parameters. A profound understanding of the main properties of native heart tissue can guide the efforts to obtain biomaterials with desirable biomimicking properties that improve the effectiveness of future fabricated myocardial biomaterials. Moreover, the injectable hydrogels and cardiac patches with reactive oxygen species scavenging properties will be reviewed in detail owing to the promising results of in vitro and in vivo studies on cardiac regeneration after myocardial infarction. This review can pave the way for an optimized design for effective cardiac biomaterials by considering the optimum ranges for physical, chemical, and biological characteristics of biomaterials, as well as the study of undetected parameters that can be investigated in future studies. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) constitutes a severe condition characterized by a sudden decrease in kidney function. Utilizing lineage-restricted stem/progenitor cells, directly reprogrammed from somatic cells, is a promising therapeutic option in personalized medicine for serious and incurable diseases such as AKI. The present study describes the therapeutic potential of induced nephron progenitor cell-sourced molecules (iNPC-SMs) as a cell-free strategy against cisplatin (CP)-induced nephrotoxicity, employing hyaluronic acid (HA) hydrogel-mediated local delivery to minimize systemic leakage and degradation. iNPC-SMs exhibited anti-apoptotic effects on HK-2 cells by inhibiting CP-induced ROS generation. Additionally, the localized biodistribution facilitated by hydrogel-mediated iNPC-SM delivery contributed to enhanced renal function, anti-inflammatory response, and renal regeneration in AKI mice. This study could serve as a 'proof of concept' for injectable hydrogel-mediated iNPC-SM delivery in AKI and as a model for further exploration of the development of cell-free regenerative medicine strategies. [ABSTRACT FROM AUTHOR]

In order to overcome the harmful effects of radiation exposure on lung tissue in radiation therapy, a complete comparative analysis was performed between the injectable pure hydrogel and a novel composite hydrogel, taking into account the addition of cellulose nanoparticles in varying ratios. Initially, both chitosan and tragacanth hydrogels were chemically were modified, and then characterized by FTIR spectroscopy and rheology measurement. For in vivo studies, 42 rats were divided into seven groups. Rats in group 1, were not exposed to radiation, and no injection was done. Rats in group 2 were exposed to a radiation dose of 15 Gy without any injection. Rats in groups 3, 4, and 5 got injectable chitosan/ tragacanth hydrogel containing nanocellulose 25, 50, and 75 mg/kg BW, respectively, along with a radiation dose of 15 Gy. Rats in group 6 got a radiation dose of 15 Gy and an IP injection optimal dose of cellulose nanoparticle and PBS. Rat in group 7 got a radiation dose of 15 Gy and an IP injection of hydrogel containing only chitosan–tragacanth. The pathological results demonstrated that the 25 mg/kg BW dose of nanocellulose‐contained hydrogel possessed less inflammation, mucus secretion, bleeding in lung tissue, and air sac wall thickening than other groups. In addition, a biochemistry assessment was conducted by examining the activity of three enzymes of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxide (GPx), which findings confirmed the hydrogel incorporated with 25 mg/kg BW dose of nanocellulose decreased cell death in a lung tissue damaged by radiation which was 52 IU/mL, 37 IU/mL, and 10 μM in comparison with 63 IU/mL, 40 IU/mL, and 1 μM for the control sample. [ABSTRACT FROM AUTHOR]

Hydrogel stands out as one of the most attractive wound dressings due to its excellent moisturizing properties and capacity to absorb wound exudates. However, conventional hydrogel dressings often lack responsiveness to the microenvironment, merely acting as protective barriers for the wound. Consequently, they exhibit limited effectiveness in preventing infection and facilitating wound repair. To address these problems, we have developed a multifunctional injectable hydrogel, CF/MS@HG, based on peroxidase-like nanozymes, aiming at rapidly healing bacterial-infected wounds. The hydrogel is mainly composed of oxidized sodium alginate, aminated gelatin, and polylysine, encapsulating MIL-101(CuFe) NPs (CF) and manganese selenide nanoparticles (MnSe2 NPs, or MS NPs). After injection, the complex rapidly gelatinizes at the infected wound site through a Schiff base reaction. In vitro experiments have demonstrated the hydrogel's strong adhesion and self-healing capabilities. Moreover, CF exhibiting peroxidase (POD)-like activity, catalyzes in situ hydrogen peroxide (H2O2) to generate highly toxic hydroxyl radicals (·OH) within the wound microenvironment, inducing oxidative damage to bacteria. Meanwhile, MS decomposes into H2Se in the slightly acidic wound microenvironment, disrupting bacterial metabolism and inhibiting proliferation. The addition of polylysine further enhances the hydrogel's antibacterial properties. In vivo experiments have shown that the hydrogel exhibits excellent biological safety and significantly promotes wound healing. This multifunctional smart hydrogel holds great promise for the treatment of bacterial-infected wounds. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Objective Methods Conclusions Oral and maxillofacial tissue defects resulting from factors such as trauma or infection, can significantly impact both facial function and aesthetics. Additionally, the complex anatomical structure of the face often increases the difficulty of treatment. With the advantages of controlled release, targeted delivery, and enhanced mechanical properties, injectable hydrogels have been investigated for the treatment of oral and maxillofacial diseases. In the field of regeneration, injectable hydrogels have a structure similar to the extracellular matrix (ECM) and are biocompatible, which can be used as scaffolds for tissue regeneration.This review aims to summarize the literature on the current status and limitations of injectable hydrogels in the field of oral tissue regeneration.We searched Pubmed and Web of Science databases to find and summarize the articles on the application of injectable hydrogels in tissue regeneration.This review focuses on the current status and limitations of injectable hydrogels in the field of tissue regeneration (periodontal tissue, dentin‐pulp complex, bone and cartilage, salivary gland regeneration, and mucosal repair). Although fully studied in animal models, there are still challenges in clinical transformation of injectable hydrogels in promoting tissue regeneration. [ABSTRACT FROM AUTHOR]

Developing hydrogels with excellent 3D printability, injectability, and mechanical integrity presents an imposing challenge in biomaterials research, especially in the biomedical field where biocompatibility is crucial. This study involved the development of 3D printable and injectable polysaccharide-based hydrogels with inherent self-healing capabilities. Carboxymethyl chitosan and quaternized chitosan (QCS) functioned as polymer backbones, reinforced by dialdehyde-cellulose nanocrystals (DACNC) as a cross-linker. Here, the concentrations of QCS and DACNC were adjusted and optimized for ideal performance. The cross-linking process was orchestrated in situ, integrating dynamic hydrogen bonds and Schiff base covalent bonds to achieve a multi-cross-linked hydrogel network. Comprehensive characterization of the material, including rheological measurements and macroscopic evaluations, demonstrated the hydrogel's admirable injectability, printability, and self-healing attributes. In vitro cell viability assessments on human dermal fibroblasts revealed favorable biocompatibility and minimal cytotoxicity of the hydrogels, properties influenced by the concentrations of QCS. The obtained hydrogels exhibit promising attributes suitable for fabricating 3D printable and injectable hydrogel customized for biomedical applications, particularly wound healing. [ABSTRACT FROM AUTHOR]

