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Oral ulcers can significantly reduce the life quality of patients and even lead to malignant transformations. Local treatments using topical agents are often ineffective because of the wet and dynamic environment of the oral cavity. Current clinical treatments for oral ulcers, such as corticosteroids, have limitations and side effects for long-term usage. Here, we develop adhesive hydrogel patches (AHPs) that effectively promote the healing of oral ulcers in a rat model. The AHPs are comprised of the quaternary ammonium salt of chitosan, aldehyde-functionalized hyaluronic acid, and a tridentate complex of protocatechualdehyde and Fe3+ (PF). The AHPs exhibit tunable mechanical properties, self-healing ability, and wet adhesion on the oral mucosa. Through controlling the formula of the AHPs, PF released from the AHPs in a temporal manner. We further show that the AHPs have good biocompatibility and the capability to heal oral ulcers rapidly. Both in vitro and in vivo experiments indicate that the PF released from AHPs facilitated ulcer healing by suppressing inflammation, promoting macrophage polarization, enhancing cell proliferation, and inducing epithelial-mesenchymal transition involving inflammation, proliferation, and maturation stages. This study provides insights into the healing of oral ulcers and presents an effective therapeutic biomaterial for the treatment of oral ulcers. By addressing the challenges associated with current clinical treatments for oral ulcers, the development of adhesive hydrogel patches (AHPs) presents an effective approach. These AHPs possess unique properties, such as tunable mechanical characteristics, self-healing ability, and strong adhesion to the mucosa. Through controlled release of protocatechualdehyde-Fe3+ complex, the AHPs facilitate the healing process by suppressing inflammation, promoting cell proliferation, and inducing epithelial-mesenchymal transition. The study not only provides valuable insights into the healing mechanisms of oral ulcers but also introduces a promising therapeutic biomaterial. This work holds significant scientific interest and demonstrates the potential to greatly improve the treatment outcomes and quality of life for individuals suffering from oral ulcers. [Display omitted] [ABSTRACT FROM AUTHOR]

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

Recurrent oral ulcers are common oral mucosal lesions that severely reduce patients' quality of life. Commercial mucoadhesive films are easily disrupted due to oral movement and complex wet environments, thus reducing drug utilization and even causing toxic side effects. Herein, we report a mucoadhesive film composed of Ca2+-crosslinked carboxymethylated cellulose nanofibers and alginate, in which two drugs of dexamethasone (DXM) and dyclonine hydrochloride (DYC) are loaded for the treatment of oral ulcers. The wet films have a high Young's modulus of 7.1 ± 2.6 MPa and a large strain of 53.6 ± 9.8 % and adhere to tissue strongly, which allows them to resist the deformation caused by frequent oral movement. The films also have nice durability against water and excellent biocompatibility. Moreover, the drug release was controlled at different rates. The fast release of DYC facilitates the quick relief of pain, while the slow release of DXM benefits the long-term treatment of wounds. Finally, the animal experiment demonstrates the films displayed excellent therapeutic efficacy in healing oral ulcers. [Display omitted] [ABSTRACT FROM AUTHOR]

The stable adhesion of hydrogel-based bioadhesives with tissue-matchable mechanical properties in biological environments remains a significant challenge. In this work, we propose a polyethyleneimine-polyacrylic acid (PEI-PAA, PEA) double-network polyelectrolyte hydrogel with swelling resistant capacity and tunable mechanical properties via one-step UV-initiated polymerization. Driven by electrostatic interactions and polymer-chain entanglement, this PEA hydrogel displays a distinctive microphase separation behavior, which facilitates a wide tunability in mechanical properties. Specifically, the modulus varies from 0.4 MPa to 106 MPa, and the toughness ranges from 1479 kJ/m3 to 7641 kJ/m3, respectively. Besides, the microphase separation endows PEA hydrogel with notable anti-swelling properties in saline, TBS buffer, and blood, leading to consistent adhesion to diverse moist tissues. We further demonstrate that our PEA hydrogels provide matchable mechanical properties and long-lasting adhesion to rat skin and arteries, which promote skin injury healing and effectively halt artery rupture bleeding in vivo. This work presents a straightforward method to generate non-swelling hydrogels and offers novel insight into the development of bioadhesives to meet diverse mechanical requirements. • A facile method is developed to prepare polyelectrolyte hydrogels with ultrahigh mechanical tunability. • Microphase separation structure endows hydrogels with excellent mechanical and anti-swelling performances. •The tissue-matchable hydrogels exhibit instant and stable adhesion for versatile wound healing. [ABSTRACT FROM AUTHOR]

Following removal of hides and viscera during beef processing, carcasses are inspected for tissue adhesions that can affect meat quality or harbor bacteria. Carcasses with pleural or abdominal adhesions may be diverted from the production line for manual excision and then returned to the line. No published data indicate whether adhesion excision is associated with bacterial contamination. Therefore, our objective was to determine the presence and concentration of generic Escherichia coli and non–E. coli coliforms from the internal and external surfaces of carcasses that were, or were not, diverted for adhesion excision. During 9 processing days over a 4-month period in a large commercial beef processing facility, 1,738 carcass sponge samples from 2,730 cm2 areas on both the internal and the external surfaces of carcasses with and without tissue adhesions were collected. Coliforms and E. coli were cultured and enumerated using Petrifilm procedures, and data were analyzed with mixed models. Coliforms were present at higher concentrations than E. coli, and prevalence and mean log concentrations of both coliforms and E. coli were significantly higher for samples from the external than from the internal surfaces of carcasses. However, differences in prevalence and concentration of coliforms between external and internal surfaces varied significantly based on whether carcasses had adhesions excised. The difference was greatest for coliforms present on the external (2.06 log CFU/100 cm2) versus the internal (0.93 log CFU/100 cm2) carcass surfaces without adhesions, whereas the difference in concentrations from the external (1.80 log CFU/100 cm2) and the internal (1.31 log CFU/100 cm2) surfaces of carcasses with adhesions was not as large. These results indicate that surveillance of carcass bacteria may be affected by whether the external versus the internal surfaces are sampled and whether carcasses are diverted for excision of adhesions. [ABSTRACT FROM AUTHOR]

