Triple-crosslinked double-network alginate/dextran/dendrimer hydrogel with tunable mechanical and adhesive properties: A potential candidate for sutureless keratoplasty.

An ideal adhesive hydrogel must possess high adhesion to the native tissue, biocompatibility, eligible biodegradability, and good mechanical compliance with the substrate tissues. We constructed an interpenetrating double-network hydrogel containing polysaccharides (alginate and dextran) and nanosized spherical dendrimer by both physical and chemical crosslinking, thus endowing the hydrogel with a broad range of mechanical properties, adhesive properties, and biological functions. The double-network hydrogel has moderate pore sizes and swelling properties. The chelation of calcium ions significantly enhances the tensile and compressive properties. The incorporation of dendrimer improves both the mechanical and adhesive properties. This multicomponent interpenetrating network hydrogel has excellent biocompatibility, tunable mechanical and adhesive properties, and satisfied multi-functions to meet the complex requirements of wound healing and tissue engineering. The hydrogel exhibits promising corneal adhesion capabilities in vitro, potentially supplanting the need for sutures in corneal stromal surgery and mitigating the risks associated with donor corneal damage and graft rejection during corneal transplantation. This novel polysaccharide and dendrimer hydrogel also shows good results in sutureless keratoplasty, with high efficiency and reliability. Based on the clinical requirements for tissue bonding and wound closure, the hydrogel provides insight into solving the mechanical properties and adhesive strength of tissue adhesives.

Suture reinforcement using a modified cyanoacrylate glue to prevent anastomotic leak in colorectal surgery: a prospective multicentre randomized trial : The Rectal Anastomotic seaL (ReAL) trial.

BACKGROUND: Anastomotic leakage (AL) is the most frequent life-threating complication following colorectal surgery. Several attempts have been made to prevent AL. This prospective, randomized, multicentre trial aimed to evaluate the safety and efficacy of nebulised modified cyanoacrylate in preventing AL after rectal surgery. METHODS: Patients submitted to colorectal surgery for carcinoma of the high-medium rectum across five high-volume centres between June 2021 and January 2023 entered the study and were randomized into group A (anastomotic reinforcement with cyanoacrylate) and group B (no reinforcement) and followed up for 30 days. Anastomotic reinforcement was performed via nebulisation of 1 mL of a modified cyanoacrylate glue. Preoperative features and intraoperative and postoperative results were recorded and compared. The study was registered at ClinicalTrials.gov (ID number NCT03941938). RESULTS: Out of 152 patients, 133 (control group, n = 72; cyanoacrylate group, n = 61) completed the follow-up. ALs were detected in nine patients (12.5%) in the control group (four grade B and five grade C) and in four patients (6.6%), in the cyanoacrylate group (three grade B and one grade C); however, despite this trend, the differences were not statistically significant (p = 0.36). However, Clavien-Dindo complications grade > 2 were significantly higher in the control group (12.5% vs. 3.3%, p = 0.04). No adverse effects related to the glue application were reported. CONCLUSION: The role of modified cyanoacrylate application in AL prevention remains unclear. However its use to seal colorectal anastomoses is safe and could help to reduce severe postoperative complications.

Mussel-Inspired Injectable Adhesive Hydrogels for Biomedical Applications.

The impressive adhesive capacity of marine mussels has inspired various fascinating designs in biomedical fields. Mussel-inspired injectable adhesive hydrogels, as a type of promising mussel-inspired material, have attracted much attention due to their minimally invasive property and desirable functions provided by mussel-inspired components. In recent decades, various mussel-inspired injectable adhesive hydrogels have been designed and widely applied in numerous biomedical fields. The rational incorporation of mussel-inspired catechol groups endows the injectable hydrogels with the potential to exhibit many properties, including tissue adhesiveness and self-healing, antimicrobial, and antioxidant capabilities, broadening the applications of injectable hydrogels in biomedical fields. In this review, we first give a brief introduction to the adhesion mechanism of mussels and the characteristics of injectable hydrogels. Further, the typical design strategies of mussel-inspired injectable adhesive hydrogels are summarized. The methodologies for integrating catechol groups into polymers and the crosslinking methods of mussel-inspired hydrogels are discussed in this section. In addition, we systematically overview recent mussel-inspired injectable adhesive hydrogels for biomedical applications, with a focus on how the unique properties of these hydrogels benefit their applications in these fields. The challenges and perspectives of mussel-inspired injectable hydrogels are discussed in the last section. This review may provide new inspiration for the design of novel bioinspired injectable hydrogels and facilitate their application in various biomedical fields.

