Swift Covalent Gelation Coupled with Robust Wet Adhesive Powder: A Novel Approach for Acute Massive Hemorrhage Control in Dynamic and High-Pressure Wound Environments.

The quest for efficient hemostatic agents in emergency medicine is critical, particularly for managing massive hemorrhages in dynamic and high-pressure wound environments. Traditional self-gelling powders, while beneficial due to their ease of application and rapid action, fall short in such challenging conditions. To bridge this gap, the research introduces a novel self-gelling powder that combines ultrafast covalent gelation and robust wet adhesion, presenting a significant advancement in acute hemorrhage control. This ternary system comprises ε-polylysine (ε-PLL) and 4-arm polyethylene glycol succinyl succinate (4-arm-PEG-NHS) forming the hydrogel framework. Na2HPO4 functions as the "H+ sucker" to expedite the amidation reaction, slashing gelation time to under 10 s, crucial for immediate blood loss restriction. Moreover, PEG chains' hydrophilicity facilitates efficient absorption of interfacial blood, increasing the generated hydrogel's cross-linking density and strengthens its tissue bonding, thereby resulting in excellent mechanical and wet adhesion properties. In vitro experiments reveal the optimized formulation's exceptional tissue compliance, procoagulant activity, biocompatibility and antibacterial efficacy. In porcine models of heart injuries and arterial punctures, it outperforms commercial hemostatic agent Celox, confirming its rapid and effective hemostasis. Conclusively, this study presents a transformative approach to hemostasis, offering a reliable and potent solution for the emergency management of massive hemorrhage.

Hydrogel-mesh composite for wound closure.

During operations, surgical mesh is commonly fixed on tissues through fasteners such as sutures and staples. Attributes of surgical mesh include biocompatibility, flexibility, strength, and permeability, but sutures and staples may cause stress concentration and tissue damage. Here, we show that the functions of surgical mesh can be significantly broadened by developing a family of materials called hydrogel-mesh composites (HMCs). The HMCs retain all the attributes of surgical mesh and add one more: adhesion to tissues. We fabricate an HMC by soaking a surgical mesh with a precursor, and upon cure, the precursor forms a polymer network of a hydrogel, in macrotopological entanglement with the fibers of the surgical mesh. In a surgery, the HMC is pressed onto a tissue, and the polymers in the hydrogel form covalent bonds with the tissue. To demonstrate the concept, we use a poly(N-isopropylacrylamide) (PNIPAAm)/chitosan hydrogel and a polyethylene terephthalate (PET) surgical mesh. In the presence a bioconjugation agent, the chitosan and the tissue form covalent bonds, and the adhesion energy reaches above 100 J⋅m-2 At body temperature, PNIPAAm becomes hydrophobic, so that the hydrogel does not swell and the adhesion is stable. Compared with sutured surgical mesh, the HMC distributes force over a large area. In vitro experiments are conducted to study the application of HMCs to wound closure, especially on tissues under high mechanical stress. The performance of HMCs on dynamic living tissues is further investigated in the surgery of a sheep.

A Tough Hydrogel Adhesive for the Repair of Archeological Pottery.

Pottery is the oldest art and plays a landmark role in human civilization. The repair of ceramic relics often uses acrylic resins and cyanoacrylate adhesives. However, existing adhesives often take hours to get cured, and wet adhesion is not possible. We herein propose a redox initiator-triggered hydrogel adhesive, of which robust (∼700 J m-2) and wet adhesion with potsherds can be achieved within a few seconds. The high toughness lies in the self-limited delocalized rupture of the porous interface, and the wet adhesion is due to the hydrophilic precursor and its free radical polymerization. The hydrogel adhesive also exhibits high aging resistance for stable preservation of ∼400 annuals. We have applied the adhesive to the restoration of artifacts excavated from Yinxu, Anyang (∼1300 BC) and the Xia Jiao Shan site (∼4000 BC, Neolithic), and the adhesive is expected to be extended to applications beyond archeology.

Instant tough bioadhesive with triggerable benign detachment.

Bioadhesives such as tissue adhesives, hemostatic agents, and tissue sealants have potential advantages over sutures and staples for wound closure, hemostasis, and integration of implantable devices onto wet tissues. However, existing bioadhesives display several limitations including slow adhesion formation, weak bonding, low biocompatibility, poor mechanical match with tissues, and/or lack of triggerable benign detachment. Here, we report a bioadhesive that can form instant tough adhesion on various wet dynamic tissues and can be benignly detached from the adhered tissues on demand with a biocompatible triggering solution. The adhesion of the bioadhesive relies on the removal of interfacial water from the tissue surface, followed by physical and covalent cross-linking with the tissue surface. The triggerable detachment of the bioadhesive results from the cleavage of bioadhesive's cross-links with the tissue surface by the triggering solution. After it is adhered to wet tissues, the bioadhesive becomes a tough hydrogel with mechanical compliance and stretchability comparable with those of soft tissues. We validate in vivo biocompatibility of the bioadhesive and the triggering solution in a rat model and demonstrate potential applications of the bioadhesive with triggerable benign detachment in ex vivo porcine models.