Injectable polymers (IPs) exhibiting in situ hydrogel formation have attracted attention as vascular embolization and postoperative adhesion prevention materials. While utilizing hydrogels for such purposes, it is essential to ensure that they have appropriate and controllable tissue adhesion property, as it is crucial for them to not detach from their deposited location in the blood vessel or abdominal cavity. Additionally, it is important to maintain gel state in vivo for the desired period at such locations, where large amounts of body fluid exist. We had previously reported on a biodegradable IP system exhibiting temperature-responsive gelation and subsequent covalent cross-link formation. We had utilized triblock copolymers of aliphatic polyester and poly(ethylene glycol) (tri-PCGs) and its derivative containing acrylate group at the termini (tri-PCG-Acryl), exhibiting a longer and more controllable duration time of the gel state. In this study, the introduction of aldehyde groups by the addition of aldehyde-modified Pluronic (PL-CHO) was performed for conferring controllable and appropriate tissue adhesive properties on these IP systems. The IP systems containing PL-CHO, which were not covalently incorporated into the hydrogel network, exhibited tissue adhesive properties through Schiff base formation. The adhesion strength could be controlled by the amount of PL-CHO added. The IP system showed good vascular embolization performance and pressure resistance in the blood vessels. The IP hydrogel remained at the administration site in the abdominal space for 2 days and displayed effective adhesion prevention performance. Injectable polymers (IPs), which exhibit in situ hydrogel formation, are expected to be utilized as vascular embolization and postoperative adhesion prevention materials. The tissue adhesion properties of hydrogels are important for such applications. We succeeded in conferring tissue adhesion properties onto a previously reported IP system by mixing it with Pluronic modified with aldehyde groups (PL-CHO). The aldehyde groups allowed for the formation of Schiff bases at the tissue surfaces. The tissue adhesion property could be conveniently controlled by altering the amount of PL-CHO. We revealed that the in vitro embolization properties of IPs in blood vessels could be substantially improved by mixing with PL-CHO. The IP system containing PL-CHO also exhibited good in vivo performance for postoperative adhesion prevention. [Display omitted] [ABSTRACT FROM AUTHOR]

Bioadhesive is a substitute or complement to traditional surgical sutures for promoting wound closure. In this study, we developed a simply formulated tough bioadhesive based on the co-assembly of ε-poly-L-lysine (ε-PLL) and hyaluronan (HA) using a vacuum drying strategy. The formula of the bioadhesive was optimized by adjusting the solute content and the ε-PLL/HA mass ratio. The intermolecular interactions were characterized using infrared spectroscopy. Rheological behaviors, including apparent viscosity (cohesion) and fluid types of the adhesives, were investigated. The ε-PLL/HA bioadhesive demonstrated strong adhesion to wet tissues and other abiotic substrates. [Display omitted] • A simply formulated tough bioadhesive is created through the co-assembly of ε-PLL and HA. • The bioadhesive can effectively maintain viscosity and demonstrate shear-thinning properties. • The bioadhesive exhibits a strong capability to bond wet tissues with robust adhesion strength. [ABSTRACT FROM AUTHOR]

Tissue adhesives have been developed for sealing tissue damaged in surgery. Among these, sheet-type adhesives require a relatively long time to adhere to biological tissue under wet conditions. To address this clinical problem, we fabricated a tissue-adhesive fiber sheet (AdFS) based on decanyl group (C10) modified Alaska pollock-derived gelatin (C10-ApGltn) using electrospinning. Ultraviolet (UV) irradiation of the AdFS was performed to increase the affinity between the AdFS and wet biological tissue by introducing hydrophilic functional groups. The UV irradiated AdFS (UV-C10-AdFS) strongly adhered to porcine pleura within 2 min under wet conditions and showed higher burst strength compared with the original ApGltn (Org-ApGltn) sheet. Hematoxylin-eosin stained sections revealed that a dense UV-C10-AdFS layer remained on the surface of the porcine pleura even after burst strength measurement. Moreover, UV-C10-AdFS has excellent cytocompatibility and efficiently supports the growth of L929 cells. UV-C10-AdFS is a promising adhesive material for sealing wet biological tissue. [ABSTRACT FROM AUTHOR]

Postoperative adhesion can lead to an increase in the number of surgeries required, longer operation times, and high medical costs, resulting in the quality of life of the patient being lowered. To address these clinical problems, we developed a surgical sealant with anti-adhesion properties for the prevention of postoperative adhesion following application to the large intestine surface. The developed sealant was composed of octyl (C8) group-modified Alaska pollock-derived gelatin (C8-ApGltn) and a poly(ethylene)glycol-based 4-armed crosslinker (4S-PEG) (C8-ApGltn/4S-PEG sealant). Hydrophobic modification of the ApGltn molecule with C8 groups effectively enhanced both the burst strength on the large intestine surface and the bulk modulus. An in vitro anti-adhesion test indicated that cured C8-ApGltn/4S-PEG sealant adhered to the large intestine surface showed low adhesive strength compared with commercial anti-adhesion film. Besides, cured C8-ApGltn/4S-PEG sealant effectively inhibited albumin permeation and penetration of L929 fibroblasts. In vivo experiments using a rat peritoneal anti-adhesion model showed that C8-ApGltn/4S-PEG sealant acted as a sealing barrier on the target cecum surface and also provided an anti-adhesion barrier to prevent postoperative adhesion between the peritoneum and cecum. C8-ApGltn/4S-PEG sealant showed sufficient cytocompatibility and biodegradability and therefore has potential for use in gastroenterological surgery. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Anti-washout and tissue adhesion properties are essential for the clinical application of injectable bone materials. In this study, we prepared calcium phosphate cement (CPC) with anti-washout and tissue adhesion properties and attempted to build covalent bonds between CPC and the amino groups in bone tissue under a self-regulating pH system in the CPC (acidic to basic). The results of push-out tests demonstrated that a significant enhancement (from 6.42 ± 0.76 N to 61.5 ± 4.09 N) in tissue adhesion was obtained with the addition of 6% (w/w) oxidized sodium alginate (OSA) in CPC. The FTIR, XRD, anti-washout test, XPS, pH test, and SEM results suggested that the synergistic effect of OSA-citric acid (CA) led to the formation of a three-dimensional gel network structure in the CPC, and the Schiff base reaction between aldehyde and amino groups induced adhesion between CPC and the bone tissue. Further, the addition of less OSA had no significant negative effect on the hydration properties of CPC. Our work aims to promote the development of injectable bone material in clinical applications. [ABSTRACT FROM AUTHOR]

