Injectable Thermosensitive Hydrogel Research Articles

Responsively aggregatable nanochelator-mediated antiangiogenesis to enhance interventional therapies for liver cancer

Transarterial chemoembolization (TACE) requires the complete embolization of tumor vessels. However, after embolization, tumor hypoxia and angiogenesis increase, and copper ions (Cu2+) play a key role in the regulation of angiogenesis. Decreasing the undesirable release of Cu2+ into serum and tumor tissues is a major challenge in the use of TACE. In this study, we constructed an adhesive injectable thermosensitive hydrogel (poly(N-isopropylacrylamide-codopamine methacrylamide), PND) loaded with a small Cu chelator (SO-N) for use in synergistic tumor embolization; this agent is called PNDS. SO-N chelates Cu2+ in a highly selective manner and can effectively consume the biocopper that is involved in angiogenesis. In addition, the adhesive thermosensitive hydrogel rapidly formed a gel in situ, which further inhibited the local blood ny to the tumor and accelerated ischemic necrosis. Moreover, the ability of PNDS to efficiently chelate Cu2+ and inhibit angiogenesis was investigated in vitro. Our in vivo experiments demonstrated that PNDS can promote tumor necrosis, reduce tumor Cu2+ levels, inhibit angiogenesis and tumor metastasis, and greatly prolong rabbit survival. This study is the first to show elevated serum Cu2+ levels in liver cancer patients with TACE failure/refractoriness; PNDS provides a promising approach for improving the efficacy of TACE for liver cancer by regulating Cu homeostasis.

Cabazitaxel-Loaded Thermosensitive Hydrogel System for Suppressed Orthotopic Colorectal Cancer and Liver Metastasis.

The treatment of colorectal cancer is always a major challenge in the field of cancer research. The number of estimated new cases of colorectal cancer worldwide in 2020 is 1 148 515, and the estimated number of deaths is 576 858, revealing that mortality accounted for approximately half of the disease incidence. The development of new drugs and strategies for colorectal cancer treatment is urgently needed. Thermosensitive injectable hydrogel PDLLA-PEG-PDLLA (PLEL) loaded with cabazitaxel (CTX) is used to explore its anti-tumor effect on mice with orthotopic colorectal cancer. CTX/PLEL is characterized by a solution state at room temperature and a hydrogel state at physiologic temperature. The excipients MPEG-PCL and PDLLA-PEG-PDLLA have good biocompatibility and biodegradability. The simple material synthesis and preparation process renders this system cost-effective and more conducive to clinical transformation. An orthotopic colorectal cancer model is established by transplantation subcutaneous tumors onto the cecum of mice. According to the results of experiments in vivo, CTX/PLEL significantly inhibits orthotopic colorectal cancer and liver metastasis in mice. The results indicate that CTX/PLEL nanoparticle preparations have high security and excellent anti-tumor effects, and have great application potential in colorectal cancer therapy.

An injectable thermosensitive hydrogel delivering M2 macrophage-derived exosomes alleviates osteoarthritis by promoting synovial lymphangiogenesis

Osteoarthritis (OA) is a prevalent chronic degenerative disease affecting millions worldwide, with current treatment measures lacking efficacy in slowing disease progression. The synovial lymphatic system (SLS) has emerged as a crucial player in OA pathogenesis, with compromised drainage function contributing to disease advancement. Lymphatic endothelial cells (LECs) within the SLS are influenced by synovial macrophages, whose precise impact on LEC function remains unclear. Exosomes released by macrophages may serve as mediators of this interaction, with potential implications for OA progression. Here, we propose that polarized macrophages modulate LEC activity via exosome release in synovial tissue, with M2 macrophage-derived exosomes (M2Exo) promoting LEC proliferation, migration, and lymphangiogenesis, potentially offering a therapeutic avenue for OA. Moreover, we developed an injectable thermosensitive hydrogel with the characteristic of sustained release of M2Exo for alleviating OA. The hydrogel was prepared by dynamically linking hyaluronic acid (HA) and Pluronic F-127 and loading M2Exo, termed as M2Exo loaded HP hydrogel. The in vitro and in vivo experiments showed that M2Exo loaded HP hydrogel exhibits a controlled release profile of exosomes, thereby efficaciously fostering synovial lymphangiogenesis and enhancing synovial lymphatic drainage functionality under OA conditions, thus alleviating OA progression, and providing promising insights into OA therapeutic strategies. Statement of significanceOsteoarthritis (OA) is a widespread degenerative disease with limited effective treatments to halt its progression. This research highlights the critical role of the synovial lymphatic system (SLS) in OA, focusing on how macrophage-derived exosomes influence lymphatic endothelial cell (LEC) function. We propose that M2 macrophage-derived exosomes (M2Exo) enhance LEC activity, promoting lymphangiogenesis, and offering a therapeutic approach for OA. Furthermore, we developed an injectable thermosensitive hydrogel (M2Exo loaded HP hydrogel) for sustained M2Exo release. Our in vitro and in vivo experiments demonstrate that this hydrogel supports synovial lymphangiogenesis and improves lymphatic drainage, effectively alleviating OA progression. This study presents significant advancements in OA therapy, offering new insights into its management.