Conventional pulp capping materials have limited anti-inflammatory capacity. It is necessary to develop more effective pulp capping material for the treatment of inflamed pulps. Tannic acid (TA) is a natural, water-soluble polyphenol with antimicrobial and anti-inflammatory properties. This study aimed to investigate the effects of a tannin-containing hydroxypropyl chitin hydrogel (HPCH/TA hydrogel) as an innovative pulp capping material. The physicochemical properties of the composite hydrogels were characterized. The effects of HPCH/TA hydrogel as a pulp capping material were evaluated in vitro and in vivo. The underlying mechanism of the anti-inflammatory effects of HPCH/TA hydrogel was explored. The HPCH/TA hydrogel demonstrated favorable temperature sensitivity, injectability, and antibacterial properties. In vitro, the HPCH/TA hydrogel effectively promoted the proliferation of human dental pulp cells and inhibited interleukin-1β, interleukin-6, and tumor necrosis factor-α expression, possibly by suppressing the nuclear factor kappa-B pathway. In vivo, on the fourth day after capping, the HPCH/TA hydrogel group showed lower inflammatory scores compared to the control and iRoot BP Plus (commercial pulp capping material) group. By the sixth week, complete reparative dentin formation was observed in the HPCH/TA hydrogel group, with no difference in thickness compared to the iRoot BP Plus group. Collectively, the HPCH/TA hydrogel holds promise as a bioactive pulp capping material for promoting the repair of inflamed pulp in vital pulp therapy. [ABSTRACT FROM AUTHOR]

Adapting the mechanical strength between the implant materials and the brain tissue is crucial for the postoperative treatment of glioblastoma. However, no related study has been reported. Herein, we report an injectable lipoic acid‑iron (LA-Fe) hydrogel (LFH) that can adapt to the mechanical strength of various brain tissues, including human brain tissue, by coordinating Fe3+ into a hybrid hydrogel of LA and its sodium salt (LANa). When LFH, which matches the mechanical properties of mouse brain tissue (337 ± 8.06 Pa), was injected into the brain resection cavity, the water content of the brain tissue was maintained at a normal level (77%). Similarly, LFH did not induce the activation or hypertrophy of glial astrocytes, effectively preventing brain edema and scar hyperplasia. Notably, LFH spontaneously degrades in the interstitial fluid, releasing LA and Fe3+ into tumor cells. The redox couples LA/DHLA (dihydrolipoic acid, reduction form of LA in cells) and Fe3+/Fe2+ would regenerate each other to continuously provide ROS to induce ferroptosis and activate immunogenic cell death. As loaded the anti-PDL1, anti-PDL1@LFH further enhanced the efficacy of tumor-immunotherapy and promoted tumor ferroptosis. The injectable hydrogel that adapted the mechanical strength of tissues shed a new light for the tumor postoperative treatment. TOC Graph: The first injectable hydrogel that can adapt the mechanical strength of different brain tissues including human brain has been developed for the GBM postoperative treatment without the involvement of anti-tumor drugs by coordinating Fe3+ into the hybrid hydrogel of B vitamin lipoic acid (LA) and its sodium salt (LANa). [Display omitted] • By coordinating Fe3+ into the hybrid hydrogel of lipoic acid (LA) and its sodium salt (LANa) formed an injectable hydrogel. • The LA-Fe hydrogel (LFH) can adapt the mechanical strength of multiple brain tissues including human brain. • The LFH circumvented the foreign body reaction caused by material implantation, and effectively inhibited tumor recurrence. • As loaded the anti-PDL1, anti-PDL1@LFH further enhanced the tumor-immunotherapy efficacy and promoted the tumor ferroptosis. [ABSTRACT FROM AUTHOR]

Wound infections caused by Staphylococcus aureus often result in localized suppurative lesions that severely impede the healing process, so it is urgent to develop a dress with efficient antimicrobial and pro-healing functions. In this study, the bifunctional injectable hydrogel lactoferrin (Lf)/NZ2114/lithium magnesium silicate hydrogel (LMSH) was first successfully prepared through the electrostatic interaction method. The physical, biological, and efficacy properties are systematically analyzed with good shear-thinning capacity and biocompatibility. More importantly, it inhibits infection and promotes wound healing in a mouse wound infection model after 14 d treatment, and the bactericidal rate and healing rate were over 99.92% and nearly 100%, respectively. Meanwhile, the massive reduction of inflammatory cells, restoration of tissue structure, and angiogenesis in mice showed the anti-inflammatory and pro-healing properties of the hydrogel. The healed wounds showed thickening with more hair follicles and glands, suggesting that the hydrogel Lf/NZ2114/LMSH (Three in One) could be a better dressing candidate for the treatment of S. aureus-induced wound infections. [ABSTRACT FROM AUTHOR]

Irreversible fibrosis following myocardial infarction (MI) stiffens the infarcted myocardium, which remains challenging to restore. This study aimed to investigate whether the injectable RLP12 hydrogel, derived from recombinant resilin protein, could serve as a vehicle for stem cells to enhance the function of the infarcted myocardium. The RLP12 hydrogel was prepared and injected into the myocardium of rats with MI, and brown adipose-derived mesenchymal stem cells (BADSCs) were loaded. The survival and differentiation of BADSCs in vivo were investigated using immunofluorescence one week and four weeks after treatment, respectively. The heart function, MI area, collagen deposition, and microvessel density were further assessed four weeks after treatment through echocardiography, histology, immunohistochemistry, and immunofluorescence. The RLP12 hydrogel was prepared with a shear modulus of 10–15 kPa. Four weeks after transplantation, the RLP12 hydrogel significantly improved cardiac function by increasing microvessel density and reducing infarct area size and collagen deposition in MI rats. Furthermore, the distribution ratio of collagen III to I increased in both the centre and edge areas of the MI, indicating the improved compliance of the infarct heart. Moreover, the RLP12 hydrogel also promoted the survival and differentiation of BADSCs into cardiac troponin T- and α-smooth muscle-positive cells. The RLP12 hydrogel can be utilised as an injectable vehicle of BADSCs for treating MI and regulating collagen I and III expression profiles to improve the mechanical microenvironment of the infarct site, thereby restoring heart function. The study provides novel insights into the mechanical interactions between the hydrogel and the infarct microenvironment. [ABSTRACT FROM AUTHOR]

Injectable, tissue mimetic, bioactive, and biodegradable hydrogels offer less invasive regeneration and repair of tissues. The monitoring swelling and in vitro degradation capacities of hydrogels are highly important for drug delivery and tissue regeneration processes. Bioactivity of bone tissue engineered constructs in terms of mineralized apatite formation capacity is also pivotal. We have previously reported in situ forming chitosan‐based injectable hydrogels integrated with hydroxyapatite and heparin for bone regeneration, promoting angiogenesis. These hydrogels were functionalized by glycerol and pH to improve their mechano‐structural properties. In the present study, functionalized hybrid hydrogels were investigated for their swelling, in vitro degradation, and bioactivity performances. Hydrogels have degraded gradually in phosphate‐buffered saline (PBS) with and without lysozyme enzyme. The percentage weight loss of hydrogels and their morphological and chemical properties, and pH of media were analyzed. The swelling ratio of hydrogels (55%–68%(wt), 6 h of equilibrium) indicated a high degree of cross‐linking, can be suitable for controlled drug release. Hydrogels have gradually degraded reaching to 60%–70% (wt%) in 42 days in the presence and absence of lysozyme, respectively. Simulated body fluid (SBF)‐treated hydrogels containing hydroxyapatite‐induced needle‐like carbonated‐apatite mineralization was further enhanced by heparin content significantly. [ABSTRACT FROM AUTHOR]