Hyaluronic Acid/Gelatin-Based Multifunctional Bioadhesive Hydrogel Loaded with a Broad-Spectrum Bacteriocin for Enhancing Diabetic Wound Healing.

The development of multifunctional wound adhesives is critical in clinical settings due to the scarcity of dressings with effective adhesive properties while protecting against infection by drug-resistant bacteria. Polysaccharide and gelatin-based hydrogels, known for their biocompatibility and bioactivity, assist in wound healing. This study introduces a multifunctional bioadhesive hydrogel developed through dynamic covalent bonding and light-triggered covalent bonding, comprising oxidized hyaluronic acid, methacrylated gelatin, and the bacteriocin recently discovered by our lab, named jileicin (JC). The adhesion strength of the hydrogel, measured at 180 kPa, was 4.35 times higher than that of the fibrin glue. Furthermore, the hydrogel demonstrated robust platelet adhesion, procoagulant activity, and outstanding hemostatic properties in a mouse liver injury model. Incorporating JC significantly enhanced the phagocytosis and bactericidal capabilities of the macrophages. This immunomodulatory function on host cells, coupled with its potent bacterial membrane-disrupting ability, makes JC an effective killer against methicillin-resistant Staphylococcus aureus. In wound repair experiments on diabetic mice with infected full-thickness skin defects, the hydrogel treatment group showed a notable reduction in bacterial load, accelerated M2-type macrophage polarization, diminished inflammation, and hastened wound healing. Owing to its outstanding biocompatibility, antibacterial activity, and controlled adhesion, this hydrogel presents a promising therapeutic option for treating infected skin wounds.

Recyclable surgical, consumer, and industrial adhesives of poly(α-lipoic acid).

Polymer adhesives play an important role in many medical, consumer, and industrial products. Polymers of α-lipoic acid (αLA) have the potential to fulfill the need for versatile and environmentally friendly adhesives, but their performance is plagued by spontaneous depolymerization. We report a family of stabilized αLA polymer adhesives that can be tailored for a variety of medical or nonmedical uses and sustainably sourced and recycled in a closed-loop manner. Minor changes in monomer composition afforded a pressure-sensitive adhesive that functions well in dry and wet conditions, as well as a structural adhesive with strength equivalent to that of conventional epoxies. αLA surgical superglue successfully sealed murine amniotic sac ruptures, increasing fetal survival from 0 to 100%.

Thermoresponsive On-Demand Adhesion and Detachment of a Polyurethane-Urea Bioadhesive.

The development of bioadhesives with strong adhesion and on-demand adhesion-detachment behavior is still critically important and challenging for facilitating painless and damage-free removal in clinical applications. In this work, for the first time, we report the easy fabrication of novel polyurethane-urea (PUU)-based bioadhesives with thermoresponsive on-demand adhesion and detachment behavior. The PUU copolymer was synthesized by a simple copolymerization of low-molecular-weight, hydrophilic, and biocompatible poly(ethylene glycol), glyceryl monolaurate (GML, a special chain extender with a long side hydrophobic alkyl group), and isophorone diisocyanate (IPDI). Here, GML was expected to not only adjust the temperature-dependent adhesion behavior but also act as an internal plasticizer. By simple adjustment of the water content, the adhesion strength of the 15 wt % water-containing PUU film toward porcine skin is as high as 55 kPa with an adhesion energy of 128 J/m2 at 37 °C. The adhesion strength dramatically decreases to only 3 kPa at 10 °C, exhibiting switching efficiency as high as 0.95. Furthermore, the present PUU-based adhesive also shows good on-demand underwater adhesion and detachment with a cell viability close to 100%. We propose that biomaterial research fields, especially novel PUU/polyurethane (PU)-based functional materials and bioadhesives, could benefit from such a novel thermoresponsive copolymer with outstanding mechanical and functional performances and an easy synthesis and scaled-up process as described in this article.

