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Depression is a type of mental disorder with a significant and persistent low mood as the main clinical feature. It is often accompanied by symptoms such as slow thinking, decreased will, loss of appetite, and weight loss. The current treatment methods for depression are mainly medical treatment, psychotherapy, and physical therapy. These treatments are dependent on the patient's autonomy and the patients may suspend treatment due to forgetting or refusing. Therefore, an anti-depressant intelligent drug release system was designed, which can achieve autonomously controlled doses for the treatment of depression by transdermal drug delivery system. The work of this study is as follows: (1) The first module: the electrothermal material heating layer. Several preparation methods were screened, and multiple sets of graphene (GE) electric thermogenic layers were successfully prepared. After increasing the actual energization area to 1 cm × 1 cm, the GE electric thermogenic layer is used as the heating layer of the electrothermal material of the system, and can reach a uniform surface temperature of (45 ± 0.5) °C within 15 s at a voltage of 6 V keeping the temperature fluctuation range not exceeding ±0.03 °C, and the resistance fluctuation range not exceeding ±20 Ω, which plays a role in controlling the temperature and heat treatment of the drug loaded gel layer. (2) The second module: the drug-loaded gel layer. Based on the L16 (45) orthogonal test, the best formulation and process of N-Isopropyl acrylamide-Acrylamide copolymer (P(NIPAAm-co-AAm)) hydrogel was determined. Then, the percutaneous permeability of Selegiline liposome was studied in vitro. (3) A rat model of depression was established using chronic unpredictable mild stress (CUMS) combined with separation. From the aspects of behavior (body weight, sucrose preference test, forced swimming test, open field test) and biochemical indexes (serum proinflammatory cytokines (IL-1ß, TNF-α), hippocampus HE staining observation), the therapeutic effect of hyperthermia, Selegiline oral administration and transdermal administration was discussed.

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Safe and efficient drug delivery to the inner ear has always been the focus of prevention and treatment of sensorineural deafness. The rapid development of nanodrug delivery systems based on hydrogel has provided a new opportunity. Among them, thermo-sensitive hydrogels promote the development of new dosage form for intratympanic injection. This smart biomaterial could transform to semisolid phase when the temperature increased. Thermo-sensitive hydrogel nanodrug delivery system is expected to achieve safe, efficient, and sustained inner ear drug administration. This article introduces the key techniques and the latest progress in this field.

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As a leading cause of vision impairment and blindness, corneal alkali burns lead to long-term visual deterioration or even permanent visual impairment while effective treatment strategies remain a challenge. Herein, a thermo-sensitive hydrogel with the combination of multi-functional protein progranulin (PGRN), a biological macromolecule consisting of several hundred amino acids and possessing a high molecular weight, is efficiently prepared through a convenient stirring and mixing at the low temperature. The hydrogel can be easily administrated to the ocular surface contacting with the cornea, which can be immediately transformed into gel-like state due to the thermo-responsive behavior, realizing a site-specific coating to isolate further external stimulation. The smart coating not only exhibits excellent transparency and biocompatibility, but also presents a constant delivery of PGRN, creating a nutritious and supportive micro-environment for the ocular surface. The results show that the prepared functional hydrogel can efficiently suppress inflammation, accelerate re-epithelization, and intriguingly enhance axonal regeneration via modulation of multiple signaling pathways, indicating the novel designed HydrogelPGRN is a promising therapy option for serious corneal injury.