A Photocured Bio-based Shape Memory Thermoplastics for Reversible Wet Adhesion.

Development of reversible wet or underwater adhesives remains a grand challenge. Because weakened intermolecular interactions by water molecules or/and low effective contact area cause poor interface to the wet surfaces, which significantly decreases adhesive strength. Herein, a new photocured, bio-based shape memory polymer (SMP) that shows both chemical and structural wet adhesion to various types of surfaces is developed. The SMP is polymerized from three monomers mainly from bio-sources to form linear polymer chains dangled with hydrophobic side chains. The hydrogen acceptor and donor groups in the chains form hydrogen bonding with the surfaces, which is protected by the hydrophobic chains in the interface. The SMP shows tunable phase transition temperature (Tg) of 17-38 °C. In a rubbery state above Tg, the adhesive forms conformable contact with the targeted surfaces. Below Tg, a transition to a glassy state locks the conformed shapes to largely increase the effective contact area. As a result, the adhesive exhibits long-term underwater adhesion of > 15 days with the best adhesion strength of ~ 0.9 MPa. Its applications in leak repair, underwater on-skin sensors were demonstrated. This new, general strategy would pave avenues to designing bio-based, long-lasting, and reversible adhesives from renewable feedstocks for widespread applications.

Mussel Inspired Trigger-Detachable Adhesive Hydrogel.

Adhesion to many kinds of surfaces, including biological tissues, is important in many fields but has been proved to be extremely challenging. Furthermore, peeling from strong adhesion is needed in many conditions, but is sometimes painful. Herein, a mussel inspired hydrogel is developed to achieve both strong adhesion and trigger-detachment. The former is actualized by electrostatic interactions, covalent bonds, and physical interpenetration, while the latter is triggered, on-demand, through combining a thixotropic supramolecular network and polymer double network. The results of the experiments show that the hydrogel can adhere to various material surfaces and tissues. Moreover, triggered by shear force, non-covalent interactions of the supramolecular network are destroyed. This adhesion can be peeled easily. The possible mechanism involved is discussed and proved. This work will bring new insight into electronic engineering and tissue repair like skin care for premature infants and burn victims.

Engineering Bio-Adhesives Based on Protein-Polysaccharide Phase Separation.

Glue-type bio-adhesives are in high demand for many applications, including hemostasis, wound closure, and integration of bioelectronic devices, due to their injectable ability and in situ adhesion. However, most glue-type bio-adhesives cannot be used for short-term tissue adhesion due to their weak instant cohesion. Here, we show a novel glue-type bio-adhesive based on the phase separation of proteins and polysaccharides by functionalizing polysaccharides with dopa. The bio-adhesive exhibits increased adhesion performance and enhanced phase separation behaviors. Because of the cohesion from phase separation and adhesion from dopa, the bio-adhesive shows excellent instant and long-term adhesion performance for both organic and inorganic substrates. The long-term adhesion strength of the bio-glue on wet tissues reached 1.48 MPa (shear strength), while the interfacial toughness reached ~880 J m-2. Due to the unique phase separation behaviors, the bio-glue can even work normally in aqueous environments. At last, the feasibility of this glue-type bio-adhesive in the adhesion of various visceral tissues in vitro was demonstrated to have excellent biocompatibility. Given the convenience of application, biocompatibility, and robust bio-adhesion, we anticipate the bio-glue may find broad biomedical and clinical applications.

Environmentally Compatible Wearable Electronics Based on Ionically Conductive Organohydrogels for Health Monitoring with Thermal Compatibility, Anti-Dehydration, and Underwater Adhesion.