AbstractGraphene oxide (GO) is widely used in bone tissue engineering due to its good biocompatibility and proliferation, and is often used in combination with other hydrogels, which not only reduces the cytotoxicity of GO but also improves the mechanical properties of the hydrogels. We developed injectable carboxymethyl chitosan (CMC)/hydroxyethyl cellulose (HEC)/β-tricalcium phosphate (β-TCP)/GO hydrogel via hydrogen bonding cross-linked between (CMC) and (HEC), also, calcium cross-linked by β-TCP was also involved to further improvement of mechanical properties of the hydrogel, and incorporate different concentration of GO in these hydrogel systems. The characterization of the novel hydrogel was tested by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FT-IR). The swelling ratio and mechanical properties were investigated, the results showed that the addition of GO was able to reduce the swelling rate of hydrogels and improve their mechanical properties, with the best effect in the case of 1 mg/mL content. In vivo experimental studies showed that the hydrogel significantly promoted the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs), with the best effect at a concentration of 2 mg/mL. The results of the cellular experiments were similar. Therefore, the novel environment-friendly and non-toxic injectable CMC/HEC/β-TCP/GO hydrogel system may have potential applications in bone tissue engineering. [ABSTRACT FROM AUTHOR]

With the rising prevalence of diabetes, a growing number of patients are at high risk for chronic nonhealing wounds. These wounds are a severe complication of diabetes, associated with increased rates of infection, amputation, and mortality. Currently, there are no established clinical approaches for effectively treating diabetic wounds, resulting in a significant socioeconomic burden on both patients and healthcare systems. Diabetic wound healing is frequently hampered by excessive reactive oxygen species (ROS) biogenesis and unrestrained bacterial infection, with methicillin-resistant Staphylococcus aureus (MRSA) being a particularly aggressive pathogen in this setting. Polydopamine nanoparticles (PDA NPs) can readily scavenge ROS and facilitate efficient photoconversion. In this study, an injectable gelatin methacryloyl (GelMA)/PDA NPs hydrogel, designated GMP, was designed as an approach to overcoming these diabetic issues through the incorporation of PDA NPs into GelMA hydrogels. The prepared GMP hydrogel exhibited a porous 3D structure amenable to injection such that it can produce a hydrogel barrier that protects the wound site, rapidly providing hemostasis and absorbing wound-related exudates. GMP was then able to scavenge ROS and exert photothermal sterilizing effects, ultimately alleviating oxidative stress and eliminating bacteria from the site of wounding. This GMP hydrogel was also biocompatible with building blocks derived from natural materials. In vitro and in vivo, this GMP hydrogel containing PDA NPs was able to improve MRSA-infected diabetic wound healing, underscoring its value as a tool for the treatment of such wounds in a clinical setting. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is considered as a significant cause of death globally. Exosomes (EXOs) are essential for intercellular communication and pathophysiology of several cardiovascular diseases. Nevertheless, the short half-life and rapid clearance of EXOs leads to a lack of therapeutic doses delivered to the lesioned area. Therefore, an injectable silk fibroin and alginate (SF/Alg) composite hydrogel was developed to bind folate receptor-targeted EXOs (FA-EXOs) derived from H9C2 cells for the therapy of myocardial injury following myocardial infarction-ischemia/reperfusion (MI-I/R). The resulting composite exhibits a variety of properties, including adjustable gelation kinetics, shear-thinning injectability, soft and dynamic stability that adapts to the heartbeat, and outstanding cytocompatibility. After injected into the damaged rat heart, administration of SF/Alg + FA-EXOs significantly enhanced cardiac function as demonstrated by improved ejection fraction, fractional shortening and decreased fibrosis area. The results of real-time PCR and immunofluorescence staining show a remarkable up-regulation in the expression of proteins (CD31) and genes (VWF and Serca2a) related to the heart. Conversely, expression of fibrosis-related genes (TGF-β1) decreased significantly. Therefore, the obtained SF/Alg + FA-EXOs system remarkably enhanced the intercellular interactions, promoted cell proliferation and angiogenesis, and achieved an outstanding therapeutic effect on MI. [ABSTRACT FROM AUTHOR]

[Display omitted] An injectable hydrogel dressing, Zr/Fc-MOF@CuO 2 @FH, was constructed by combing acid-triggered chemodynamic treatment (CDT) with low-temperature photothermal treatment (LT-PTT) to effectively eliminate bacteria without harming the surrounding normal tissues. The Zr/Fc-MOF acts as both photothermal reagent and nanozyme to generate reactive oxygen species (ROS). The CuO 2 nanolayer can be decomposed by the acidic microenvironment of the bacterial infection to release Cu2+ and H 2 O 2 , which not only induces Fenton-like reaction but also enhances the catalytic capability of the Zr/Fc-MOF. The generated heat augments ROS production, resulting in highly efficient bacterial elimination at low temperature. Precisely, injectable hydrogel dressing can match irregular wound sites, which shortens the distance of heat dissipation and ROS diffusion to bacteria, thus improving sterilization efficacy and decreasing non-specific systemic toxicity. Both in vitro and in vivo experiments validated the predominant sterilization efficiency of drug-resistant methicillin-resistant Staphylococcus aureus (MRSA) and kanamycin-resistant Escherichia coli (KREC), presenting great potential for application in clinical therapy. [ABSTRACT FROM AUTHOR]

The integration of barrier materials with pharmacological therapy is a promising strategy to treat intrauterine adhesions (IUAs). However, most of these materials are surgically implanted in a fixed shape and incongruence with the natural mechanical properties of the uterus, causing poor adaptability and significant discomfort to the patients. Herein, an injectable, biodegradable, and mechanically adaptive hydrogel loaded with platelet-rich plasma (PRP) is created by L‑serine and allyl functionalized chitosan (ACS) to achieve efficient, comfortable, and minimally invasive treatment of IUAs. L‑serine induces fast gelation and mechanical reinforcement of the hydrogel, while ACS introduces, imparting a good injectability and complaint yet strong feature to the hydrogel. This design enables the hydrogel to adapt to the complex geometry and match the mechanical properties of the uterine. Moreover, the hydrogel exhibits proper degradability, sustained growth factors (GFs) of PRP release ability, and good biocompatibility. Consequently, the hydrogel shows promising therapeutic efficacy by reducing collagen fiber deposition and facilitating endometrium cell proliferation, thereby restoring the fertility function of the uterus in an IUAs model of rats. Accordingly, the combination of L‑serine and ACS-induced hydrogel with such advantages holds great potential for treating IUAs. This research introduces a breakthrough in the treatment of intrauterine adhesions (IUAs) with an injectable, biodegradable and mechanically adaptive hydrogel using L‑serine and allyl functionalized chitosan (ACS). Unlike traditional surgical treatments, this hydrogel uniquely conforms to the uterus's geometry and mechanical properties, offering a minimally invasive, comfortable, and more effective solution. The hydrogel is designed to release growth factors from platelet-rich plasma (PRP) sustainably, promoting tissue regeneration by enhancing collagen fiber deposition and endometrium cell proliferation. Demonstrated efficacy in a rat model of IUAs indicates its great potential to significantly improve fertility restoration treatments. This advancement represents a significant leap in reproductive medicine, promising to transform IUAs treatment with its innovative approach to achieving efficient, comfortable, and minimally invasive therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer among women worldwide, and adjuvant radiotherapy (RT) following tumor removal is one of the most commonly used treatments for breast cancer. However, the high risk of tumor recurrence and inevitable radiation skin injury after RT remain fatal problems, seriously challenging the patient's postoperative rehabilitation. Herein, a multifunctional poly (lipoic acid)-based hydrogel is constructed through one-step heating the mixture of α-lipoic acid (LA)/arginine (Arg)/silk fibroin (SF), without introducing any non-natural molecules. The multiple synergistic interactions among LA, Arg, and SF not only enhance the solubilization of LA in aqueous systems but also stabilize poly(lipoic acid) through strong salt bridge hydrogen bonds and ionic hydrogen bonds. Intriguingly, the LA-based surfactant induced β-sheet transformation of SF can further modulate the bulk strength of the hydrogel. Regulating the content of LA in hydrogels not only allows efficient control of hydrogel bioactivity but also enables the evolution of hydrogels from injectable forms to adhesive patches. Based on the different biological activities and forms of hydrogels, they can be implanted internally or applied externally on the mice's skin, achieving simultaneous prevention of tumor recurrence post-surgery and assistance in treating radiation-induced skin damage after radiotherapy.