Anastomotic leakage and tissue adhesion are significant complications associated with colorectal surgeries, such as the resection of colorectal cancer. However, an effective biomedical apparatus has yet to be developed to address both complications. In the present study, we developed a tissue-sealing, anti-adhesive hydrogel composed of decyl group-modified gelatin (C10-ApGltn) and a poly (ethylene glycol)-based crosslinker. C10-ApGltn based hydrogel (C10-gel) demonstrated increased elastic modulus and suppressed swelling ratio compared with the unmodified ApGltn. Furthermore, C10-gel effectively sealed a water leakage model of intestine tissue and prevented contact between two intestinal tissue samples. In vivo experiments revealed that C10-gel degraded almost entirely in 28 days and prevented cell infiltration for 14 days, which effectively inhibits tissue adhesion. Therefore, C10-gel is a biocompatible hydrogel that can be used to mitigate or prevent anastomotic leakage and prevent tissue adhesion in colorectal surgery. Unlabelled Image [ABSTRACT FROM AUTHOR]

Hydrogels have been widely used in the biomedical field. Wound healing is a complex process, and improper handling can lead to inflammation, damage to health and increase pain. Moreover, wounds in joints are difficult to protect. Here, a stretchable, adhesion, anti-freezing and antibacterial hydrogel (ATSHQ) for wound healing is facilely prepared by photopolymerization under green LED irradiation, with acrylamide (AM), N-[tris(hydroxymethyl)methyl] acrylamide (THMA) and sulfobetaine methacrylate (SBMA) as the skeleton, hyaluronic acid (HA) as wound healing accelerator, and quaternized chitosan (QCS) as antibacterial component. This hydrogel design has the advantage of being cross-linked without adding specific cross-linking agents that may increase toxicity. ATSHQ hydrogels present excellent mechanical properties (the maximum stress can reach 343 kPa), strong extensibility (the maximum strain can reach 1587%), adequate tissue adhesion, rapid self-healing, tough anti-freezing, and anti-dehydration. The balanced mechanical property and adhesion of the hydrogel allow for stable joint adhesion and easy removal without damage. Furthermore, the biocompatibility and antibacterial properties of ATSHQ hydrogels were confirmed. [Display omitted] • A rapid preparation method by photopolymerization without the use of specific cross-linking agents. • The use of THMA provides good adhesion and avoids the problem of easily oxidized catechol structures. • The balanced and broad range of properties enhances the potential for the hydrogel to be used as a wound dressing. [ABSTRACT FROM AUTHOR]

Adhesive hydrogel patches have received great recognitions in wound healing applications. Structural manipulation and functional enhancement are current trends aiming to achieve better curative effect. Herein, adhesive microparticles (AMPs) were prepared via microfluidic electrospray as novel patch for would healing. The AMPs were composed of chitosan oligosaccharide-polyacrylic acid (CSO-PAA) hydrogel matrix embedded with natural melanin nanoparticles. The AMPs exhibited excellent wet adhesion ability, and their particulate structure made them easily adaptable to irregular wound sites. Additionally, the incorporated melanin nanoparticles endowed the AMPs with reactive oxygen species-scavenging and photothermal conversion capacities. Based on these features, the AMPs were employed to close the fractured wound and promote wound healing in vivo , especially under near-infrared irradiation. Therefore, we believe that the multifunctional AMPs are promising adhesive patch for wound management, and potential applications can be expected in battlefield nursing, postoperative management, and household healthcare. [Display omitted] • Adhesive microparticles were prepared via microfluidic electrospray as novel patch for would healing. • The adhesive microparticles exhibited excellent wet adhesion ability and shape-fitting performance to irregular wounds. • The incorporated melanin particles endowed the adhesive microparticles with antioxidant property and photothermal effect. [ABSTRACT FROM AUTHOR]

The objective of this study was to present an effective injectable adhesion barrier comprised of TEMPO-oxidized cellulose nanofiber (TOCN), methyl cellulose, carboxymethyl cellulose, and polyethylene glycol. Hydrogels with different concentrations (0.2, 0.5, 0.8, 1% w / v) of bio compatible TOCN were investigated to determine their abilities to prevent post-surgical peritoneal adhesion using a rat cecal wall abrasion model. Sol-gel transition at body temperature (37 °C) was optimized by adjusting concentration of sodium ions (Na+), with a gelation time of 45 ± 7 s. These TOCN containing hydrogels showed non cytotoxicity to rat bone marrow mesenchymal stem cells (RBMSCs) and L929 fibroblast cells as cell models during in vitro assessment. Degradation studies revealed that, TOCN concentration in hydrogel was inversely proportional to hydrolytic degradation rate. From in vivo evaluations, TOCN 0.2 hydrogel significantly reduced peritoneal adhesion in rat (n = 8) compared to untreated controls based on gross observation, histological analysis, and expression analysis of marker proteins. By taking advantages of thermo gelling, high stability, non-invasive way of application and rapid recovery potential, TOCN containing bio compatible hydrogel could be used as a cost-effective barrier to efficiently inhibit post-surgical peritoneal adhesions. Unlabelled Image • Development of a biodegradable, noncytotoxic and cost-effective thermosensitive hydrogel • Fast gelling hydrogel formed in the absence of chemical or enzymatic modification. • A simple and easy to handle thermosensitive hydrogel for laparoscopic surgery • Hydrogel with 0.2% TOCN was found to have the most potential for anti-adhesion application. [ABSTRACT FROM AUTHOR]