Synthesis and in vitro study of biodegradable and thermoresponsive polymer based on polysuccinimide for drug delivery

Hydrogels, defined as polymer networks with a high water content and insoluble in water, have emerged as pivotal materials in biomedical research due to their resemblance to the natural extracellular matrix. The aim of this study is to develop an injectable, thermoresponsive, and biodegradable hydrogel. The hydrogel (PSI-t) was derived from poly (aspartic acid) (PSI) by grafting hydrophobic dodecylamine (DA) and hydrophilic ethanolamine (EA) groups onto its backbone. PSI-t was found to exhibit a unique sol state at room temperature, which facilitates facile injection, and undergoes rapid gelation at physiological temperatures, highlighting its potential as an injectable thermosensitive hydrogel for targeted drug delivery. In vitro tests confirmed the biocompatibility of the thermosensitive hydrogel, and sustained drug release studies using the model drug, acetaminophen (AP), underscored the efficacy of the hydrogel as a controlled release vehicle. Furthermore, the hydrogel was found to be easily eliminated through bio-hydrolysis, thus enabling prolonged drug effects while mitigating any potential toxicity. These findings suggest that PSI-t is a promising candidate for an innovative and injectable drug delivery system in biomedical applications.

An Injectable Thermosensitive Hydrogel with Antibacterial and Antioxidation Properties for Accelerating Wound Healing.

As a new type of wound dressing, hydrogels have attracted more and more attention. However, traditional hydrogel wound dressings lack inherent antibacterial properties and are difficult to match irregular wounds, which leads to an easy wound bacterial infection. To solve the problems associated with traditional hydrogels, in this research, a thermosensitive hydrogel (PFLD) for wound dressings was developed based on Poloxamer 407 (PF127), lysine (Lys), and 3,4-dihydroxyphenylacetic acid (DOPAC). Rheological tests indicated that the PFLD hydrogel possesses injectability, adaptability to deformation, and sufficient mechanical strength for wound dressing applications. In addition, it could in situ gel at 33 °C, which indicated that the hydrogel could undergo sol-to-gel transition under body temperature. Upon using it in wound treatment, it could adapt to irregular wounds to achieve full coverage of the wound and promote the rapid hemostasis of wound bleeding. Due to the presence of DOPAC in the hydrogel, it exhibited excellent antibacterial and antioxidant properties on the wounds. The skin defect model showed that the wound shrinkage was the fastest after PFLD hydrogel treatment. On day 14, the wound shrinkage rates were 81.68 and 99.77% for the control and PFLD hydrogel groups, respectively. Therefore, the PFLD hydrogel has a broad application prospect as a dressing for the treatment of irregular wounds.