While mild hyperthermia holds great potential in the treatment of solid tumors, the thermal stress-triggered self-repairing autophagy significantly compromises its efficacy. To circumvent this obstacle, an injectable hydrogel (NO-Gel) composed of thermosensitive poly(ethylene glycol)-polypeptide copolymers modified with abundant NO donors on their side chains is developed. Meanwhile, ferrimagnetic Zn0.5Fe2.5O4 magnetic nanoparticles (MNPs) with high magnetic-heat conversion efficiency are synthesized and loaded into NO-Gel to obtain MNPs@NO-Gel. The MNPs@NO-Gel system exhibits a sol-gel transition upon heating, and has the ability to perform multiple magnetic hyperthermia therapy (MHT) after only one administration due to the even distribution and strong immobilization of MNPs in NO-Gel. NO can be continuously liberated from NO-Gel and this process is markedly accelerated by MHT. Additionally, MNPs@NO-Gel maintains its integrity in vivo for over one month and the released MNPs are metabolized by the spleen. After a single administration of MNPs@NO-Gel at the tumor site, three mild MHT treatments with similar effects are fulfilled, and the sufficient supply of NO effectively inhibits MHT-induced autophagic flux via blocking the formation of autophagosomes and synchronously destroying lysosomes, thereby substantially boosting the efficacy of mild MHT. As a consequence, CT-26 colon tumors are completely eliminated without causing severe side-effects.

Current cancer immunotherapies exhibit low response rates attributed to suppressive tumor immune microenvironments (TIMEs). To address these unfavorable TIMEs, supplementation with tumor-associated antigens and stimulation of immune cells at target sites are indispensable for eliciting anti-tumoral immune responses. Previous research has explored the induction of immunotherapy through multiple injections and implants; however, these approaches lack consideration for patient convenience and the implementation of finely tunable immune response control systems to mitigate the side effects of over-inflammatory responses, such as cytokine storms. In this context, we describe a patient-centric nano-gel-nano system capable of sustained generation of tumor-associated antigens and release of adjuvants. This is achieved through the specific delivery of drugs to cancer cells and antigens/adjuvants to immune cells over the long term, maintaining proper concentrations within the tumor site with a single injection. This system demonstrates local immunity against tumors with a single injection, enhances the therapeutic efficacy of immune checkpoint blockades, and induces systemic and memory T cell responses, thus minimizing systemic side effects.

Regulating macrophage phenotypes to reconcile the conflict between bacterial suppression and tissue regeneration is ideal for treating infectious skin wounds. Here, an injectable immunoregulatory hydrogel (SrmE20) that sequentially drives macrophage phenotypic polarization (M0 to M1, then to M2) was constructed by integrating anti-inflammatory components and proinflammatory solvents. In vitro experiments demonstrated that the proinflammatory solvent ethanol stabilized the hydrogel structure, maintained the phenolic hydroxyl group activity, and achieved macrophages' proinflammatory transition (M0 to M1) to enhance antibacterial effects. With ethanol depletion, the hydrogel's cations and phenolic hydroxyl groups synergistically regulated macrophages' anti-inflammatory transition (M1 to M2) to initiate regeneration. In the anti-contraction full-thickness wound model with infection, this hydrogel effectively eliminated bacteria and even achieved anti-inflammatory M2 macrophage accumulation at three days post-surgery, accelerated angiogenesis and collagen deposition. By sequentially driving macrophage phenotypic polarization, this injectable immunoregulatory hydrogel will bring new guidance for the care and treatment of infected wounds.

Cataract patients look forwards to fewer postoperative complications and higher vision quality after surgery. However, the current intraocular lens (IOL) implanted after cataract surgery neither can adjust focal length in response to ciliary muscle contraction as natural lens nor have the ability to prevent postoperative complications. Herein, a thermosensitve Poloxamer based hybrid hydrogel with antibacterial anti-inflammatory and photothermal functional elements doping was designed and used as injectable, in situ curable, and adjustable IOL (FHTAB IOL). The FHTAB IOL was composed of thermosensitve triblock-polymer F127DA and a small amount of HAMA, combined with BP NS, TA, and Ag NPs. FHTAB IOL can be injected into the empty lens capsule after cataract surgery via an injectable thermos-gel under NIR illumination and then be rapidly cured to form a full-size IOL under short-time blue light irradiation. The designed injectable FHTAB IOL possesses high transparency and transmittance, with a refractive index similar to the natural lens and adjustable properties. It was stabilized as a refractive medium without any leakage in the eye. In addition, the TA and Ag NPs loaded in the FHTAB IOL displayed significant antibacterial and anti-inflammatory effects in vitro and vivo. This study presents a potentially effective new strategy for the development of multifunctional adjustable IOLs.

Rheumatoid arthritis (RA) remains a formidable healthcare challenge due to its chronic nature and potential for irreversible joint damage. Methotrexate (MTX) is a cornerstone treatment for RA but carries significant risks of adverse effects with repeated administration, necessitating the exploration of alternative delivery methods. Injectable hydrogels loaded with MTX for intra-articular injection present a promising solution, allowing sustained drug release directly into affected joints. However, current hydrogel systems often lack extended therapeutic periods and the ability to self-regulate drug release according to disease state. Furthermore, RA is associated with excessive production of reactive oxygen species (ROS), which exacerbates inflammation and joint damage. Herein, we developed an advanced injectable hydrogel (MPDANPs/MTX HA-PEG gel) based on "bio-orthogonal chemistry", combining hyaluronic acid and polyethylene glycol (PEG) matrices co -loaded with mesoporous polydopamine nanoparticles (MPDANPs) and MTX. MPDANPs/MTX HA-PEG gel achieved prolonged, staged, and self-regulated MTX release, coupled with ROS scavenging capabilities for enhanced therapeutic efficacy. Due to its optimized MTX release behavior and significant ROS scavenging function, MPDANPs/MTX HA-PEG gel exhibited potent anti-inflammatory effects in collagen-induced arthritis (CIA) rats following a single intra-articular injection. Our findings highlight the potential of MPDANPs/MTX HA-PEG gel as a highly effective treatment strategy for RA, offering a promising avenue for improving patient outcomes. [Display omitted] • MPDANPs/MTX HA-PEG gel enabled prolonged, staged, and ROS-responsive MTX release. • Optimized MTX release behavior, combined with ROS scavenging capacities, contributed to efficient RA therapy. • Single intra-articular injection of MPDANPs/MTX HA-PEG gel showed significant anti-inflammatory effects in CIA rats. [ABSTRACT FROM AUTHOR]