• Marine-inspired adhesives can address an unmet clinical need: wet tissue adhesion. • Tissue adhesives with mussel-inspired catechols performed well in animal studies. • Sandcastle worm-inspired adhesives mimic coacervates worms use to build their homes. • Cephalopod-inspired materials incorporate suction cups for robust wet adhesion. • Future work: materials inspired by multiple and unexplored marine animals. Medical adhesives that are strong, easy to apply and biocompatible are promising alternatives to sutures and staples in a large variety of surgical and clinical procedures. Despite progress in the development and regulatory approval of adhesives for use in the clinic, adhesion to wet tissue remains challenging. Marine organisms have evolved a diverse set of highly effective wet adhesive approaches that have inspired the design of new medical adhesives. Here we provide an overview of selected marine animals and their chemical and physical adhesion strategies, the state of clinical translation of adhesives inspired by these organisms, and target applications where marine-inspired adhesives can have a significant impact. We will focus on medical adhesive polymers inspired by mussels, sandcastle worms, and cephalopods, emphasize the history of bioinspired medical adhesives from the peer reviewed and patent literature, and explore future directions including overlooked sources of bioinspiration and materials that exploit multiple bioinspired strategies. [ABSTRACT FROM AUTHOR]

Abstract Uncontrolled hemorrhage is closely related to the high risk of death. However, local hemostats still have various defects and side effects. Herein, an aldehyde dextran (PDA) sponge with proper absorption and adhesion properties is developed for hemorrhage control. PDA sponge with pore size of ∼30–50 μm fabricated by lyophilization not only absorbs blood quickly (47.7 g/g), but also possesses strong tissue adhesion (∼100 kPa). PDA sponge with low cytotoxicity and hemolysis achieves effective hemostasis and remarkable blood loss reduction in the ear vein, femoral artery and liver injuries of rabbit models. Furthermore, the exploration of hemostatic mechanisms related to tissue, blood, plasma, cells and coagulation system indicates that PDA sponge can significantly accelerate coagulation by rapid wound block, fast cells aggregation and initiation, and high coagulation factors concentration, instead of by the coagulation cascade activation. Importantly, this hemostat exhibits excellent biodegradability and nearly no skin irritation. Overall, the biodegradable and tissue adhesive PDA sponge will be a promising quick-hemostatic dressing for uncontrollable hemorrhage. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

The inflammatory microenvironment and inferior chondrogenesis are major symptoms after cartilage defect. Although various modifications strategies associated with hydrogels exhibit remarkable capacity of pro-cartilage regeneration, the adverse effect by prolonging inflammation is still formidable to hamper potential biomedical applications of different hydrogel implants. Herein, inspired by the repair microenvironment of articular cartilage defects, an injectable, immunomodulatory, and chondrogenic L-MNS-CMDA hydrogel is prepared through grafting vinyl and catechol groups to chitosan macromolecules using amide reaction, then further loading MnO 2 nanosheets (MNS). The double crosslinking of photopolymerization and catechol oxidative polymerization endows L-MNS-CMDA hydrogel with preferable mechanical property, affording a suitable mechanical support for cartilage defect repair. Additionally, the robust tissue adhesion capability stemming from catechol groups guarantees the long-term retention of the hydrogel in the defect site. Meanwhile, L-MNS-CMDA hydrogel decomposes exogenous and intracellular H 2 O 2 into O 2 and H 2 O, to effectively alleviate cellular oxidative stress caused by long-term hypoxia. Under the synergies of catechol groups and MNS, L-MNS-CMDA hydrogel not only inhibits macrophages polarizing into M1 phenotype, but encourages them turn into M2 phenotype, thereby, reconstructing an immunization friendly microenvironment to ultimately enhance cartilage regeneration. Predictably, the hydrogel markedly induces rat bone marrow mesenchymal stem cells differentiating into chondrocytes by expressing abundant glycosaminoglycan and type II collagen. A cartilage defect model of rat knee joint indicates that L-MNS-CMDA hydrogel visually regulate the early inflammatory response of post-implantation, and facilitate cartilage regeneration and recovery of joint function after 12 weeks of post-implantation. All in all, this multifunctional L-MNS-CMDA hydrogel exhibits superior immunomodulatory and chondrogenic properties, holding immense clinical potential in the treatment of cartilage defects. [ABSTRACT FROM AUTHOR]

The mussel-inspired polymeric hydrogels have been attractively explored owing to their self-repairing or adhesive property when the catechol groups of dopamine could chelate metal ions. However, it was a challenge for self-repairing hydrogels owning high mechanical properties. Herein, a synergistic strategy was proposed by combining catechol-Fe 3+ complexes and hydrophobic association. The resulting hydrogels exhibited seamless self-repairing behavior, tissue adhesion and high mechanical property. Moreover, the pH-dependent stoichiometry of catechol-Fe 3+ and temperature-sensitive hydrophobic association endue hydrogels with pH/thermo responsive characteristics. Subsequently, the self-repairing rate and mechanical property of hydrogels were investigated at different pH and temperature. This bio-inspired strategy would build an avenue for designing and constructing a new generation of self-repairing, tissue-adhesive and tough hydrogel. [ABSTRACT FROM AUTHOR]

It is very crucial to develop ideal tissue adhesive materials with high toughness, super tissue adhesion, biodegradability and biocompatibility for the treatment of accidental trauma and surgery. Inspired by mussels, a novel injectable bioadhesive chitosan-based hydrogel was developed by dual-ionic crosslinking in this paper, which was composed of catechol-modified chitosan (Cat-CS), thermosensitive polymer (PNAM) and NaHCO 3. The gelation time of Cat–CS–PNAM/NaHCO 3 hydrogel is 50 s at 37 °C, showing good sol-gel transition under different temperatures. The prepared hydrogels have the ability to adhere to a variety of materials surface, wherein the adhesion strength to metal surface is 126.20 ± 15.17 kPa. They also possess compact microstructure and excellent dry/wet adhesion to tissues due to the interaction between catechol/amino groups and tissues, combined with physical crosslinking. In addition, the hydrogels can be completely degraded after 14 days in vitro and show good cytocompatibility. This newly designed mussel-inspired chitosan hydrogels have the characteristics of injectability, fast gelation, bioadhesion and biocompatibility, with great potential for application in biomedical fields. Inspired by mussels, chitosan-based hydrogel was developed by dual-ionic crosslinking, with the characteristics of injectability, fast gelation, bioadhesion, biodegradability and biocompatibility. [Display omitted] • Inspired by mussel, injectable chitosan hydrogels as tissue adhesive were developed. • They were composed of catechol-modified chitosan, thermosensitive polymer and NaHCO 3. • The gelation time of Cat–CS–PNAM/NaHCO 3 hydrogel was 50 s at 37 °C. • The hydrogels can adhere to various substrates such as organic and inorganic surface. • The hydrogels had excellent bioadhesion, biodegradability and biocompatibility. [ABSTRACT FROM AUTHOR]