Development of an in-situ forming collagen-based hydrogel as a regenerative bioadhesive for corneal perforations.

Corneal injuries play a significant role in global visual impairment, underscoring the demand for innovative biomaterials with specific attributes such as adhesion, cohesion, and regenerative potential. In this study, we have developed a biocompatible bioadhesive for corneal reconstruction. Derived from Collagen type I, naturally present in human corneal stromal tissue, the bioadhesive was cross-linked with modified polyethylene glycol diacrylate (PEGDA-DOPA), rendering it curable through visible light exposure and exhibiting superior adhesion to biological tissues even in wet conditions. The physicochemical characteristics of the proposed bioadhesive were customized by manipulating the concentration of its precursor polymers and adjusting the duration of photocrosslinking. To identify the optimal sample with maximum adhesion, mechanical strength, and biocompatibility, characterization tests were conducted. The optimal specimen, consisting of 30 % (w/v) PEGDA-DOPA and cured with visible light for 5 min, exhibited commendable adhesive strength of 783.6 kPa and shear strength of 53.7 kPa, surpassing that of commercialized eye adhesives.Additionally, biocompatibility test results indicated a notably high survival rate (>100 %) of keratocytes seeded on the hydrogel adhesive after 7 days of incubation. Consequently, this designed bioadhesive, characterized by high adhesion strength, robust mechanical strength, and excellent biocompatibility, is anticipated to enhance the spontaneous repair process of damaged corneal stromal tissue.

Epidermal growth factor-loaded, dehydrated physical microgel-formed adhesive hydrogel enables integrated care of wet wounds.

Integrated wound care, a sequential process of promoting wound hemostasis, sealing, and healing, is of great clinical significance. However, the wet environment of wounds poses formidable challenges for integrated care. Herein, we developed an epidermal growth factor (EGF)-loaded, dehydrated physical microgel (DPM)-formed adhesive hydrogel for the integrated care of wet wounds. The DPMs were designed using the rational combination of hygroscopicity and reversible crosslinking of physical hydrogels. Unlike regular bioadhesives, which consider interfacial water as a barrier to adhesion, DPMs utilize water to form desirable adhesive structures. The hygroscopicity allowed the DPMs to absorb interfacial water and subsequently, the interfacial adhesion was realized by the interactions between tissue and DPMs. The reversible crosslinks further enabled DPMs to integrate into hydrogels (DPM-Gels), thus achieving wet adhesion. Importantly, the water-absorbing gelation mode of DPMs enabled facile loading of biologically active EGF to promote wound healing. We demonstrated that the DPM-Gels possessed wet tissue adhesive performance, with about 40 times the wet adhesive strength of fibrin glue and about 4 times the burst pressure of human blood pressure. Upon application at the injury site, the EGF-loaded DPM-Gels sequentially promoted efficient wound hemostasis, stable sealing, and quick healing, achieving integrated care of wet wounds.

Engineered Regenerative and Adhesive Hydrogel for Concurrent Sealing and Healing of Enterocutaneous Fistulas.

In addressing the intricate challenges of enterocutaneous fistula (ECF) treatment, such as internal bleeding, effluent leakage, inflammation, and infection, our research is dedicated to introducing a regenerative adhesive hydrogel that can seal and expedite the healing process. A double syringe setup was utilized, with dopagelatin and platelet-rich plasma (PRP) in one syringe and Laponite and sodium periodate in another. The hydrogel begins to cross-link immediately after passing through a mixing tip and exhibits tissue adhesive properties. Results demonstrated that PRP deposits within the pores of the cross-linked hydrogel and releases sustainably, enhancing its regenerative capabilities. The addition of PRP further improved the mechanical properties and slowed down the degradation of the hydrogel. Furthermore, the hydrogel demonstrated cytocompatibility, hemostatic properties, and time-dependent macrophage M1 to M2 phase transition, suggesting the anti-inflammatory response of the material. In an in vitro bench test simulating high-pressure fistula conditions, the hydrogel effectively occluded pressures up to 300 mmHg. In conclusion, this innovative hydrogel holds promise for ECF treatment and diverse fistula cases, marking a significant advancement in its therapeutic approaches.

Temperature- and pH-induced dual-crosslinked methylcellulose/chitosan-gallol conjugate composite hydrogels with improved mechanical, tissue adhesive, and hemostatic properties.