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Purpose: Endoscopic ultrasound-guided fine-needle injection (EUS-FNI) offers a promising minimally invasive approach for locally targeted management of advanced pancreatic cancer. However, the efficacy is limited due to the rapid plasma clearance of chemotherapeutic agents. Injectable hydrogels can form drug release depots, which provide a feasible solution for optimizing targeted chemotherapy through EUS-FNI. Methods: A drug delivery system was developed, consisting of gemcitabine (GEM) and thermo-sensitive hydrogel (PLGA-PEG-PLGA, PPP). The injectability, gel formation ability, biocompatibility and sustained drug delivery properties of PPP hydrogel were verified in vitro and in vivo. The effects of GEM/PPP hydrogel on cell proliferation, invasion, metastasis, and apoptosis were explored through co-culturing with PANC-1 cells. The therapeutic effects of GEM/PPP hydrogel on xenograft mice were compared with those of GEM, ethanol and polidocanol using the precisely targeted EUS-FNI technology. Tumor sections were examined by H&E, Ki-67, and TUNEL staining. Results: GEM/PPP hydrogel exhibited excellent injectability, biocompatibility, and the capability of sustained drug delivery for up to 7 days by forming a gel triggered by body temperature. It demonstrated the best therapeutic effects, significantly reducing proliferation, invasion and migration of PANC-1 cells while promoting apoptosis. After precise injection using EUS-FNI technology, GEM/PPP hydrogel resulted in a reduction of tumor weight by up to 75.96% and extending the survival period by 14.4 days with negligible adverse effects. Pathological examination revealed no systemic toxicity and significant apoptosis and minimal proliferation as well. Conclusion: The combination of GEM/PPP hydrogel and EUS-FNI technology provides an optimal approach of precise chemotherapy for pancreatic cancer, builds a bridge for clinical translation of basic research, and brings great hope for innovation of minimally invasive treatment modalities. The first-hand EUS image data obtained in this study also serves as a crucial reference for future clinical trials.

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Postoperative pain is a major concern for most of the surgical patients, and an inadequate postoperative pain control may cause a series of complications. With an effective pain control and lesser side effects, local anesthetics are preferred for use in postoperative pain management. However, the action duration of current local anesthetics is too short to meet the requirements of postoperative analgesia. In this study, an injectable levobupivacaine (LB)-loaded thermo-sensitive hydrogel system based on biodegradable poly(D,L-lactide)-poly(ethylene glycol)-poly(D,L-lactide) (PLEL) was developed for long-acting local anesthetic, in which the soluble charged cation form of LB (LB HCl) was partly alkalified to the poorly soluble base form (LB base). This hybrid LB loaded PLEL system (hLB/PLEL) is a free flowable liquid at room temperature and changes into a semi-solid hydrogel once injection in response to the physiological temperature. Then, the dissolved LB HCl could release firstly from the hydrogel contributing to a quick work, and the insoluble LB base dissolved and released gradually as the decrease of the pH during the biodegradation of PLEL hydrogel, resulting in a long-term LB release in local. The drug release behavior, pharmacokinetic, and biocompatibility of the thermo-sensitive hLB/PLEL were studied in vitro and in vivo. The anesthetic effects of hLB/PLEL system were evaluated in the rat models of sciatic nerve block, subcutaneous infiltration anesthesia and postoperative pain as well. This hLB/PLEL system generated a significantly prolonged analgesic effect in rat models, which produced approximately 7 times longer duration than 0.75% LB HCl and effectively relieved the spontaneous pain for 3 days. In general, the presented hLB/PLEL system can not only achieve a fast-acting but also sustainably release LB to block the nerve and significantly extend the effect of local analgesia, which means a promising candidate for long-acting postoperative pain management.

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Due to the heterogeneity and the complexity of the tumor microenvironment, combination therapy, especially the combination of chemotherapy and photothermal therapy (PTT), had received increasing attention. However, the co-delivery of small molecule drugs for chemotherapy and photothermal agents was a key issue. Herein, we prepared a novel thermo-sensitive hydrogel loading with elemene (ELE)-loaded and nano graphene oxide (NGO)-based liposomes for enhanced combined therapy. ELE was applied as the model drug for chemotherapy because it was a natural sesquiterpene drug with broad-spectrum and efficient antitumor activity. NGO was applied as drug carrier and photothermal agent simultaneously due to its two-dimensional structure and high photo-thermal conversion efficacy. NGO was further modified with glycyrrhetinic acid (GA) to improve its water dispersion, biocompatibility and tumor-targeting ability. ELE was loaded by GA-modified NGO (GA/NGO) to prepare the liposomes designated as ELE-GA/NGO-Lip, which was further mixed with chitosan (CS) solution and ß-glycerin sodium phosphate (ß-GP) solution to prepare the thermo-sensitive hydrogel designated as ELE-GA/NGO-Lip-gel. The obtained ELE-GA/NGO-Lip-gel had the gelling temperature of 37°C, temperature and pH-response gel dissolution and high photo-thermal conversion effect. More importantly, ELE-GA/NGO-Lip-gel upon 808 nm laser irradiation had relative high anti-tumor efficiency against SMMC-7721 cells in vitro. This research might provide a potent platform for the application of thermos-sensitive injectable hydrogel in combined tumor therapy.