A reliable electrophysiological electrode interface (EEI) between bioelectronic devices and biological tissues is indispensable to achieve the high fidelity recording of bioelectricity. However, there is an inherent tradeoff among EEI's electrochemical characteristics, mechanical properties and biocompatibility when considering the desired nanostructure and optimum composition. Here, we proposed a mechanically matched, highly conductive and biocompatible EEI, a tissue-like metal-doped hydrogel which could enable excellent electro-biosensing, by bringing disulfide modified silver nanowires into difunctional hyaluronan/carboxymethyl chitosan composite. The intensity of cortical signals at specific frequency domain recorded by the hydrogel-based EEI is doubled, which is significant for the diagnosis of epilepsy. Furthermore, the natural gel matrix could lead to seamless bio-integration between EEI and the tissue site of interest, minimizing signal dissipation without causing obvious inflammatory response. Overall, the EEI we designed contributes to improving tissue-device integration as well as bioelectronic device's performance and further leads to more effective human-computer interfaces. [Display omitted] [ABSTRACT FROM AUTHOR]

BACKGROUND: A laparotomy is still considered mandatory for patients without previous abdominal surgery presenting with a small bowel obstruction (SBO) because of a perceived high incidence of underlying lesions. However, there is no evidence in literature to support this assumption. We analyzed the etiology of SBO in this subgroup of patients to establish the need for a mandatory laparotomy. METHODS: A retrospective analysis was conducted over a 5-year period. Basic demographics, radiology results, operative findings, and outpatient investigations were analyzed. RESULTS: Of 689 patients presenting with an SBO, a total of 62 patients, 9.0%, had a virgin abdomen. A known underlying disease (inflammatory bowel disease, malignancy) was the cause in 13 patients. The remaining 49 patients had adhesions in 75.5% and a newly diagnosed malignancy in 10.2% as a cause. CONCLUSIONS: Adhesions are by far the most likely cause of SBO in patients without previous abdominal surgery followed by a small number of newly diagnosed malignancies. Both prevalences are in equal proportion to patients with previous abdominal surgery. A trial of nonoperative management may therefore be justified. [ABSTRACT FROM AUTHOR]

[Display omitted] • Double cross-linked for self-healing polysaccharide hydrogel fabrication. • The rapid gelation time make the hydrogel have spray film-forming ability. • The hydrogel exhibited a superior adhesion and hemostatic property. • The hydrogel also showed antibacterial property and good biocompatibility. • CM loaded hydrogel could enhance the biocompatibility and wound repair ability. Developing multifunctional self-healing hydrogels as wound dressings, including strong tissue adhesion, spray film-forming ability, and excellent bioactivity, are highly desired for full-thickness skin wound healing applications. In this study, chondroitin sulfate (CSA) was firstly oxidized to aldehyde-based chondroitin sulfate (OHC-CSA), and then dopamine (DA) was grafted onto OHC-CSA to form OHC-CSA-DA. Thereafter, the OHC-CSA-DA and carboxymethyl chitosan (COOH-CS) based hydrogel (CSA-DA-CS) was successfully fabricated through integrating enzymatic crosslinking, Schiff base and hydrogen bonding interactions. The optimum adhesive strength of the hydrogel was obtained by an orthogonal design when the concentrations of polymer, HRP enzyme, and H 2 O 2 were 30 mg/mL, 0.24 U/mL, and 0.00085%, respectively. This novel hydrogel showed rapid self-healing performance, robust mechanical strength and strong adhesion, spray film-forming ability, hemostatic property, antibacterial property and good biocompatibility, which are beneficial to function as a wound dressing. Besides, the addition of mesenchymal stem cell-conditioned medium (CM) can further improve the biocompatibility and wound repair ability of the hydrogel.Therefore, this novel hydrogel is an outstanding wound dressing candidate for full-thickness wound healing. [ABSTRACT FROM AUTHOR]

Abstract: The existing surgical adhesives are not ideal for wet tissue adhesion required in many surgeries such as those for internal organs. Developing surgical adhesives with strong wet tissue adhesion, controlled degradability and mechanical properties, and excellent biocompatibility has been a significant challenge. Herein, learning from nature, we report a one-step synthesis of a family of injectable citrate-based mussel-inspired bioadhesives (iCMBAs) for surgical use. Within the formulations investigated, iCMBAs showed 2.5–8.0 folds stronger wet tissue adhesion strength over the clinically used fibrin glue, demonstrated controlled degradability and tissue-like elastomeric mechanical properties, and exhibited excellent cyto/tissue-compatibility both in vitro and in vivo. iCMBAs were able to stop bleeding instantly and suturelessly, and close wounds (2 cm long × 0.5 cm deep) created on the back of Sprague–Dawley rats, which is impossible when using existing gold standard, fibrin glue, due to its weak wet tissue adhesion strength. Equally important, the new bioadhesives facilitate wound healing, and are completely degraded and absorbed without eliciting significant inflammatory response. Our results support that iCMBA technology is highly translational and could have broad impact on surgeries where surgical tissue adhesives, sealants, and hemostatic agents are used. [Copyright &y& Elsevier]

Abstract: A reconstructive technique and physical therapy protocol is presented for the treatment of extensor hallucis longus (EHL) lacerations with critical size defects caused by tendon retraction. The primary goal of treatment was to restore EHL structure and function without the use of a bridging allograft or tendon transfer. The technique is performed by split lengthening the distal segment of the lacerated EHL and rotating the lengthened segment proximally 180° to bridge the tendon defect. The lengthened tendon is then sutured to the proximal segment of the EHL. The EHL is then tubularized with an acellular dermal scaffold at the region of tendon rotation to improve tendon strength, minimize the probability of tendon overlengthening or re-rupture, and improve the tendon gliding motion, which can be compromised by the tendon irregularity caused by rotation of the tendon. Postoperative range of motion therapy should be initiated at 3 weeks postoperatively. A case report of this technique and postoperative mobilization protocol is presented. The American Orthopaedic Foot and Ankle Society midfoot score at 3 and 6 months postoperatively was 90 of 100. The patient regained active dorsiflexion motion of the hallux without functional limitations, deformity, or contracture of the hallux. The advantages of this technique include that a large cadaveric allograft is not needed to bridge a critical size tendon defect and tendon lengthening provides a biologically active tendon graft without the secondary comorbidities and dysfunction commonly associated with tendon transfer procedures. [Copyright &y& Elsevier]