Gauze or bandages are commonly used to effectively control bleeding during trauma and surgery. However, conventional treatment methods can sometimes lead to secondary damages. In recent years, there has been increased interest in developing adhesive hemostatic hydrogels as a safer alternative for achieving hemostasis. Methylcellulose (MC) is a well-known thermo-sensitive polymer with excellent biocompatibility that is capable of forming a hydrogel through physical crosslinking owing to its inherent thermo-reversible properties. However, the poor mechanical properties of the MC hydrogel comprising a single crosslinked network (SN) limit its application as a hemostatic material. To address this issue, we incorporated a chitosan-gallol (CS-GA) conjugate, which has the ability to form chemical crosslinks through self-crosslinking reactions under specific pH conditions, into the MC hydrogel to reinforce the MC hydrogel network. The resulting MC/CS-GA hydrogel with a dual-crosslinked network (DN), involving both physical and chemical crosslinks, exhibited synergistic effects of the two types of crosslinks. Thus, compared with those of the SN hydrogel, the composite DN hydrogel exhibited significantly enhanced mechanical strength and tissue adhesive properties. Moreover, the DN hydrogel presented excellent biological activity in vitro. Additionally, in rat hepatic hemorrhage models, the DN hydrogel exhibited high hemostatic efficiency, showcasing its multifunctional capabilities.

Evaluation of composition effects on the tissue-adhesive, mechanical and physical properties of physically crosslinked hydrogels based on chitosan and pullulan for wound healing applications.

Tissue adhesion of hydrogels plays an important role in wound healing, which can improve the efficiency of wound treatment, stop bleeding, facilitate tissue growth and wound closure. However, most non-covalent crosslinked hydrogels have weak tissue adhesion and rheological properties. Furthermore, it remains a challenge to synthesize a fully physically crosslinked hydrogel with good rheological properties without compromising its tissue adhesion strength. In this paper, a physically crosslinked hydrogel was developed from a mixture of chitosan and pullulan in different polymer volume ratios using aqueous NaOH. Fourier transform infrared spectroscopy, scanning electron microscopy, thermal analysis, rheological and lap shear tests were used to evaluate the influence of polymer volume ratios on the rheological, and tissue adhesive properties of the hydrogels. It was found that the hydrogels possessed high tissue adhesive strength ranging from 18.0 ± 0.90 to 49.0 ± 2.45 kPa and good storage moduli up to 5.157 ± 1.062 kPa. Gentamicin was incorporated into this polymer matrix and the release profile was investigated. The ratio of chitosan and pullulan to obtain hydrogels with optimum viscoelastic and tissue adhesive properties was identified to be CS/PUL 2:1. These results indicated that the synthesized hydrogels can be potential materials for biomedical applications such as medical adhesives and wound dressings.

Organism-Inspired Antioxidant Bioadhesive with Strong Sealing Ability to Prevent Epidural Adhesion.

Epidural adhesion or epidural fibrosis is the major reason for postoperative pain, which remains a clinically challenging problem. Current physical barriers fail to provide a satisfactory therapeutic outcome mainly due to their lack of adhesion, inability to prevent fluid leakage, and exhibiting limited antioxidant properties. Herein, we fabricated a cysteine-modified bioadhesive (SECAgel) with improved sealing and antioxidant properties for epidural adhesion prevention, inspired by the organism's antioxidant systems. The resulting SECAgel showed good injectability and in situ adhesion ability, effectively covering every corner of the irregular wound. Besides, it possessed efficient sealing properties (395.2 mmHg), effectively stopping blood leakage in the rabbit carotid artery transection model. The antioxidant experiments demonstrated that the SECAgel effectively scavenged various radicals and saved the cells from oxidative stress. Two animal models were used to show that the SECAgel effectively inhibited adhesion in both situations with and without cerebrospinal fluid leakage. The RNA sequencing analysis showed that SECAgel treatment effectively inhibited the expression of key genes related to adhesion development, inflammatory response, and oxidative stress. The SECAgel, together with good biocompatibility, can be a good candidate for preventing epidural adhesion in the clinic.

Composite Hydrogel Sealants for Annulus Fibrosus Repair.