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Hydrogels are a promising material for a variety of applications after appropriate functional and structural design, which alters the physicochemical properties and cell signaling pathways of the hydrogels. Over the past few decades, considerable scientific research has made breakthroughs in a variety of applications such as pharmaceuticals, biotechnology, agriculture, biosensors, bioseparation, defense, and cosmetics. In the present review, different classifications of hydrogels and their limitations have been discussed. In addition, techniques involved in improving the physical, mechanical, and biological properties of hydrogels by admixing various organic and inorganic materials are explored. Future 3D printing technology will substantially advance the ability to pattern molecules, cells, and organs. With significant potential for producing living tissue structures or organs, hydrogels can successfully print mammalian cells and retain their functionalities. Furthermore, recent advances in functional hydrogels such as photo- and pH-responsive hydrogels and drug-delivery hydrogels are discussed in detail for biomedical applications.

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Chemotherapy is one of the main therapeutic strategies for the treatment of malignant melanoma. Conventional chemotherapeutic agents often lack targeting abilities, and efficacy is hampered by their high toxic effects to normal tissues and rapid clearance from the circulation. In this study, porous paclitaxel (PTX)-loaded polylactide (PLA) microspheres (PPMSs) were prepared by a modified double-emulsion-solvent evaporation method. In addition, PPMSs and cisplatin (DDP) were co-embedded in a thermosensitive hydrogel to construct a dual-drug co-delivery hydrogel system (PPMSs/DDP@Gel) for in-situ chemotherapy to treat melanoma by means of an intra-tumoral injection. The system allows for the sustained release of two drugs and exhibits good temperature-sensitive properties. In vitro antitumor activity showed that this hydrogel composite can induce B16 cell apoptosis and inhibit its migration. In vivo, anti-tumor studies have shown that the PPMSs/DDP@Gel significantly inhibited tumor growth, prolonged the survival of tumor-bearing mice, and had no obvious toxic side effects on major organs. Furthermore, immunohistochemical analysis revealed that PPMSs/DDP@Gel significantly inhibited tumor cell proliferation and promoted apoptosis of tumor cells. Taken together, the injectable temperature-sensitive PPMSs/DDP@Gel is a promising candidate for the local treatment of melanoma.

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Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide, posing a severe threat to human health. Surgical resection remains the most preferred option for gastric cancer treatment. However, for advanced gastric cancer, the curative effect of surgical resection is usually limited by the local recurrence, peritoneal carcinomatosis, or distal metastasis. Intraoperative chemotherapy is an attractive in situ adjuvant treatment strategy to reduce the recurrence and metastasis after surgical resection. Here, we designed a 5-fluorouracil (5-FU) and cis-platinum (DDP) co-delivery system based on a biodegradable temperature-sensitive hydrogel (PDLLA-PEG-PDLLA, PLEL) for intraoperative adjuvant combination chemotherapy of gastric cancer. This 5-FU + DDP/PLEL hydrogel system characterized by a special sol-gel phase transition in response to physiological temperature and presented sustained drug release in vitro and in vivo. A strong synergistic cell proliferation inhibition and apoptosis promotion of 5-FU + DDP/PLEL were observed against gastric cancer MKN45-luc cells. After intraperitoneal injection, the dual-drug loaded hydrogel formulation showed superior anti-tumor effects than the single-drug carrying hydrogels and combination of free 5-FU and DDP on the gastric cancer peritoneal carcinomatosis model. The use of hydrogel for dual-drug delivery had benefited to fewer side effects as well. What's more, we established a mouse model for postsurgical residual tumors and peritoneal carcinomatosis of gastric cancer, in which the intraoperative administration of 5-FU + DDP/PLEL also remarkably inhibited the local recurrence of the orthotopic tumors and the growth of the abdominal metastatic tumors, resulting in an extended lifetime. Hence, this developed dual-drug loaded hydrogel system has great potential in the intraoperative chemotherapy of gastric cancer, that suggests a clinically-relevant and valuable option for postsurgical management of gastric cancer.