Abstract Acute myocardial infarction (AMI) has been treated via injectable hydrogels and biomaterial patches invented using tissue engineering advancements over the past decade. Yet the curative potential of injectable hydrogels and stem cells is limited. Here, we propose the development of an injectable and conductive hydrogel composed of oxidised macromolecular hyaluronic acid and chitosan-grafted aniline tetramer polymeric components. In an attempt to enhance the therapeutic potential of AMI therapy, mesenchymal stem cells derived from human umbilical cord blood (HUCB-MSC) have been integrated into the formulation of a conductive hydrogel. For reliable connection to the beating hearts, the hydrogel exhibited suitable adhesive properties. Hydrogel’s potent biocompatibility was determined by in vitro investigations of cell viability and proliferation of NRCMs and H9C2 cardiomyocytes. After myocardial injection, longer HUCB-MSCs survival length, cardiac functioning, and histology in SD rat myocardium were demonstrated, greatly associated by up-regulation and downregulation of cardiac-related relative gene expressions of angiogenic factors and inflammatory factors, respectively. The injectable hydrogel that contained HUCB-MSCs substantially enhanced the therapeutic benefits, indicating a potentially beneficial therapeutic approach to AMI therapy.

Periodontitis is associated with several systemic diseases, and advanced periodontitis is often linked to an extensive inflammatory microenvironment and irregularly shaped alveolar bone defects. However, eliminating periodontal inflammation in a minimally invasive manner while repairing irregularly shaped bone defects is clinically challenging. In comparison to traditional bone grafts, a thermo-sensitive hydrogel can be injected into deep periodontal pockets, forming and filling the alveolar bone defects in situ. In this study, porous injectable thermo-sensitive hydrogels containing magnesium ions were prepared by adding magnesium particles (MPs) to a glycerophosphate solution and combining this mixture with a chitosan solution. The incorporation of MPs created interconnected pores in the hydrogel, exhibiting high cytocompatibility and maintaining cell viability, proliferation, spreading, and osteogenesis in vitro. Evaluation on an experimental periodontitis rat model, using micro-computed tomography and histological analyses, demonstrated that this Mg2+-containing hydrogel effectively reduced periodontal inflammation, inhibited osteoclast activity, and partially repaired inflammation-induced alveolar bone loss. These results suggest that Mg2+-containing thermo-sensitive porous hydrogels might be promising candidates for treating periodontitis.

Abstract Background Elderly patients suffering from osteoporotic fractures are more susceptible to delayed union or nonunion, and their bodies then are in a state of low-grade chronic inflammation with decreased antioxidant capacity. Tanshinone IIA is widely used in treating cardiovascular and cerebrovascular diseases in China and has anti-inflammatory and antioxidant effects. We aimed to observe the antioxidant effects of Tanshinone IIA on mesenchymal stem cells (MSCs), which play important roles in bone repair, and the effects of local application of Tanshinone IIA using an injectable biodegradable hydrogel on osteoporotic fracture healing. Methods MSCs were pretreated with or without different concentrations of Tanshinone IIA followed by H2O2 treatment. Ovariectomized (OVX) C57BL/6 mice received a mid-shaft transverse osteotomy fracture on the left tibia, and Tanshinone IIA was applied to the fracture site using an injectable hydrogel. Results Tanshinone IIA pretreatment promoted the expression of nuclear factor erythroid 2-related factor 2 and antioxidant enzymes, and inhibited H2O2-induced reactive oxygen species accumulation in MSCs. Furthermore, Tanshinone IIA reversed H2O2-induced apoptosis and decrease in osteogenic differentiation in MSCs. After 4 weeks of treatment with Tanshinone IIA in OVX mice, the bone mineral density of the callus was significantly increased and the biomechanical properties of the healed tibias were improved. Cell apoptosis was decreased and Nrf2 expression was increased in the early stage of callus formation. Conclusions Taken together, these results indicate that Tanshinone IIA can activate antioxidant enzymes to protect MSCs from H2O2-induced cell apoptosis and osteogenic differentiation inhibition. Local application of Tanshinone IIA accelerates fracture healing in ovariectomized mice.

Abstract Background Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, and it leads to irreversible inflammation in intra-articular joints. Current treatment approaches for RA include non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), corticosteroids, and biological agents. To overcome the drug-associated toxicity of conventional therapy and transdermal tissue barrier, an injectable NSAID-loaded hydrogel system was developed and explored its efficacy. Results The surface morphology and porosity of the hydrogels indicate that they mimic the natural ECM, which is greatly beneficial for tissue healing. Further, NSAIDs, i.e., diclofenac sodium, were loaded into the hydrogel, and the in vitro drug release pattern was found to be burst release for 24 h and subsequently sustainable release of 50% drug up to 10 days. The DPPH assay revealed that the hydrogels have good radical scavenging activity. The biocompatibility study carried out by MTT assay proved good biocompatibility and anti-inflammatory activity of the hydrogels was carried out by gene expression study in RAW 264.7 cells, which indicate the downregulation of several key inflammatory genes such as COX-2, TNF-α & 18s. Conclusion In summary, the proposed ECM-mimetic, thermo-sensitive in situ hydrogels may be utilized for intra-articular inflammation modulation and can be beneficial by reducing the frequency of medication and providing optimum lubrication at intra-articular joints. Graphical Abstract

Abstract The need for tumor postoperative treatments aimed at recurrence prevention and tissue regeneration have raised wide considerations in the context of the design and functionalization of implants. Herein, an injectable hydrogel system encapsulated with anti-tumor, anti-oxidant dual functional nanoparticles has been developed in order to prevent tumor relapse after surgery and promote wound repair. The utilization of biocompatible gelatin methacryloyl (GelMA) was geared towards localized therapeutic intervention. Zeolitic imidazolate framework-8@ceric oxide (ZIF-8@CeO2, ZC) nanoparticles (NPs) were purposefully devised for their proficiency as reactive oxygen species (ROS) scavengers. Furthermore, injectable GelMA hydrogels loaded with ZC NPs carrying doxorubicin (ZC-DOX@GEL) were tailored as multifunctional postoperative implants, ensuring the efficacious eradication of residual tumor cells and alleviation of oxidative stress. In vitro and in vivo experiments were conducted to substantiate the efficacy in cancer cell elimination and the prevention of tumor recurrence through the synergistic chemotherapy approach employed with ZC-DOX@GEL. The acceleration of tissue regeneration and in vitro ROS scavenging attributes of ZC@GEL were corroborated using rat models of wound healing. The results underscore the potential of the multifaceted hydrogels presented herein for their promising application in tumor postoperative treatments.