Injectable thermosensitive hydrogels loaded with irradiated tumor cell-derived microparticles and manganese activate anti-tumor immunity

Immunosuppressive tumor microenvironment and inadequate activation of the innate immune system are important reasons for the failure of systemic anti-tumor immunotherapy. Irradiated tumor cell-derived microparticles (RMPs) can induce immunogenic cell death (ICD) of tumor cells and inhibit the M2-like phenotype of tumor-associated macrophages (TAMs). The current study found that double-stranded DNA was enriched in RMPs, which combined with manganese ions (Mn2+), the natural activator of cGAS-STING signaling, and synergistically amplified cGAS-STING signaling cascade in antigen-presenting cells (APCs). On this basis, a polyamino acid thermosensitive hydrogel delivery system was designed to simultaneously load RMPs and Mn2+. The obtained RMPs@Mn2+ hydrogel exhibited thermosensitivity, biocompatibility and sustained release characteristics. The intratumoral injection of RMPs@Mn2+ slowly released RMPs and Mn2+, inducing ICD of tumor cells, continuously activating cGAS-STING signaling of APCs, reprograming TAMs to M1-like phenotype, and promoting the activation of dendritic cells in tumor draining lymph nodes. The full activation of innate immunity at the tumor site further promoted priming and tumor infiltration of T cells, leading to tumor regression. RMPs@Mn2+ combined with anti-PD-1 achieved strong anti-cancer efficacy in a refractory malignant ascites model, in which more than 50 % of mice with malignant ascites achieved complete regression and long-term immune memory.

Biomineralized MnO2 Nanoparticle-Constituted Hydrogels Promote Spinal Cord Injury Repair by Modulating Redox Microenvironment and Inhibiting Ferroptosis.

Spinal cord injury (SCI) is one of the most severe injuries, characterized by multiple positive feedback regulatory signaling networks formed by oxidative stress and inflammation in the injury microenvironment, leading to neuronal cell damage and even death. Here, astragaloside IV (AS), known for its regulatory role in ferroptosis, was encapsulated in the cavity of apoferritin (HFn) after an in situ biomineralization process involving MnO2, resulting in the synthesis of HFn@MnO2/AS nanoparticles. These nanoparticles were then dispersed in chitosan/polyvinyl alcohol/glutaraldehyde/sodium β-glycerophosphate (CGPG) hydrogels to form CGPG-HFn@MnO2/AS injectable thermosensitive hydrogels that can scavenge reactive oxygen species (ROS) in the microenvironment. Our findings indicated that the prepared CGPG-HFn@MnO2/AS hydrogel exhibited remarkable efficacy in scavenging ROS in vitro, effectively ameliorating the oxidative stress microenvironment post-SCI. Furthermore, it inhibited oxidative stress-induced ferroptosis in vitro and in vivo by regulating SIRT1 signaling, thereby promoting neuronal cell migration and repair. Hence, the developed hydrogel combining MnO2 and AS exhibited multifaceted abilities to modulate the pathological microenvironment, providing a promising therapeutic strategy for central nervous system (CNS) diseases.

A photothermal responsive system accelerating nitric oxide release to enhance bone repair by promoting osteogenesis and angiogenesis

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.

Synthesis and characterization of injectable thermosensitive hydrogel based on Pluronic-grafted silk fibroin copolymer containing hydroxyapatite nanoparticles as potential for bone tissue engineering

Injectable hydrogels are promising for bone tissue engineering due to their minimally invasive application and adaptability to irregular defects. This study presents the development of pluronic grafted silk fibroin (PF-127-g-SF), a temperature-sensitive graft copolymer synthesized from SF and modified PF-127 via a carbodiimide coupling reaction. The PF-127-g-SF copolymer exhibited a higher sol-gel transition temperature (34 °C at 16 % w/v) compared to PF-127 (23 °C), making it suitable for injectable applications. It also showed improved flexibility and strength, with a yielding point increase from <10 % to nearly 30 %. Unlike PF-127 gel, which degrades within 72 h in aqueous media, the PF-127-g-SF copolymer maintained a stable gel structure for over two weeks due to its robust crosslinked hydrogel network. Incorporating hydroxyapatite nanoparticles (n-HA) into the hydrogel reduced pore size and decreased swelling and degradation rates, extending structural stability to four weeks. Increasing n-HA concentration from 0 % to 20 % reduced porosity from 80 % to 66 %. Rheological studies indicated that n-HA enhanced the scaffold's strength and mechanical properties without altering gelation temperature. Cellular studies with MG-63 cells showed that n-HA concentration influenced cell viability and mineralization, highlighting the scaffold's potential in bone tissue engineering.