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Radical pelvic surgery is commonly accompanied by the risk of postoperative erectile dysfunction induced by cavernous nerve injury (CNI-ED). The strategy of using adipose mesenchymal stem cell-derived exosomes (ADSC-Exo) to treat neurodegenerative diseases has shown promising results. However, it remains challenging to prolong the retention of unbound ADSC-Exo in damaged tissues to exert therapeutic effects. Herein, we develop a novel injectable thermo-sensitive hydroxyethyl chitosan/sodium ß-glycerophosphate hydrogel (HG) encapsulating ADSC-Exo (HG@Exo) to manage CNI-ED. The HG exhibits excellent injectability, structural stability, and body temperature sensitivity. In vivo assessment demonstrates that the designed ADSC-Exo-loaded HG hydrogel enhances the retention of ADSC-Exo and displays a slow release. Furthermore, when HG@Exo is applied to the site of nerve injury, erectile function in the bilateral cavernous nerve injury rat model is significantly improved. Thus, our finding indicates that the developed bioactive hydrogel presents a promising strategy for the effective management of CNI-ED.

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Poloxamers are negatively temperature-sensitive hydrogels and their hydrophilic groups interact with water molecules at lower temperatures (liquid phase) while their hydrophobic groups interact more strongly with increases in temperature causing gelation. To investigate the factors affecting the rheological properties of poloxamers, various parameters including different poloxamer P407 concentrations, poloxamers P407/P188 blending ratios and additives were examined. The results presented a clear trend of decreasing gelling temperature/time when P407 was at higher concentrations. Moreover, the addition of P188 enhanced the gelling temperature regardless of poloxamer concentration. Polysaccharides and their derivatives have been widely used as components of hydrogel and we found that alginic acid (AA) or carboxymethyl cellulose (CMC) reduced the gelling temperature of poloxamers. In addition, AA-containing poloxamer promoted cell proliferation and both AA -and CMC-containing poloxamer hydrogels reduced cell migration. This study investigated the intriguing characteristics of poloxamer-based hydrogel, providing useful information to compounding an ideal and desired thermo-sensitive hydrogel for further potential clinical applications such as development of sprayable anti-adhesive barrier, wound-healing dressings or injectable drug-delivery system for cartilage repair.

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BACKGROUND: Combination of chemotherapy and immune checkpoint inhibitor therapy has greatly improved the anticancer effect on multiple malignancies. However, the efficiency on triple-negative breast cancer (TNBC) is limited, since most patients bear "cold" tumors with low tumor immunogenicity. Doxorubicin (DOX), one of the most effective chemotherapy agents, can induce immunogenic cell death (ICD) and thus initiating immune response. METHODS: In this study, to maximize the ICD effect induced by DOX, chitosan and cell-penetrating peptide (R6F3)-modified nanoparticles (PNPs) loaded with ginsenoside Rg3 (Rg3) were fabricated using the self-assembly technique, followed by co-encapsulation with DOX based on thermo-sensitive hydrogel. Orthotopic tumor model and contralateral tumor model were established to observe the antitumor efficacy of the thermo-sensitive hydrogel combined with anti-PD-L1 immunotherapy, besides, the biocompatibility was also evaluated by histopathological. RESULTS: Rg3-PNPs strengthened the immunogenic cell death (ICD) effect induced by DOX. Moreover, the hydrogel co-loading Rg3-PNPs and DOX provoked stronger immune response in originally nonimmunogenic 4T1 tumors than DOX monotherapy. Following combination with PD-L1 blocking, substantial antitumor effect was achieved due to the recruitment of memory T cells and the decline of adaptive PD-L1 enrichment. CONCLUSION: The hydrogel encapsulating DOX and highly permeable Rg3-PNPs provided an efficient strategy for remodeling immunosuppressive tumor microenvironment and converting immune "cold" 4T1 into "hot" tumors.