Abstract: Post-surgical adhesions, abnormal fibrous linkages between adjacent tissue surfaces, represent one of the most common and significant complications facing surgical recovery today. Physical barriers and gels have been the most successful at limiting their formation, yet are not effective in cases where the pro-adhesive site is either unknown or difficult to reach (e.g. during laparoscopic surgery). In this work, poly(methacrylic acid-co-t-butylmethacrylate)-b-poly(ethylene glycol () methacrylate) diblock and statistical copolymers were synthesized as a platform for designing self-forming adhesion barriers, which can attach to exposed pro-adhesive sites through binding with the positively charged extracellular matrix, basement membrane proteins and deposited fibrin. An experimental model based upon a quartz crystal microbalance with dissipation was developed to test the diblock copolymers ability (i) to adsorb to an amine-terminated self-assembled monolayer, and (ii) to inhibit subsequent protein adsorption. These results were also confirmed using an in vitro cell attachment model. As the mole fraction of methacrylic acid content increased, polymer adsorption increased. All synthesized diblock copolymers investigated provided high resistance to protein adsorption, with blockade ranging from 55% to 81%. Except for the uncharged control polymers, the ability of these materials to resist cellular attachment showed similar trends, with the suppression of attachment approaching 75%. Energy dissipation analysis and variable-angle spectroscopic ellipsometry revealed two competing adsorption mechanisms depending on the molecular properties of the polymer. [Copyright &y& Elsevier]

[Display omitted] • A wound dressing hydrogel was prepared by one-step assembly of tannic acid, silk fibroin and diclofenac potassium. • The composite hydrogel has excellent underwater adhesion ability, hemostasis function and favorable biocompatibility both in vivo and in vitro. • The adhesive can significantly down-regulate inflammatory cytokines in vivo and in vitro , matching the needs of acute wounds. Acute wounds often cause overdeveloped inflammation, which can adversely affect wound healing. Wound dressing has been widely used, but it is still challenging to achieve an effective anti-inflammation treatment due to the complex wet environment of the wounds. Here, we proposed a wound sealant, tannic acid-silk fibroin-diclofenac potassium (TA-SF-DP, TSD) hydrogels. And evaluated their wet-adhesion performance and the potency on inflammation regulation through comprehensive mechanical tests and molecular biology research. The TSD hydrogels exhibited an outstanding wet-adhesion property to porcine soft tissues even in blood (up to (38.6 ± 4.6) kPa) and strong hemostatic ability in rat tail truncation model ((reduced hemostasis time from (685 ± 55) s to (160 ± 72) s and reduced blood loss from (0.59 ± 0.07) g to (0.06 ± 0.03) g compared with the gauze group). Simultaneously, the hydrogels showed satisfactory anti-inflammatory effects (sustained reduction of inflammation at 6 h and 24 h, generally the peak and persistent state of severe postoperative reaction, respectively), which works by releasing non-steroidal anti-inflammatory drug DP conforming to physiological needs. Combined with the wet adhesion, anti-inflammatory property and remarkable biocompatibility, the TSD hydrogels have the potential to be a clinical wound sealant to manage acute wounds. [ABSTRACT FROM AUTHOR]

• Highly stretchable, tissue adhesive, self-healable hydrogels developed. • 41.6 S/m conductivity maintained by incorporation of PEDOT:PSS. • Multifunctional bonds formed well-connected electric path. • The hydrogel show excellent strain sensing property for human motion detection. A new generation of wearable devices using hydrogel-based sensors has attracted attention for human motion monitoring detection. On the other hand, integrating multiple properties, such as self-adhesiveness, repeatable adhesion, stretchability, high conductivity, good mechanical performance, and good electrical stability within a single hydrogel, which remains a challenge. In this study, hydrogels composed of borate crosslinked pendant catechol groups of carboxymethyl cellulose-dopamine conjugate (CMC-DA) in a polyacrylamide (PAM) crosslinked network (CDB-PAM) were developed. The stretchability (2763%) and tensile strength (36.9 ± 2.3 KPa) of the CDB-PAM hydrogel were improved when 4 wt% of CMC-DA was used for hydrogel preparation. The incorporation of 2.0 wt% PEDOT:PSS greatly improved the tensile stress (44.9 ± 2.6 KPa), low elastic modulus (3.1 ± 0.15 KPa), and stretchability (2873%). The CDB-PAM-PEDOT:PSS hydrogel had self-healing and recoverable properties. The hydrogel demonstrated self-adhesive properties (e.g., skin adhesion to porcine skin 65.1 ± 2.2) with long-term reusability by maintaining redox-active catechol groups in the hydrogel. The in vitro biocompatibility test using skin fibroblasts and keratinocytes cells confirmed the good biocompatibility of the hydrogels. The PEDOT:PSS-incorporated CDB-PAM hydrogel showed good conductivity (41.6 S/m) because of the charge transfer between PEDOT and catechol/quinone groups of CMC-DA in the hydrogel, forming a well-connected electric path. Furthermore, the developed hydrogel-based strain sensor was sensitive to human flexible wearable devices in bioelectronic applications. Overall, the hydrogel with multiple properties, such as high stretchability, self-healing, and high conductivity, demonstrated promising for flexible wearable devices in bioelectronic applications. [ABSTRACT FROM AUTHOR]