Intervertebral disc (IVD) herniation is a leading cause of disability and lower back pain, causing enormous socioeconomic burdens. The standard of care for disc herniation is nucleotomy, which alleviates pain but does not repair the annulus fibrosus (AF) defect nor recover the biomechanical function of the disc. Existing bioadhesives for AF repair are limited by insufficient adhesion and significant mechanical and geometrical mismatch with the AF tissue, resulting in the recurrence of protrusion or detachment of bioadhesives. Here, we report a composite hydrogel sealant constructed from a composite of a three-dimensional (3D)-printed thermoplastic polyurethane (TPU) mesh and tough hydrogel. We tailored the fiber angle and volume fraction of the TPU mesh design to match the angle-ply structure and mechanical properties of native AF. Also, we proposed and tested three types of geometrical design of the composite hydrogel sealant to match the defect shape and size. Our results show that the sealant could mimic native AF in terms of the elastic modulus, flexural modulus, and fracture toughness and form strong adhesion with the human AF tissue. The bovine IVD tests show the effectiveness of the composite hydrogel sealant for AF repair and biomechanics recovery and for preventing herniation with its heightened stiffness and superior adhesion. By harnessing the combined capabilities of 3D printing and bioadhesives, these composite hydrogel sealants demonstrate promising potential for diverse applications in tissue repair and regeneration.

Injectable Tissue Adhesive Microgel Composite Containing Antifibrotic Drug for Vocal Fold Scarring.

Vocal fold (VF) scarring, a complex problem in laryngology, results from injury and inflammation of the layered architecture of the VFs. The resultant voice hoarseness, for which successful therapeutic options are currently limited, affects the patient's quality of life. A promising strategy to reverse this disorder is the use of antifibrotic drugs. The present study proposes a novel microbead-embedded injectable hydrogel that can sustain the release of the anti-fibrotic drug pirfenidone (PFD) for vocal fold scarring. Microbeads were developed using sodium alginate and gelatin, which were further embedded into a biomimetic and tissue adhesive gellan gum (GG) hydrogel. The microbead-embedded hydrogel exhibited improved injectability, viscoelasticity, tissue adhesiveness, degradability, and swelling compared to the hydrogel without beads. Additionally, the bead-embedded hydrogel could sustain the release of the PFD for a week. In vitro studies showed that the drug-loaded hydrogel could reduce the migration and proliferation of fibroblast cells in a dose-dependent manner. In summary, this study demonstrates the potential of a PFD-loaded injectable hydrogel with enhanced viscoelastic and tissue-adhesive properties for vocal fold scarring applications.

Biodegradable Plant Oil-Based Bioadhesive with Ultrastrong Wet-Tissue Adhesion for Instant Sealing Hemostasis.

The key to saving lives is to achieve instant and effective sealing hemostasis in the event of emergency bleeding. Herein, a plant oil-based EMTA/Zn2+ bioadhesive is prepared by a facile reaction of epoxidized soybean oil (ESO) with methacrylic acid (MAA) and tannic acid (TA), followed by the addition of zinc ions for coordination with TA. The EMTA/Zn2+ bioadhesive can be rapidly cured in situ at the wound site through photo-cross-linking under ultraviolet (UV) light-emitting diode (LED) irradiation within 30 s, achieving ultrastrong wet-tissue adhesion performance of 92.4 and 51.8 kPa to porcine skin and aortic skin after 7 days underwater, respectively. Especially, the EMTA/Zn2+ bioadhesive exhibits outstanding sealing performance in vitro with the high burst pressure of 525 mmHg (70 kPa) and 337.5 mmHg (45 kPa) to porcine skin and aortic skin, respectively. Moreover, the EMTA/Zn2+ bioadhesive not only has outstanding hemocompatibility and good biodegradability but also exhibits excellent cytocompatibility and antibacterial properties. Notably, the EMTA/Zn2+ bioadhesive has remarkable instant sealing hemostatic ability for hemorrhaging liver in vivo. Therefore, the prepared plant oil-based EMTA/Zn2+ bioadhesive can serve as a charming alternative candidate for instant sealing hemostasis in clinical applications, especially in traumatic internal organs and arterial bleeding.

A pilot study on endoscopic delivery of injectable bioadhesive for esophageal repair in a porcine model.