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Purpose: Spinal cord injury (SCI) has a damaging impact on patients, amid being a worldwide problem with no effective treatment. Herein, we reported a method for functional therapy of SCI in rats, wherein we combined thermo-sensitive hydrogel with Sonic Hedgehog (SHH) expressed in rat bone-marrow derived mesenchymal stem cells (RMSCs). Methods: Bone marrow-derived mesenchymal stem cells (BMSCs) were isolated from Sprague-Dawley (SD) female rats. The SHH was optimized and transferred into RMSCs via cationic liposomes, while thermo-sensitive hydrogel was reformed with hyaluronate (HA) and Pluronic F127. Then, a rat model with SCI was established accordingly by male SD rats and randomized into sham, model, RMSCs with hydrogel and SHH-RMSCs with hydrogel. The evaluation of SCI repair based on Basso, Beattie Bresnahanlocomotor rating scale (BBB scale) and inclined plate score. Immunofluorescence, immunohistochemistry and hematoxylin-eosin were utilized to explore the expression of protein (GFAP, GAP43, NF200 and MBP) and histopathology. Results: It was demonstrated that transfection of SHH with cationic liposomes exhibited more effect in RMSCs than lipofectamine 2000. As shown in SEM, 3.5% HA-F127 demonstrated porous structure. In the MTT and dead/live assay, 3.5% HA-F127 showed good biocompatibility for RMSCs. Both RMSCs and SHH-RMSCs groups could significantly promote BBB and inclined plate scores (p < 0.01) compared with the model. Furthermore, the SHH-RMSC group was significantly improved than RMSC with the expression of related proteins, where NF200, MBP, and GAP43 were principally enhanced with the GFAP expression being virtually down-regulated. Conclusion: All in all, the results suggested that transplantation of RMSCs with SHH could improve the function of SCI and promote nerve regeneration.

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Local treatment after resection to inhibit glioma recurrence is thought to able to meet the real medical needs. However, the only clinically approved local glioma treatment-wafer containing bis(2-chloroethyl) nitrosourea (BCNU) showed very limited effects. Herein, in order to inhibit tumor recurrence with prolonged and synergistic therapeutic effect of drugs after tumor resection, an in situ dual-sensitive hydrogel drug delivery system loaded with two synergistic chemo-drugs BCNU and temozolomide (TMZ) was developed. The thermosensitive hydrogel was loaded with reactive oxygen species (ROS)-sensitive poly (lactic-co-glycolic) acid nanoparticles (NPs) encapsulating both BCNU and TMZ and also free BCNU and TMZ. The in vitro synergistic effect of BCNU and TMZ and in vivo presence of ROS at the residual tumor site were confirmed. The prepared ROS-sensitive NPs and thermosensitive hydrogel, as well as the long-term release behavior of drugs and NPs, were fully characterized both in vitro and in vivo. After >90% glioblastoma resection, the dual-sensitive hydrogel drug delivery system was injected into the resection cavity. The median survival time of the experimental group reached 65 days which was twice as long as the Resection only group, implying that this in situ drug delivery system effectively inhibited tumor recurrence. Overall, this study provides new ideas and strategies for the inhibition of postoperative glioma recurrence.

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Malignant tumor is one of the major diseases with high morbidity and mortality. The purpose of this study is to prepare berberine hydrochloride (BH) in situ thermo-sensitive hydrogel based on glycyrrhetinic acid (GA) modified nano graphene oxide (NGO) (GA-BH-NGO-gel). NGO was taken as the photosensitizer, GA was taken as the target molecule, and BH was taken as the model drug. The physicochemical properties and anti-tumor activity in vivo and in vitro were also studied. This subject could provide a certain theoretical basis for the chemo-photothermal therapy combined treatment of malignant tumor. The release behavior of GA-BH-NGO-gel in vitro presented sustained and temperature-dependent drug release effect. The anti-tumor activity studies in vivo and in vitro had shown that GA-BH-NGO-gel had stronger anti-tumor activity, which could be targeting distributed to the tumor tissues. Moreover, the inhibitory effect of GA-BH-NGO-gel was enhanced when combined with 808 nm of laser irradiation. In this research, the chemo-photothermal combination therapy was applied into the tumor treatment, which may provide certain research ideas for the clinical treatment of malignant tumor.