Coordinating Macrophage Targeting and Antioxidation by Injectable Nanocomposite Hydrogel for Enhanced Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA), an immune-mediated inflammatory disease, is characterized by a large number of infiltrated immune cells and abnormally elevated reactive oxygen species (ROS) in the joint. Various proinflammatory factors secreted by macrophages and the elevated ROS by inflammatory cells are deeply intertwined and together contribute to joint damage. Targeted and sustained anti-inflammation and antioxidation strategies are needed for RA treatment. To alleviate the oxidative stress and target the source of inflammatory cytokines, we developed a thermosensitive injectable hydrogel, Dex-DSLip/Cro@Gel, to coordinate the targeted anti-inflammatory and antioxidation effects. Within the injectable gel, dexamethasone (Dex)-loaded liposomes (Dex-DSLip), modified with dextran sulfate (DS), target macrophages via interaction with scavenger receptor A (SR-A). Simultaneously, crocin I (Cro) is loaded in the gel with a high loading capacity. The porous structure of Dex-DSLip/Cro@Gel successfully prolongs the retention time of both drugs and sustains the release of Dex and Cro. After intra-articular injection of Dex-DSLip/Cro@Gel in RA rats, the expression of inflammatory factors in the ankle joints was significantly reduced. Joint erythema and bone erosion were markedly alleviated. Through the synergistic effects of Dex and Cro, Dex-DSLip/Cro@Gel demonstrates targeted anti-inflammatory and antioxidation effects as well as mitigated bone erosion and long-term therapeutic effects for RA. This thermosensitive injectable nanocomposite hydrogel synergizes anti-inflammatory and antioxidation effects and targets the microenvironment in the joint, offering a new approach for RA treatment.

Chemodynamic therapy combined with endogenous ferroptosis based on “sea urchin-like” copper sulfide hydrogel for enhancing anti-tumor efficacy

Chemodynamic therapy (CDT) is a promising strategy for cancer treatment, however, its application is restricted by low hydrogen peroxide (H2O2) concentration, insufficient reactive oxygen species (ROS) generation, and high glutathione (GSH) levels. Here, we developed an injectable thermosensitive hydrogel (DSUC-Gel) based on “sea urchin-like” copper sulfide nanoparticles (UCuS) loaded with dihydroartemisinin (DHA) and sulfasalazine (SAS) to overcome these limitations of CDT. DSUC was cleaved to release DHA, SAS and Cu2+ under acidic tumor microenvironment to enhance CDT. DHA with peroxide bridge responded to intracellular Fe2+ to alleviate H2O2 deficiency. SAS prevented GSH synthesis by targeting SLC7A11 and inhibited glutathione peroxidase (GPX4) activity to induce endogenous ferroptosis. ROS produced by Fenton-like reaction of Cu2+ promoted lipid peroxidation (LPO) accumulation to promote ferroptosis. Enhanced CDT and ferroptosis induced immunogenic cell death (ICD), promoted dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) infiltration. As a result, DSUC-Gel significantly inhibited tumor growth both in vitro and in vivo. Our study provides a novel approach for enhancing anti-tumor efficacy by combining CDT, endogenous ferroptosis and ICD.

Two-dimensional polydopamine nanosheet-based thermosensitive supramolecular hydrogels for photothermal-chemo synergistic treatment of melanoma

The development of injectable thermosensitive hydrogels with photothermal elimination of tumors and precisely controllable drug release properties is critical for tumor eradication. Herein, a novel injectable thermosensitive supramolecular hydrogel PDAns@CPT-peg/α-CD was developed, which was formed by using two-dimensional polydopamine nanosheets (PDAns) as the photothermal backbone, loaded with the PEGylated camptothecin prodrug (CPT-peg) through π-π stacking and hydrophobic binding, and then crosslinked by the introduction of α-cyclodextrin (α-CD) host–guest self-assembly. PDAns as hydrogel skeleton endowed the hydrogel with excellent photothermal conversion effect, and the large specific surface area of PDAns enables efficient loading of hydrophobic anticancer drugs and avoids undesired leakage. Moreover, the dynamic host–guest cross-linking endows the hydrogel with reversible gel-sol transition and injectability, the gel-sol transition temperature can be easily tunable by the CD concentration, under 808 nm laser irradiation, the PDAns@CPT-peg/α-CD hydrogel can be rapidly heated to the temperature required for photothermal therapy, simultaneously triggering the thermosensitive gel-sol transition followed by the on-demand release of CPT-peg. In vivo evaluation demonstrated that the synergistic photothermal-chemotherapeutic effect mediated by PDAns@CPT-peg/α-CD hydrogel almost eradicated melanoma under low-dose NIR laser (0.15 W cm−2) irradiation. This work provides an effective and convenient strategy for constructing a multifunctional hydrogel platform for the photothermal-chemo synergistic treatment of tumors.