Endoscopic submucosal dissection (ESD) is the gold-standard surgical procedure for superficial esophageal cancer. A significant and challenging complication of this technique is post-ESD esophageal stricture. In this study, the feasibility of endoscopic catheter delivery of bioadhesive to esophageal lesions in a porcine model was tested. Injectable bioadhesive was composed of oxidized dextran (ODA) and chitosan hydrochloride (CS), its physicochemical properties, injectability, antibacterial activity, and cytocompatibility were investigated beforein vivotest. ODA-CS bioadhesive was delivered to the wound bed of the esophageal tissue using a custom-made catheter device after ESD in a porcine model. Our results show that the ODA-CS bioadhesive is of good injectability, tissue adhesive strength, antibacterial capacity, and blood compatibility.In vivodelivery was achieved by endoscopic spraying of ODA and CS in separate catheters fixed on the endoscopic probe. ODA and CS can be mixed well to allow in situ bioadhesive formation and firmly adhere to the esophageal wound surface. After two weeks, the bioadhesive maintained structural integrity and adhered to the surface of esophageal wounds. However, histological analysis reveals that the ODA-CS bioadhesive did not show improvement in attenuating inflammatory response after ESD. This pilot study demonstrates the feasibility of ODA-CS bioadhesive for shielding esophageal wounds after ESD, whereas efforts need to improve its anti-inflammatory activity to reduce fibrosis for stricture prevention.

Artiss fibrin sealant for the fixation of autografts in pediatric burn care.

BACKGROUND: Traditional fixation of autografts in the treatment of burns involves the use of sutures and staples. A novel fibrin sealant, Artiss, has been introduced as an alternate method of fixation and has shown promising safety and efficacy results in the adult population. Our study assessed the effectiveness of fibrin sealant to secure autologous split thickness skin grafts (ASTSG) in the pediatric burn population. METHODS: We performed a retrospective cohort study of pediatric patients under 18 years of age who received autografting for the treatment of burns at our institution between 2017 and 2023. We compared ASTSG secured with fibrin sealant to those managed traditionally with sutures or staples. Outcomes of interest include the need for return trips to the operating room (OR), time to wound healing, graft take, and total time in the operating room. RESULTS: 83 patients underwent a total of 142 individual ASTSGs for management of unique body area injuries. 66.3 % were male, median age was 79 months, and scald was the most common mechanism of injury (41.0 %). Forty-five (39.5 %) traditionally affixed ASTSG required at least one return to the OR while only one (3.6 %) ASTSG secured with fibrin sealant required an additional return to the OR (p < 0.001). Graft take was similar in both groups (92.9 % for fibrin sealant vs. 93.9 % for traditional methods, p = 1). Time to wound healing was also similar: 16 vs. 15 days for fibrin glue and traditional methods, respectively (p = 0.23). CONCLUSION: Outcomes from autograft fixation with fibrin sealant were comparable to those treated with traditional methods, with a reduction in the need for return trips to the operating room. These data suggest that fibrin sealant is a suitable alternative to traditional fixation methods in pediatric autografting.

A dry double-sided tape post-treated with tannic acid for long-term adhesion in a wet environment.

Medical adhesives have been used for wound closure with many advantages over sutures, but the wet environment in the human body poses a big challenge for its application. The currently used dry double-sided tape (DST) can remove the water barrier by water absorption, but its over-swelling makes it difficult to achieve long-term adhesion. In this study, a dry double-sided tape post-treated with tannic acid (DST-TA) was developed. A double network adhesive composed of polyacrylic acid and gelatin was first prepared by free radical photocrosslinking, and was post-treated in acidic (pH = 2) tannic acid solution. Tannic acid was immobilized in the DST through the catecholyl group, which could form hydrogen bonds with the DST, or react with the amino group on the gelatin by oxidizing to quinone. In vivo and in vitro studies demonstrated that DST-TA had significantly higher swelling resistance and tensile strength than DST. The introduced catecholyl group could reduce over-swelling of the DST, and improve short-term and long-term adhesion in a wet environment. We also demonstrated that the DST-TA had good hemocompatibility, biodegradability, and no cytotoxicity, offering a potential option for long-term medical adhesive in a wet environment.