Surgical resection remains the mainstream treatment for malignant melanoma. However, challenges in wound healing and residual tumor metastasis pose significant hurdles, resulting in high recurrence rates in patients. Herein, a bioactive injectable hydrogel (BG‐Mngel) formed by crosslinking sodium alginate (SA) with manganese‐doped bioactive glass (BG‐Mn) is developed as a versatile platform for anti‐tumor immunotherapy and postoperative wound healing for melanoma. The incorporation of Mn2+ within bioactive glass (BG) can activate the cGAS‐STING immune pathway to elicit robust immune response for cancer immunotherapy. Furthermore, doping Mn2+ in BG endows system with excellent photothermal properties, hence facilitating STING activation and reversing the tumor immune‐suppressive microenvironment. BG exhibits favorable angiogenic capacity and tissue regenerative potential, and Mn2+ promotes cell migration in vitro. When combining BG‐Mngel with anti‐PD‐1 antibody (α‐PD‐1) for the treatment of malignant melanoma, it shows enhanced anti‐tumor immune response and long‐term immune memory response. Remarkably, BG‐Mngel can upregulate the expression of genes related to blood vessel formation and promote skin tissue regeneration when treating full‐thickness wounds. Overall, BG‐MnGel serves as an effective adjuvant therapy to regulate tumor metastasis and wound healing for malignant melanoma. [ABSTRACT FROM AUTHOR]

The regenerative microenvironment after peripheral nerve injury is imbalanced and difficult to rebalance, which is mainly affected by inflammation, oxidative stress, and inadequate blood supply. The difficulty in remodeling the nerve regeneration microenvironment is the main reason for slow nerve regeneration. Traditional drug treatments have certain limitations, such as difficulty in penetrating the blood-nerve barrier and lack of pleiotropic effects. Therefore, there is an urgent need to build multifunctional nerve grafts that can effectively regulate the regenerative microenvironment and promote nerve regeneration. Nitric oxide (NO), a highly effective gas transmitter with diatomic radicals, is an important regulator of axonal growth and migration, synaptic plasticity, proliferation of neural precursor cells, and neuronal survival. Moreover, NO provides potential anti-inflammation, anti-oxidation, and blood vessel promotion applications. However, excess NO may cause cell death and neuroinflammatory cell damage. The prerequisite for NO treatment of peripheral nerve injury is that it is gradually released over time. In this study, we constructed an injectable NO slow-release system with two main components, including macromolecular NO donor nanoparticles (mPEG-P(MSNO-EG) nanoparticles, NO-NPs) and a carrier for the nanoparticles, mPEG-PA-PP injectable temperature-sensitive hydrogel. Due to the multiple physiological regulation of NO and better physiological barrier penetration, the conduit effectively regulates the inflammatory response and oxidative stress of damaged peripheral nerves, promotes nerve vascularization, and nerve regeneration and docking, accelerating the nerve regeneration process. The slow regeneration speed of peripheral nerves is mainly due to the destruction of the regeneration microenvironment. Neural conduits with drug delivery capabilities have the potential to improve the microenvironment of nerve regeneration. However, traditional drugs are hindered by the blood nerve barrier and cannot effectively target the injured area. NO, an endogenous gas signaling molecule, can freely cross the blood nerve barrier and act on target cells. However, excessive NO can lead to cell apoptosis. In this study, a NO sustained-release system was constructed to regulate the microenvironment of nerve regeneration through various pathways and promote nerve regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

The microvascular network plays an important role in providing nutrients to the injured tissue and exchanging various metabolites. However, how to achieve efficient penetration of the injured tissue is an important bottleneck restricting the reconstruction of microvascular network. Herein, the hydrogel precursor solution can efficiently penetrate the damaged tissue area, and ultrasound triggers the release of thrombin from liposomes in the solution to hydrolyze fibrinogen, forming a fibrin solid hydrogel network in situ with calcium ions and transglutaminase as catalysts, effectively solving the penetration impedance bottleneck of damaged tissues and ultimately significantly promoting the formation of microvascular networks within tissues. First, the fibrinogen complex solution is effectively permeated into the injured tissue. Second, ultrasound triggered the release of calcium ions and thrombin, activates transglutaminase, and hydrolyzes fibrinogen. Third, fibrin monomers are catalyzed to form fibrin hydrogels in situ in the damaged tissue area. In vitro studies have shown that the fibrinogen complex solution effectively penetrated the artificial bone tissue within 15 s after ultrasonic triggering, and formed a hydrogel after continuous triggering for 30 s. Overall, this innovative strategy effectively solved the problem of penetration resistance of ultrasound‐triggered hydrogels in the injured tissues, and finally activates in situ microvascular networks regeneration. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (AMI) has been treated via injectable hydrogels and biomaterial patches invented using tissue engineering advancements over the past decade. Yet the curative potential of injectable hydrogels and stem cells is limited. Here, we propose the development of an injectable and conductive hydrogel composed of oxidised macromolecular hyaluronic acid and chitosan-grafted aniline tetramer polymeric components. In an attempt to enhance the therapeutic potential of AMI therapy, mesenchymal stem cells derived from human umbilical cord blood (HUCB-MSC) have been integrated into the formulation of a conductive hydrogel. For reliable connection to the beating hearts, the hydrogel exhibited suitable adhesive properties. Hydrogel's potent biocompatibility was determined by in vitro investigations of cell viability and proliferation of NRCMs and H9C2 cardiomyocytes. After myocardial injection, longer HUCB-MSCs survival length, cardiac functioning, and histology in SD rat myocardium were demonstrated, greatly associated by up-regulation and downregulation of cardiac-related relative gene expressions of angiogenic factors and inflammatory factors, respectively. The injectable hydrogel that contained HUCB-MSCs substantially enhanced the therapeutic benefits, indicating a potentially beneficial therapeutic approach to AMI therapy. [ABSTRACT FROM AUTHOR]

Peri-implantitis is an excessive inflammatory response induced by complex interactions between the bacteria, host immune system, and tissues around the dental implant. Alveolar bone resorption caused by peri-implantitis is a significant cause of implant failure. However, to restore the osteogenic microenvironment, a multifaceted therapeutic method that simultaneously encompasses anti-inflammatory and tissue regenerative strategies is indispensable. In this study, a temperature-sensitive hydrogel (FMXO) loaded with MXene and MgO was used to develop a multifunctional injectable MXene-based hydrogel. This hydrogel could release MXene and MgO in irregular bone defect areas in situ with no toxicity, either in vitro or in vivo. Our results showed that FMXO effectively inhibited the NF-κB signaling pathway in RAW264.7 cells and simultaneously upregulated the expression of ALP, Runx2, and OCN in bone marrow mesenchymal stromal cells (BMSCs). Therefore, FMXO exerted pharmacological effects on inflammation and bone regeneration. Moreover, we found that FMXO, when exposed to near-infrared (NIR) light, exhibited high efficacy against Porphyromonas gingivalis , Fusobacterium nucleatum , and their plaque microorganisms, which were considered the initiating factors of peri-implantitis. The multifunctionality of FMXO was also confirmed in an immediate peri-implant rat model in vivo, suggesting the great potential for peri-implantitis therapy in the dental clinic. [ABSTRACT FROM AUTHOR]

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

The primary request nowadays is for innovative and superior scaffold designs that mimic the characteristics of native tissue in cartilage tissue engineering. GelMA/Alginate (G/A) interpenetrating polymer network (IPN) has become a popular hydrogel material for tissue engineering because of its superior mechanical and biological properties. Here, to balance the properties, a hydrogel composed of G/A and covalent organic frameworks (COF) nanoparticles is specially designed. In this study, a hydrogel of GelMA/Alginate/COF (G/A/C) with improved properties such as pore size, swelling, mechanical strength, shear‐thinning behavior, and biocompatibility is produced. Furthermore, the G/A/C hydrogel facilitate the printing of complex three dimensional (3D) scaffolds. The test result demonstrates that the addition of COF up to 1% (w/w) enhances the porosity and decreases pore size (0.2 times), improves the compression strength (six times), and decreases the degradation ratio (0.05 times) and the swelling (0.3 times) compared to the G/A hydrogel sample. Besides, the cell viability test confirms the cell growth during the incubation and great biological behavior (more than 98%). The suitable performance of the G/A hydrogel containing 1% COF and its shape fidelity during the injection by 3D printer is confirmed. Nanocomposite IPN hydrogel based on G/A/C could be useful in tissue engineering applications. [ABSTRACT FROM AUTHOR]