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Severe skin injuries are hard to repair and susceptible to bacterial infection. Development of a versatile antimicrobial anti-inflammatory hydrogel dressing that eliminates concern over antibiotic resistance is urgently needed but remains an elusive goal. Our research, described herein, the design and fabrication of a new family of supramolecular hydrogels based on hydroxypropyl chitosan (HPCS) and poly(N-isopropylacrylamide) (PNIPAM) may prove to be that goal. Employing the reversible cross-linking by ß-cyclodextrin (ß-CD) and adamantyl (AD) pre-assembly, the hydrogels can be formed in a facile one-pot method. Additionally, the structure and performance of the hydrogels can be controlled by a simple adjustment of the AD content. The obtained hydrogels exhibit an abundance of desired properties; they are injectable, thermosensitive, highly ductile, self-healable (will self-heal recurring damage to the hydrogel bandage of up to several millimeters wide), biocompatible, and have antimicrobial activity against Staphylococcus aureus when infused with dipotassium glycyrrhizinate (DG). Using a mouse full-thickness skin defect model, in vivo wound healing evaluations revealed that the DG-loaded hydrogels (HP-3/DG10) applied to the wound resulted in rapid wound closure. The hydrogels promoted efficient tissue remolding, collagen deposition, decreased inflammation and performed better than the control groups of commercial TegadermTM film and 3M dressing. Given their multifunctionality and in vivo efficacy, the DG-loaded HP hydrogels hold great potential as a wound dressing for full-thickness skin repair. STATEMENT OF SIGNIFICANCE: Injectable hydrogels are receiving increasing attention as an ideal wound dressing. To the best of our knowledge, however, injectable and wide-crack self-healing hydrogel dressings have been hardly studied. A versatile antimicrobial hydrogel without drug resistance or cytotoxicity is also highly required. Therefore, in the present study, we constructed injectable thermosensitive and wide-crack self-healing hydrogels with antibacterial and anti-inflammatory properties. These hydrogels were developed through novel strategies of the wide-crack self-healing design and the loading of the bioactive antibacterial and anti-inflammatory agent dipotassium glycyrrhizinate. The simple preparation method and multifunctionality of the studied hydrogel composites may provide important insights for the development of future biomaterials for wound dressings and other biomedical applications.

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The bone formation promoter recombinant human parathyroid hormone 1-34 [PTH (1-34)] has a short half-life and low bioavailability. In this study, we prepared a biodegradable and temperature-sensitive hyaluronic acid-poly-N-isopropyl acrylamide (AHA-g-PNIPAAm), and further investigated its effects of PTH (1-34) release and cell behavior as drug carrier. The structure of AHA-g-PNIPAAM was confirmed by hydrogen nuclear magnetic resonance spectroscopy and infrared spectroscopy. Next, PTH (1-34) loaded thermo-sensitive hydrogels were prepared by physical swelling method and their stability was investigated. The morphology of hydrogel was observed by scanning electron microscope. The minimum critical transition temperature and drug release behavior of hydrogels were investigated by ultraviolet spectrophotometry. The tetrazolium-based colorimetric assay (MTT assay) was used to investigate the toxicity and proliferation effects of PTH (1-34)-loaded thermo-sensitive hydrogel on mouse mononuclear macrophage RAW264.7 and mouse precranial osteoblasts MC3T3-E1. The effect of PTH (1-34)-loaded thermo-sensitive hydrogel on the differentiation of RAW264.7 was investigated by the tartrate-resistant acid phosphatase assay. The results showed that the PTH (1-34)-loaded thermo-sensitive hydrogel prepared in this study displayed regular three-dimensional honeycomb structure, and had good stability, thermo-sensitivity and sustained and controlled release properties, which could promote the proliferation of MC3T3-E1 cells more effectively and inhibit the differentiation of RAW264.7 into osteoclasts.