An Injectable Black Phosphorus Hydrogel for Rapid Tooth Extraction Socket Healing.

The excess production of reactive oxygen species (ROS) will delay tooth extraction socket (TES) healing. In this study, we developed an injectable thermosensitive hydrogel (NBP@BP@CS) used to treat TES healing. The hydrogel formulation incorporated black phosphorus (BP) nanoflakes, recognized for their accelerated alveolar bone regeneration and ROS-scavenging properties, and dl-3-n-butylphthalide (NBP), a vasodilator aimed at enhancing angiogenesis. In vivo investigations strongly demonstrated that NBP@BP@CS improved TES healing due to antioxidation and promotion of alveolar bone regeneration by BP nanoflakes. The sustained release of NBP from the hydrogel promoted neovascularization and vascular remodeling. Our results demonstrated that the designed thermosensitive hydrogel provided great opportunity not only for ROS elimination but also for the promotion of osteogenesis and angiogenesis, reflecting the "three birds with one stone" concept, and has tremendous potential for rapid TES healing.

Enhanced localized therapeutic precision: A face-to-face folate-targeted Cu2+-mediated nanotherapy with thermosensitive sustained-release system

Safe and effective Cu2+ supplementation in local lesion is crucial for minimizing toxicity of DSF-based chemotherapy. Targeted delivery of Cu2+ appears more promising. Intraperitoneal chemotherapy for peritoneal carcinoma (PC) establishes “face-to-face” contact between targeted nanocarriers and tumor tissue. Herein, this study developed a biodegradable, injectable thermosensitive hydrogel that coencapsulating DSF submicroemulsion (DSF-SE) and folate-modified liposome loading glycyrrhizic acid-Cu (FCDL). FCDL acted as ‘beneficial horse’ to target the tumor-localized folate receptor, thus liberating Cu2+ in tumor nidus. The prepared FCDL and DSF-SE were found with uniform sizes (160.2 nm, 175.4 nm), low surface charge (−25.77 mV, −16.40 mV) and high encapsulation efficiency (97.93 %, 90.08 %). In vitro drug release profile of FCDL, DSF-SE and FCDL＆DSF-SE@G followed a sustained release pattern. And the release behavior of Cu2+ from FCDL was pH-related, i.e., Cu2+ was released faster under acidic condition. When FCDL and DSF-SE were loaded into an PLGA-PEG-PLGA-based hydrogel system, FCDL＆DSF-SE@G was formed to ensure separated delivery of Cu2+ and DSF in space but synchronized release over time. The rheology experiment showed a satisfactory gelling temperature of 32.7 °C. In vitro cytotoxicity study demonstrated that FCDL＆DSF-SE@G significantly lowered the IC50 of free Cu2+/DSF, Cu2+/DSF hydrogel and non-targeted analogue by almost 70 %, 65 % and 32 %, respectively. Accordingly, in tumor-bearing mice, FCDL＆DSF-SE@G augmented the tumor inhibition rates for the same formulations by 352 %, 145 % and 44 %, respectively. The main mechanism was attributed to higher uptake of FCDL and DSF-SE, resulting in increased Cu(DDTC)2 formation, ROS production and cell apoptosis. In conclusion, this targeted nanotherapy approach with dual-nanocarriers loaded hydrogel system, with its focus on face-to-face contact between nanocarriers and tumor tissues in the peritoneal cavity, holds significant promise for intraperitoneal chemotherapy in PC.