Injectable hydrogels, which can deliver cells or drugs directly to tissue sites by minimally invasive injection methods, have attracted considerable attention. In this work, using β-cyclodextrin-grafted alginate as the host polymer and adamantane-grafted polyacrylamide as the guest polymer, an injectable supramolecular hydrogel system was developed based on the host–guest interaction between β-cyclodextrin (βCD) and adamantane (Ad). Simple physical mixing and stirring methods allowed the hydrogels to be prepared in a short time (<1 min). The rheological and mechanical properties and microscopic morphology of the hydrogels were conveniently regulated by changing the grafting degree of βCD and Ad in alginate or polyacrylamide. The shear-thinning and self-healing properties induced by reversible host–guest interactions and a natural, plant-based polysaccharide endow the developed hydrogels with good injectability and biocompatibility, respectively. Experiments showed that the hydrogels effectively adhered to pork tissue. Moreover, human umbilical vein endothelial cells and human ovarian cancer cells encapsulated in the hydrogels showed good viability and three-dimensional distribution after being cultured for three days. Overall, the rapid preparation method and the advantages of injectability, self-healing and cytocompatibility endow the proposed injectable hydrogel system with great potential as a tissue engineering material. [Display omitted] • Convenient preparation of supramolecular hydrogels based on βCD/Ad interactions. • Excellent self-healing, shear thinning, injectability, and tissue adhesion. • Hydrogels can encapsulate cells and can be potentially used in tissue engineering. [ABSTRACT FROM AUTHOR]

Burn wounds are one of the most destructive skin traumas that cause more than 180000 deaths each year. Patients with large, irregular burn wounds suffer from slow healing. Dynamic burn wounds have special requirements for hydrogel dressing due to their high frequency movement. To focus on dynamic burn wounds, we designed a novel double cross-linked hydrogel prepared by Schiff base and catechol-Fe3+ chelation bond. The unique double cross-linked structure of the hydrogel resulted in better physicochemical properties and enhanced efficacy. The enhanced physicochemical properties, such as faster gelation time (52 ± 2 s), stronger mechanical property (535 kPa of G'), enhanced adhesive strength (19.3 kPa) and better self-healing property, made the hydrogel suitable for dynamic wounds. The excellent shape adaptability (97.1 ± 1.3% of recovery) made the hydrogel suitable for wounds with irregular shapes. The hydrogel exhibited not only biodegradability during the wound healing process but also superior inherent antibacterial activity (100% killing ratio) and hemostatic property. The results showed that the hydrogel shortened the healing time of burn wounds to 13 days, and accelerated the reconstruction of skin structure and function. This double cross-linked multifunctional hydrogel is a promising candidate as a dynamic burn wound dressing. [ABSTRACT FROM AUTHOR]

This study aims to engineer a novel developed superabsorbent (NDS) as potent hemostatic agent. NDS induces coagulation process due to the high adhesion affinity to the wet tissue, high swelling ratio and clotting potency. NDS controls massive bleedings by inducing the red blood cells accumulation, platelets aggregation and fibrin network formation at the site of bleeding. [Display omitted] • NDS acts as brilliant superabsorbent that absorb 60 g of blood per one g of NDS. • NDS as a powerful hemostatic agents activated coagulation cascade process. • Biochemical, hematological, and pathological results didn't show toxic effects. Engineering of effective and biocompatible hemostatic materials to control massive bleeding is one of the interesting research fields. Herein, cellulose-based polymer modified by silica aerogel and calcium chloride was used for suitable control of bleeding. Novel developed superabsorbent (NDS) was synthesized by chemical and physical cross-linking methods. NDS not only quickly absorbs a high amount of blood component (60 g/g), but it can also adhere strongly (~90 KPa) to damaged tissue. The contributions of the freeze-drying method and presence of silica aerogel as structural modifiers led to the creation of a superabsorbent with a porosity percentage of 70% which creates a significant ability to absorb blood cells. NDS negative surface charge and presence of silica nanoparticles and calcium ions accelerate activation of the coagulation cascade process. Superior hemostatic ability of NDS compared to commercial hemostatic powder (Gelita-Cel® and Traumastem®) was proved by complementary tests such as blood absorption content, RBC attachment, blood clotting index (BCI), platelet adhesion, clotting time test and partial thromboplastin time (PTT). In vivo study results demonstrate that the NDS could successfully decrease bleeding time and blood loss amount in Wistar rat's cut-out femoral artery, 2.25 and 4.3 fold better than Gelita-Cel® and 2.13 and 4.4 fold better than Traumastem®. NDS biodegradability was proved by its implantation inside the Wistar rat's body during 14 days. Biochemical, hematological, and pathological tests did not show inflammation and toxic effects in the liver and renal tissues, skin tissues, and alteration in complete blood count parameters (CBC) in NDS treated Wistar rats. In conclusion, the cellulose-based NDS hemostatic biomaterial is suggested for future clinical trial studies due to its powerful ability in bleeding control. [ABSTRACT FROM AUTHOR]

• The eLHBC wound dressing was inspired by the adhesion mechanism of mussels. • The ε-Poly- l -lysine endowed eLHBC with highly efficient antimicrobial activity. • The BMSCs were encapsulated in eLHBC to promoting cell proliferation. • The biomimetic tissue-affinity hydrogel could promote complete skin regeneration. Hydrogels have gained great attentions as wound dressing. Binding to the tissue and preventing wound infection were the basic requirements for an "ideal dressing". We employed l -DOPA and ε-Poly- l -lysine to modify thermo-sensitive hydroxybutyl chitosan (HBC) to obtain (l -DOPA) - (ε-Poly- l -lysine)-HBC hydrogels (eLHBC). The eLHBC exhibited an almost 1.5 fold (P < 0.01) increase in wet adhesion strength compared to HBC. Upon the introduction of ε-Poly- l -lysine, eLHBC presented inherent antimicrobial property and prevented wound infection and inflammation response. Bone marrow mesenchymal stem cells (BMSCs) encapsulated in the eLHBC (BMSCs ⊂ eLHBC) could secret cytokins and growth factors via paracrine and promote the migration of fibroblast cells. BMSCs ⊂ eLHBC enhanced the complete skin-thickness wound healing via promoting collagen deposition and inhibiting infection and inflammation in vivo with wound closure rate being above 99 % after 15 days. The bioinspired, tissue-adhesive eLHBC could serve as advanced wound dressings for facilitating tissue repair and regeneration. [ABSTRACT FROM AUTHOR]