Collagen nanofibers can be employed in hydrogels to create injectable nanocomposite hydrogels, mimicking the fibrous architecture of the natural extracellular matrix (ECM). As long continuous electrospun collagen nanofibers are not applicable, fragmentation is inevitable to obtain injectable hydrogels with a fine viscosity. Here, four methods: hand grinding (HG), homogenizer (HM), mixer milling (MM), and ultrasonication (UH) are used to disintegrate and shorten collagen nanofiber mats before incorporation into an injectable hyaluronic acid hydrogel as a matrix. The Length‐to‐diameter (L/d) ratio and morphology of fragmented collagen are compared by SEM. The injection force, mechanical properties, and cell viability of the selected collagen‐incorporated hydrogels are also evaluated. UH emerges as the most effective method, yielding the highest L/d ratio of 46 and a notable compressive modulus of 8.7 ± 0.92 kPa. Assessment of the in vitro cell viability of the encapsulated chondrocytes in the collagen‐incorporated hydrogels demonstrates good biocompatibility, and hydrogels containing UH short nanofiber, in particular, show an increase in cell proliferation. This work indicates how collagen mats can be effectively broken down and combined with injectable hydrogels to enhance both their mechanical behavior and biocompatibility. [ABSTRACT FROM AUTHOR]

For various chronic wounds, bacterial infection is one of the important reasons that hinder their healing. Ion‐crosslinked antibacterial hydrogel dressings based on Ag+, Cu2+ and Zn2+, have made progress in clinical application. However, the toxicity of released metal ions cannot be ignored. Therefore, how to ensure the antibacterial performance of hydrogel dressing while reducing the amount of metal ions is a major challenge for the fabrication of metal ion based antibacterial hydrogel. In this study, a general method is proposed to design cationic ion‐crosslinked hydrogel based on thiourea groups. Taking the hydrogel formed by mixing thiourea modified hyaluronic acid (H‐ANCSN) with Ag+ (HA‐NCSN/Ag+ hydrogel) as an example, the characteristics and application potential of this kind of hydrogel are thoroughly explored. Due to the strong cationic chelation characteristics of thiourea groups, HA‐NCSN/Ag+ hydrogel can gel at low Ag+ concentration and achieve long‐term slow release of Ag+ at stable concentration to balance the antibacterial and biocompatible properties. Moreover, this dynamic thiourea‐Ag+ crosslinking also endowed the hydrogel with the property of "gelation and encapsulation first, injection to cover wound when necessary". Then, the mangiferin self‐assembled nanoparticles are loaded into HA‐NCSN/Ag+ hydrogel as the radical oxygen species scavenger. [ABSTRACT FROM AUTHOR]

Background: Elderly patients suffering from osteoporotic fractures are more susceptible to delayed union or nonunion, and their bodies then are in a state of low-grade chronic inflammation with decreased antioxidant capacity. Tanshinone IIA is widely used in treating cardiovascular and cerebrovascular diseases in China and has anti-inflammatory and antioxidant effects. We aimed to observe the antioxidant effects of Tanshinone IIA on mesenchymal stem cells (MSCs), which play important roles in bone repair, and the effects of local application of Tanshinone IIA using an injectable biodegradable hydrogel on osteoporotic fracture healing. Methods: MSCs were pretreated with or without different concentrations of Tanshinone IIA followed by H2O2 treatment. Ovariectomized (OVX) C57BL/6 mice received a mid-shaft transverse osteotomy fracture on the left tibia, and Tanshinone IIA was applied to the fracture site using an injectable hydrogel. Results: Tanshinone IIA pretreatment promoted the expression of nuclear factor erythroid 2-related factor 2 and antioxidant enzymes, and inhibited H2O2-induced reactive oxygen species accumulation in MSCs. Furthermore, Tanshinone IIA reversed H2O2-induced apoptosis and decrease in osteogenic differentiation in MSCs. After 4 weeks of treatment with Tanshinone IIA in OVX mice, the bone mineral density of the callus was significantly increased and the biomechanical properties of the healed tibias were improved. Cell apoptosis was decreased and Nrf2 expression was increased in the early stage of callus formation. Conclusions: Taken together, these results indicate that Tanshinone IIA can activate antioxidant enzymes to protect MSCs from H2O2-induced cell apoptosis and osteogenic differentiation inhibition. Local application of Tanshinone IIA accelerates fracture healing in ovariectomized mice. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, and it leads to irreversible inflammation in intra-articular joints. Current treatment approaches for RA include non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), corticosteroids, and biological agents. To overcome the drug-associated toxicity of conventional therapy and transdermal tissue barrier, an injectable NSAID-loaded hydrogel system was developed and explored its efficacy. Results: The surface morphology and porosity of the hydrogels indicate that they mimic the natural ECM, which is greatly beneficial for tissue healing. Further, NSAIDs, i.e., diclofenac sodium, were loaded into the hydrogel, and the in vitro drug release pattern was found to be burst release for 24 h and subsequently sustainable release of 50% drug up to 10 days. The DPPH assay revealed that the hydrogels have good radical scavenging activity. The biocompatibility study carried out by MTT assay proved good biocompatibility and anti-inflammatory activity of the hydrogels was carried out by gene expression study in RAW 264.7 cells, which indicate the downregulation of several key inflammatory genes such as COX-2, TNF-α & 18s. Conclusion: In summary, the proposed ECM-mimetic, thermo-sensitive in situ hydrogels may be utilized for intra-articular inflammation modulation and can be beneficial by reducing the frequency of medication and providing optimum lubrication at intra-articular joints. [ABSTRACT FROM AUTHOR]

The need for tumor postoperative treatments aimed at recurrence prevention and tissue regeneration have raised wide considerations in the context of the design and functionalization of implants. Herein, an injectable hydrogel system encapsulated with anti-tumor, anti-oxidant dual functional nanoparticles has been developed in order to prevent tumor relapse after surgery and promote wound repair. The utilization of biocompatible gelatin methacryloyl (GelMA) was geared towards localized therapeutic intervention. Zeolitic imidazolate framework-8@ceric oxide (ZIF-8@CeO2, ZC) nanoparticles (NPs) were purposefully devised for their proficiency as reactive oxygen species (ROS) scavengers. Furthermore, injectable GelMA hydrogels loaded with ZC NPs carrying doxorubicin (ZC-DOX@GEL) were tailored as multifunctional postoperative implants, ensuring the efficacious eradication of residual tumor cells and alleviation of oxidative stress. In vitro and in vivo experiments were conducted to substantiate the efficacy in cancer cell elimination and the prevention of tumor recurrence through the synergistic chemotherapy approach employed with ZC-DOX@GEL. The acceleration of tissue regeneration and in vitro ROS scavenging attributes of ZC@GEL were corroborated using rat models of wound healing. The results underscore the potential of the multifaceted hydrogels presented herein for their promising application in tumor postoperative treatments. [ABSTRACT FROM AUTHOR]