Thermosensitive injectable polysaccharide-based hydrogels: Gelation mechanisms, synthetic strategies, biomedical applications, and challenges

In recent years, thermosensitive polysaccharide-based injectable hydrogels have gained increasing attention in biomedical applications, including wound healing, drug delivery, and cartilage repair. These hydrogels have favorable biocompatibility, biodegradability, and tunable physical and chemical properties. Thermosensitive polysaccharide-based injectable hydrogels are a class of intelligent soft matter material. They can undergo a reversible liquid-solid transition when exposed to temperature stimuli. Therefore, their precursor solutions can be accurately inserted into target sites with irregular geometries in a minimally invasive way and then transformed into gels in situ by the organism’s temperature stimulation to deliver biologically active molecules. This review summarizes the recent developments of thermosensitive injectable polysaccharide-based hydrogels. The focus is on the mechanism of sol-gel phase transition, as well as the design and preparation of thermosensitive polysaccharides and their applications in biomedical fields. In addition, the outlook of the challenges in biomedical applications is provided at the end of the paper.

Engineered Exosomes with ATF5-Modified mRNA Loaded in Injectable Thermogels Alleviate Osteoarthritis by Targeting the Mitochondrial Unfolded Protein Response.

Osteoarthritis (OA) progression is highly associated with chondrocyte mitochondrial dysfunction and disorders of catabolism and anabolism of the extracellular matrix (ECM) in the articular cartilage. The mitochondrial unfolded protein response (UPRmt), which is an integral component of the mitochondrial quality control (MQC) system, is essential for maintaining chondrocyte homeostasis. We successfully validated the pivotal role of activating transcription factor 5 (ATF5) in upregulating the UPRmt, mitigating IL-1β-induced inflammation and mitochondrial dysfunction, and promoting balanced metabolism in articular cartilage ECM, proving its potential as a promising therapeutic target for OA. Modified mRNAs (modRNAs) have emerged as novel and efficient gene delivery vectors for nucleic acid therapeutic approaches. In this study, we combined Atf5-modRNA (modAtf5) with engineered exosomes derived from bone mesenchymal stem cells (ExmodAtf5) to exert cytoprotective effects on chondrocytes in articular cartilage via Atf5. However, the rapid localized metabolization of ExmodAtf5 limits its application. PLGA-PEG-PLGA (Gel), an injectable thermosensitive hydrogel, was used as a carrier of ExmodAtf5 (Gel@ExmodAtf5) to achieve a sustained release of ExmodAtf5. In vitro and in vivo, the use of Gel@ExmodAtf5 was shown to be a highly effective strategy for OA treatment. The in vivo therapeutic effect of Gel@ExmodAtf5 was evidenced by the preservation of the intact cartilage surface, low OARSI scores, fewer osteophytes, and mild subchondral bone sclerosis and cystic degeneration. Consequently, the combination of ExmodAtf5 and PLGA-PEG-PLGA could significantly enhance the therapeutic efficacy and prolong the exosome release. In addition, the mitochondrial protease ClpP enhanced chondrocyte autophagy by modulating the mTOR/Ulk1 pathway. As a result of our research, Gel@ExmodAtf5 can be considered to be effective at alleviating the progression of OA.

TSG6-Exo@CS/GP Attenuates Endometrium Fibrosis by Inhibiting Macrophage Activation in a Murine IUA Model.

Intrauterine adhesion (IUA) is characterized by the formation of fibrous scar tissue within the uterine cavity, which significantly impacts female reproductive health and even leads to infertility. Unfortunately, severe cases of IUA currently lack effective treatments. This study presents a novel approach that utilizes tumor necrosis factor-(TNF) stimulated gene 6 (TSG6)-modified exosomes (Exos) in conjunction with an injectable thermosensitive hydrogel (CS/GP) to mitigate the occurrence of IUA by reducing endometrium fibrosis in a mouse IUA model. This study demonstrate that TSG6-modified Exos effectively inhibits the activation of inflammatory M1-like macrophages during the initial stages of inflammation and maintains the balance of macrophage phenotypes (M1/M2) during the repair phase. Moreover, TSG6 inhibits the interaction between macrophages and endometrial stromal fibroblasts, thereby preventing the activation of stromal fibroblasts into myofibroblasts. Furthermore, this research indicates that CS/GP facilitates the sustained release of TSG6-modified Exos, leading to a significant reduction in both the manifestations of IUA and the extent of endometrium fibrosis. Collectively, through the successful construction of CS/GP loaded with TSG6-modified Exos, a reduction in the occurrence and progression of IUA is achieved by mitigating endometrium fibrosis. Consequently, this approach holds promise for the treatment of IUA.