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The aim of the current work is to develop a thermo-sensitive hydrogel system of moxifloxacin hydrochloride (MOX) for improved ocular delivery. Fifteen formulations were prepared at different concentrations of ß-glycerophosphate disodium salt (ß-GP) 12-20% (w/v) and chitosan (CS) 1.7-1.9% (w/v). The optimized MOX loaded thermo-sensitive hydrogel system (F8), consisting of CS (1.8%, w/v) and ß-GP (16%, w/v), showed optimum gelation temperature (35 °C) and gelation time (2 min), thus was selected for further investigations. It showed a significant decrease (p < 0.05) in the zeta potential value compared to CS solution with a favorable pH value (7.1) and confirmed thermoreversible behavior. MOX loaded F8 displayed a porous structure under scanning electron microscopy. Rheological investigation of MOX loaded F8 revealed the presence of a strong hydrogel network with high elasticity along with a small loss factor of 0.08 indicating a great ease of gel formation. The release of MOX from F8 was found to be governed by a combined mechanism of diffusion and relaxation. Biological assessment of two concentrations of MOX loaded F8 (0.25 and 0.5%) was conducted using healthy and infected male albino New Zealand rabbits, where an improved and prolonged antibacterial activity against Staphylococcus aureus compared to plain MOX (0.5%), marketed MOX eye drops (0.5%), was shown. Moreover, histopathological examination of ocular tissues confirmed the antibacterial efficacy of the optimized formulation eight days post topical therapy. Consequently, the developed CS/ß-GP thermo-sensitive hydrogel system (F8) reveals a promising potential for enhancing the ocular delivery of MOX for treatment of bacterial infections.

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BACKGROUND: We utilized the destabilization of medial meniscus (DMM)-induced mice to illustrate the osteoarthritis (OA) suppressing and pain-relieving effects of a novel prolonged-release intra-articular (IA)-dexamethasone-loaded thermo-sensitive hydrogel (DLTH). METHODS: The effects of temperature and pH on DLTH formation and in vitro DLTH release profile were assessed. C57BL/6J mice were randomly divided into three groups: Ctrl group, Model group and DLTH group. The DLTH group received joint injections of 10 µL DLTH (1 mg/kg) into the right knee once a week from week 2 to week 11. We performed micro-computed tomography (Micro-CT) and histological analyses of safranin O-fast green, hematoxylin and eosin, and tartrate-resistant acid phosphatase in knee joints. We also carried out immunohistochemical (IHC) staining for matrix metalloproteinase-9 (MMP-9), MMP-13, and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) in cartilage and Ki-67 in synovia. Pain behavioral testing was carried out in all mice. The serum content of prostaglandin E2 (PGE2) and real-time polymerase chain reaction (PCR) of inflammatory cytokines and pain-related factors in dorsal root ganglia (DRGs) were evaluated. RESULTS: It took 20 minutes to form DLTH at pH 7.0 and 37 °C. The cumulative release profiles of dexamethasone (Dex) from DLTH at 37 °C revealed a rapid release in the first 24 h and a sustained slow release for 7 days. In vivo study illustrated that DLTH attenuated OA bone destruction and ameliorated synovitis and progression of OA in DMM-induced mice. The chondroprotective effects of DLTH were mediated by decreased expressions of MMP-9, MMP-13, and ADAMTS-5. The results showed that IA-DLTH exerted pain-relieving effects in OA mice. Upregulation of nociceptive response time (NRT) and downregulations of serum PGE2, inflammatory factors, and pain-related mediators in DRGs of mice in the DLTH group were recorded. CONCLUSIONS: Data presented in this study elucidated that DLTH exhibited a long and lasting Dex release and it is a potential sustainable drug delivery system (DDS) to treat OA locally. IA-DLTH injection exerted chondroprotective and pain-relieving effects in DMM-induced arthritis. The involvement of MMP-9, MMP-13, ADAMTS-5, and inflammatory and pain-related factors, may account for the suppression of OA progression and pain.

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To develop a biomaterial to lift the lesion and promote wound healing in endoscopic submucosal dissection (ESD), we used lactobionic acid (LA) to improve the water solubility of chitosan (CS) and prepared a new three-phase hydrogel system with lactobionic acid-modified chitosan/chitosan/ß-glycerophosphate (CSLA/CS/GP). The results indicated that the hydrogel retains temperature-sensitive properties, and CSLA obviously improved the low-temperature fluidity of the hydrogel precursor solution, enabling injection of the hydrogel by endoscopic needle. The mechanical strength and bio-adhesion of the hydrogels were also improved by the addition of CSLA and the hydrogels could be maintained in acidic environment for a few days and exhibit greater protection of cells. The CSLA/CS/GP hydrogels show good cytocompatibility. The heights of cushions elevated by CSLA/CS/GP hydrogels remained ∼ 60 % 2 h post-injection in porcine stomach models. Given the unique characteristics of these materials, the CSLA/CS/GP thermo-sensitive hydrogel is a promising intraoperative biomaterial in ESD.

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