• Gallic acid−conjugated hexanoyl glycol chitosan (GA-HGC) was developed as a novel wound healing biomaterial. • GA-HGCs exhibit thermogelation, self-crosslinkability, and self-healing ability. • GA-HGC hydrogels show strong tissue adhesive strength and high compressive strength. • GA-HGC hydrogel promotes wound closure and tissue regeneration. In the present study, a novel synthetic tissue adhesive material capable of sealing wounds without the use of any crosslinking agent was developed by conjugating thermosensitive hexanoyl glycol chitosan (HGC) with gallic acid (GA). The degree of N -gallylation was manipulated to prepare GA-HGCs with different GA contents. GA-HGCs demonstrated thermosensitive sol-gel transition behavior and formed irreversible hydrogels upon natural oxidation of the pyrogallol moieties in GA, possibly leading to GA-HGC crosslinks through intra/intermolecular hydrogen bonding and chemical bonds. The GA-HGC hydrogels exhibited self-healing properties, high compressive strength, strong tissue adhesive strength and biodegradability that were adjustable according to the GA content. GA-HGCs also presented excellent biocompatibility and wound healing effects. The results of in vivo wound healing efficacy studies on GA-HGC hydrogels indicated that they significantly promote wound closure and tissue regeneration by upregulating growth factors and recruiting fibroblasts compared to the untreated control group. [ABSTRACT FROM AUTHOR]

Tissue adhesion and thermal injury bring great risk to electrosurgical cutting. The aim of this study is to propose a novel ultrasonic vibration-assisted (UV-A) electrosurgical cutting system to minimize tissue adhesion and thermal injury, and thereby improve the cutting performance. To this end, the ultrasonic vibration technology was integrated into electrosurgical cutting to develop a UV-A electrosurgical cutting system. Finite element (FE) simulations and experiments were performed to verify the effectiveness of the proposed UV-A technology. An orthogonal UV-A electrosurgical cutting FE model was developed using the Comsol Multiphysics software. Subsequently, the effect of UV-A on the temperature distribution and thermal injury during the electrosurgical cutting process was investigated. The FE simulation results indicated that UV-A can reduce the temperature distribution and thermal injury area. The experimental results demonstrated that the temperature and injury depth under UV-A electrosurgical cutting were respectively decreased by approximately 40% and 30% compared with that without UV-A. The experimental results agreed well with the FE simulation results. Hence, it is concluded that UV-A electrosurgical cutting can be a novel promising and practical technology for reducing tissue adhesion and thermal injury. Unlabelled Image • A novel ultrasonic vibration-assisted electrosurgical cutting technology were proposed. • UV-A technology can decrease the tissue adhesion and thermal injury. • UV-A technology improves the cutting performance. [ABSTRACT FROM AUTHOR]

• Hydrocortisone-modified gelatin microparticles was prepared. • Microparticles improved its adhesion strength to tissues under wet conditions. • Microparticles suppressed secretion of inflammatory cytokines from macrophages. • Novel microparticles can be used for promoting tissue regeneration. Wound dressing materials are widely used to protect wounds from the external environment and to promote wound healing. However, conventional wound dressings lack tissue adhesive properties and anti-inflammatory functions, which lead to fibrosis and stricture, in cases such as gastrointestinal wounds after endoscopic surgery. In the current study, we report tissue-adhesive and anti-inflammatory properties of a wound dressing composed of corticosteroid-modified gelatin particles. Hydrocortisone (HC), which is a class of anti-inflammatory corticosteroid, was used to modify Alaska-pollock gelatin (ApGltn) to synthesize HC-modified ApGltn (HC-ApGltn). Microparticles (MPs) of HC-ApGltn were fabricated by adding ethanol in HC-ApGltn aqueous solution and performing thermal crosslinking (TC) without the use of toxic surfactants and crosslinking reagents. Modification of ApGltn with hydrophobic HC containing cholesterol backbone structure improved its adhesion strength to gastric submucosal tissues under wet conditions owing to hydrophobic interactions. This retention of adhesive property under wet conditions allows for stable protection of wounds from the external environment. We found that HC-ApGltn MPs were taken up by macrophages and they effectively suppressed morphological changes of LPS-activated macrophages and the expression level of the inflammatory cytokine. Robust tissue adhesive and anti-inflammatory MPs may serve as an advanced wound dressing that can protect wounds and suppress inflammatory responses for promoting wound healing. [ABSTRACT FROM AUTHOR]

Significant tissue damage, scarring, and an intense inflammatory response remain the greatest concerns for conventional wound closure options, including sutures and staples. In particular, wound closure in internal organs poses major clinical challenges due to air/fluid leakage, local ischemia, and subsequent impairment of healing. Herein, to overcome these limitations, inspired by endoparasites that swell their proboscis to anchor to host's intestines, we developed a hydrogel-forming double-layered adhesive microneedle (MN) patch consisting of a swellable mussel adhesive protein (MAP)-based shell and a non-swellable silk fibroin (SF)-based core. By possessing tissue insertion capability (7-times greater than the force for porcine skin penetration), MAP-derived surface adhesion, and selective swelling-mediated physical entanglement, our hydrogel-forming adhesive MN patch achieved ex vivo superior wound sealing capacity against luminal leaks (139.7 ± 14.1 mmHg), which was comparable to suture (151.0 ± 23.3 mmHg), as well as in vivo excellent performance for wet and/or dynamic external and internal tissues. Collectively, our bioinspired adhesive MN patch can be successfully used in diverse practical applications ranging from vascular and gastrointestinal wound healing to transdermal delivery for pro-regenerative or anti-inflammatory agents to target tissues. [ABSTRACT FROM AUTHOR]

Host immune response remains an obstacle in cell-replacement therapy for treating type I diabetes. Long-term systemic immunosuppression results in suboptimal efficacy and adverse reactions. Thus, "cell-particle hybrids" of pancreatic islets and tissue-adhesive, polydopamine-coated, FK506-loaded biodegradable microspheres (PD-FK506-MS) were developed to locally modulate the immune response at the transplantation site. Coating of FK506-MS with PD enabled the rapid formation of stable cell-particle hybrids without significant changes in islet viability and functionality. Extremely low quantities of FK506 (approximately 600 ng per recipient) sustainably released from cell-particle hybrids effectively prolonged survival of xenogeneic islet graft. Interestingly, FK506 exhibited extended bioavailability in the grafts but was undetectable in systemic circulation and other tissues. Moreover, mRNA expression of inflammatory cytokines was significantly inhibited in the PD-FK506-MS-containing grafts but not in lymphoid organs. This study presents a promising platform that facilitates the translation of local immunomodulation towards an effective strategy with improved safety profiles for treating type I diabetes. [ABSTRACT FROM AUTHOR]