Synthesis of Injectable Thermosensitive Cinnamaldehyde-Loaded Chitosan Hydrogel for Antibacterial and Wound Dressing Application

The wound healing in the presence of bacterial infections is a complex process and prolonged challenge with severe implications for human health. To address this issue, injectable thermo-sensitive hydrogels as wound dressings have garnered considerable attention as a potential solution. In this study, we have developed an injectable and antibacterial thermosensitive hydrogel for wound healing, based on chitosan (CS) and β-glycerophosphate (β-GP) and modified with a range of cinnamaldehyde (CA). The CS/β-GP/CA gels demonstrate a phase transition at body temperatures, and exhibit good biocompatibility. Compared with the unmodified CS/β-GP hydrogels, incorporating CA can promote endothelial cell growth and the antibacterial property of the hydrogel system, which may lead to faster wound healing and tissue regeneration. Our findings suggest that the CS/β-GP/CA thermosensitive hydrogel emerges as a promising candidate for an injectable wound dressing in wound treatments.

Metabolic Nanoregulator Remodels Gut Microenvironment for Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is strongly related to the occurrence of accumulation of toxic reactive oxygen species (ROS), inflammation of the mucosa, and an imbalance of intestinal microbes. However, current treatments largely focus on a single factor, yielding unsatisfactory clinical outcomes. Herein, we report a biocompatible and IBD-targeted metabolic nanoregulator (TMNR) that synergistically regulates cellular and bacterial metabolism. The TMNR comprises a melanin-gallium complex (MNR) encapsulated within a thermosensitive and colitis-targeting hydrogel, all composed of natural and FDA-approved components. The TMNR confers superior broad-spectrum antioxidant properties, effectively scavenging reactive oxygen species (ROS) and blocking inflammatory signaling pathways. The presence of Ga3+ in TMNR selectively disrupts iron metabolism in pathogenic microorganisms due to its structural resemblance to the iron atom. Additionally, incorporating a thermosensitive injectable hydrogel enables targeted delivery of TMNR to inflammatory regions, prolonging their retention time and providing a physical barrier function for optimizing IBD treatment efficacy. Collectively, TMNR effectively modulates the redox balance of inflamed colonic epithelial tissue and disrupts iron metabolism in pathogenic microorganisms, thereby eliminating inflammation and restoring intestinal homeostasis against IBD. Hence, this work presents a comprehensive approach for precise spatiotemporal regulation of the intestinal microenvironmental metabolism for IBD treatment.

An injectable thermosensitive hyaluronic acid/pluronic F-127 hydrogel for deep penetration and combination therapy of frozen shoulder

Frozen shoulder (FS) is a common and progressive shoulder disorder that causes glenohumeral joint stiffness, characterized by inflammation and fibrosis. The treatment options are quite limited, and the therapeutic response is hindered by the fibrous membrane formed by excessive collagen and the rapid removal by synovial fluid. To address these challenges, we designed a hyaluronic acid/Pluronic F-127 (HP)-based injectable thermosensitive hydrogel as a drug carrier loaded with dexamethasone and collagenase (HPDC). We screened for an optimal HP hydrogel that can sustain drug release for approximately 10 days both in vitro and in vivo. In the meanwhile, we found that HP hydrogel could inhibit the proliferation and diminish the adhesion capacity of rat synovial cells induced by transforming growth factor-β1. Furthermore, using an established immobilization rat model of FS, intra-articular injection of HPDC significantly improved joint range of motion compared to medication alone. Relying on sustained drug release, the accumulated collagen fibers were degraded by collagenase to promote the deep delivery of dexamethasone. These findings showed a positive combined treatment effect of HPDC, providing a novel idea for the comprehensive treatment of FS.