Endogenous stimuli-responsive injectable hydrogels hold significant promise for practical applications due to their spatio-temporal controllable drug delivery. Herein, we report a facile strategy to construct a series of in situ formation polypeptide hydrogels with thermal responsiveness and enzyme-triggered dynamic self-assembly. The thermo-responsive hydrogels are from the diblock random copolymer mPEG-b-P(Glu-co-Tyr). The L-glutamic acid (Glu) segments with different γ-alkyl groups, including methyl, ethyl, and n-butyl, offer specific secondary structure, facilitating the formation of hydrogel. The L-tyrosine (Tyr) residues not only provide hydrogen-bond interactions and thus adjust the sol–gel transition temperatures, but also endow polypeptide enzyme-responsive properties. The PTyr segments could be phosphorylated, and the phosphotyrosine copolymers were amphiphilies, which could readily self-assemble into spherical aggregates and transform into sheet-like structures upon dephosphorylation by alkaline phosphatase (ALP). P(MGlu-co-Tyr/P) and P(MGlu-co-Tyr) copolymers showed good compatibility with both MC3T3-E1 and Hela cells, with cell viability above 80% at concentrations up to 1000 μg/mL. The prepared injectable polypeptide hydrogel and its enzyme-triggered self-assemblies show particular potential for biomedical applications. [ABSTRACT FROM AUTHOR]

Corneal stromal fibrosis is a common cause of visual impairment resulting from corneal injury, inflammation and surgery. Therefore, there is an unmet need for inhibiting corneal stromal fibrosis. However, bioavailability of topical eye drops is very low due to the tear and corneal barriers. In situ delivery offers a unique alternative to improve efficacy and minimize systemic toxicity. Herein, a drug delivery platform based on thermoresponsive injectable hydrogel/nano-micelles composite with in situ drug-controlled release and long-acting features is developed to prevent corneal scarring and reduce corneal stromal fibrosis in lamellar keratoplasty. The in-situ gelation hydrogels enabled direct delivery of celastrol to the corneal stroma. In vivo evaluation with a rabbit anterior lamellar keratoplasty model showed that hydrogel/micelles platform could effectively inhibit corneal stromal fibrosis. This strategy achieves controlled and prolonged release of celastrol in the corneal stroma of rabbit. Following a single corneal interlamellar injection, celastrol effectively alleviated fibrosis via mTORC1 signal promoting autophagy and inhibiting TGF-β1/Smad2/3 signaling pathway. Overall, this strategy demonstrates promise for the clinical application of celastrol in preventing corneal scarring and reducing corneal stromal fibrosis post-lamellar keratoplasty, highlighting the potential benefits of targeted drug delivery systems in ocular therapeutics. Thermoresponsive injectable and transparent hydrogel deliver drug locally to treat corneal scars and various eye diseases. [Display omitted] • An injectable thermoresponsive-hydrogel-based drug delivery platform was fabricated. • The in-situ gelation platform delivered celastrol directly to corneal stroma with controlled and prolonged release. • The platform hampered corneal scars in lamellar keratoplasty. • Celastrol alleviates fibrosis via promoting autophagy and inhibiting TGF-β1 pathway. [ABSTRACT FROM AUTHOR]

Injectable hyaluronic acid (HA) hydrogel plays an important role in dermal filling. However, conventional HA dermal fillers mostly lack bio‐functional diversity and frequently cause adverse reactions because of the chemical stiffness of highly modified degree and crosslinker residues. In this study, polylactic acid (PLA) was embedded into HA hydrogel as a bioactive substance and 1,4‐butanediol diglycidyl ether was used as a crosslinker to prepare the HA/PLA composite hydrogel with enhanced biocompatibility and biological performance. We aimed to investigate the properties of HA/PLA composite hydrogels as dermal fillers by assessing the rheological properties, surface microstructure, enzymolysis stability, swelling ratio, degradation rate, cytotoxicity, and anti‐wrinkle effect on photo‐aged skin. The results showed that the stability and stiffness of the composite hydrogel decreased with an increasing amount of PLA, while the in vivo safety of the HA/PLA hydrogel was enhanced, showing no adverse reactions such as edema, redness, or swelling. Moreover, the composite hydrogel with 2 wt% PLA exhibited excellent anti‐wrinkle effects, showing the highest collagen production. Thus, the PLA‐embedded HA composite hydrogel showed potential as a dermal filler with high safety, easy injectability, and excellent anti‐wrinkle effects. [ABSTRACT FROM AUTHOR]

Managing bone defects remains a formidable clinical hurdle, primarily attributed to the inadequate orchestration of vascular reconstruction and osteogenic differentiation in both spatial and temporal dimensions. This challenge persists due to the constrained availability of autogenous grafts and the limited regenerative capacity of allogeneic or synthetic bone substitutes, thus necessitating continual exploration and innovation in the realm of functional and bioactive bone graft materials. While synthetic scaffolds have emerged as promising carriers for bone grafts, their efficacy is curtailed by deficiencies in vascularization and osteoinductive potential. Nitric oxide (NO) plays a key role in revascularization and bone tissue regeneration, yet studies related to the use of NO for the treatment of bone defects remain scarce. Herein, we present a pioneering approach leveraging a photothermal-responsive system to augment NO release. This system comprises macromolecular mPEG-P nanoparticles encapsulating indocyanine green (ICG) (NO-NPs@ICG) and a mPEG-PA-PP injectable thermosensitive hydrogel carrier. By harnessing the synergistic photothermal effects of near-infrared radiation and ICG, the system achieves sustained NO release, thereby activating the soluble guanylate cyclase (SGC)-cyclic guanosine monophosphate (cGMP) signaling pathway both in vitro and in vivo. This orchestrated cascade culminates in the facilitation of angiogenesis and osteogenesis, thus expediting the reparative processes in bone defects. In a nutshell, the NO release-responsive system elucidated in this study presents a pioneering avenue for refining the bone tissue microenvironment and fostering enhanced bone regeneration.

Cyclodextrins are used to include curcumin to form complex, which is subsequently loaded into a reactive oxygen species (ROS) responsive hydrogel (Cur gel). This gel exhibits a dual ROS scavenging effect. The gel can neutralize extracellular ROS to lead to a ROS-sensitive curcumin release. The released curcumin complex can eliminate intracellular ROS. Furthermore, the Cur gel effectively downregulates the expression of CD16 and IL-1β while upregulating CD206 and TGF-β in oxygen and glucose-deprived (OGD) BV2 cells. Additionally, it restores the expression of synaptophysin and PSD95 in OGD N2a cells. Upon injection into the stroke cavity, the Cur gel reduces CD16 expression and increases CD206 expression in the peri-infarct area of stroke mice, indicating an in vivo anti-inflammatory polarization of microglia. Colocalization studies using PSD95 and VGlut-1 stains, along with Golgi staining, reveal enhanced neuroplasticity. As a result, stroke mice treated with the Cur gel exhibit the most significant motor function recovery. Mechanistic investigations demonstrate that the released curcumin complex scavenges ROS and suppresses the activation of the ROS-NF-κB signaling pathway by inhibiting the translocation of p47-phox and p67-phox to lead to anti-inflammatory microglia polarization. Consequently, the Cur gel exhibits promising potential for promoting post-stroke rehabilitation in clinics.