Hydrogel-based electronics have found widespread applications in soft sensing and health monitoring because of their remarkable biocompatibility and mechanical features similar to human skin. However, they are subjected to potential challenges like structural failure, functional degradation, and device delamination in practical applications, especially facing extreme environmental conditions (e.g., abnormal temperature and humidity). To address these, ionically conductive organohydrogel-based soft electronics are developed, which can perform at subzero and elevated temperatures (thermal compatibility) as well as at dehydrated and hydrated environments (hydration compatibility) for extended applications. More specifically, gelatin/poly(acrylic acid-N-hydrosuccinimide ester) (PAA-NHS ester)-based ionic-conductive organohydrogel is synthesized. By introducing a glycerol-water binary solvent system, the gel can maintain mechanical softness in a wide temperature range (from -80 to 60 °C). Besides, excellent conductivity is achieved under various conditions by soaking the gel into lithium chloride anhydrous (LiCl) solution. Strong adhesion with skin, even under water, can be realized by covalent bonds between NHS ester from gel and amino groups from human skin. The excellent performances of LiCl-loaded PAA-based organohydrogel (L-PAA-OH)-based electronics are further demonstrated under freezing and high temperatures as well as underwater conditions, unveiling their promising prospects in wearable health monitoring in various conditions.

Adhesive Coacervates Driven by Hydrogen-Bonding Interaction.

Coacervation plays a critical role in numerous biological activities such as constructing biological tissues and achieving robust wet adhesion of marine sessile organisms, which conventionally occurs when oppositely charged polyelectrolytes are mixed in aqueous solutions driven by electrostatic attraction. Here, a novel type of adhesive coacervate is reported, driven by hydrogen-bonding interactions, readily formed by mixing silicotungstic acid and nonionic polyethylene glycol in water, providing a new approach for developing coacervates from nonionic systems. The as-prepared coacervate is easily paintable underwater, show strong wet adhesion to diverse substrates, and has been successfully applied as a hemostatic agent to treat organ injuries without displaying hemolytic activity, while with inherent antimicrobial properties thus avoiding inflammations and infections due to microorganism accumulation. This work demonstrates that coacervation can occur in salt-free environments via non-electrostatic interactions, providing a new platform for engineering multifunctional coacervate materials as tissue glues, wound dressings and membrane-free cell systems.

Comparative and functional analysis of the digital mucus glands and secretions of tree frogs.

BACKGROUND: Mucus and mucus glands are important features of the amphibian cutis. In tree frogs, the mucus glands and their secretions are crucial components of the adhesive digital pads of these animals. Despite a variety of hypothesised functions of these components in tree frog attachment, the functional morphology of the digital mucus glands and the chemistry of the digital mucus are barely known. Here, we use an interdisciplinary comparative approach to analyse these components, and discuss their roles in tree frog attachment. RESULTS: Using synchrotron micro-computer-tomography, we discovered in the arboreal frog Hyla cinerea that the ventral digital mucus glands differ in their morphology from regular anuran mucus glands and form a subdermal gland cluster. We show the presence of this gland cluster also in several other-not exclusively arboreal-anuran families. Using cryo-histochemistry as well as infrared and sum frequency generation spectroscopy on the mucus of two arboreal (H. cinerea and Osteopilus septentrionalis) and of two terrestrial, non-climbing frog species (Pyxicephalus adspersus and Ceratophrys cranwelli), we find neutral and acidic polysaccharides, and indications for proteinaceous and lipid-like mucus components. The mucus chemistry varies only little between dorsal and ventral digital mucus in H. cinerea, ventral digital and abdominal mucus in H. cinerea and O. septentrionalis, and between the ventral abdominal mucus of all four studied species. CONCLUSIONS: The presence of a digital mucus gland cluster in various anuran families, as well as the absence of differences in the mucus chemistry between arboreal and non-arboreal frog species indicate an adaptation towards generic functional requirements as well as to attachment-related requirements. Overall, this study contributes to the understanding of the role of glands and their secretions in tree frog attachment and in bioadhesion in general, as well as the evolution of anurans.

Identification and characterization of protein phosphorylation in the soluble protein fraction of scallop (Chlamys farreri) byssus.

Protein phosphorylation is a widespread modification that and plays a significant role in marine bioadhesion. The phosphorylated proteins of the barnacle Amphibalanus amphitrite can form strong ionic bonds with mineral surfaces to adapt to marine environments. The adhesion protein PC-3 in the sandcastle worm Phragmatopoma californica contains multipleserine phosphorylations. Interactions between these phosphate groups and the Mg/Ca2+ ions are less soluble at seawater pH, making the cement less fluid and more gel-like. The scallop byssus is characterized by strong wet adhesion performance and substantial byssus secretions. Thus, the excellent underwater adhesion properties of the byssus make it an ideal candidate for studies related to the development of new and versatile composite materials. However, phosphoproteins have not been identified or studied in the scallop Chlamys farreri. Phosphorylated proteins in the C. farreri byssus protein were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and further confirmed by phosphorylation staining and in-gel digestion coupled with mass spectrometric analysis (GeLC-MS/MS). Finally, sequence analyses and potential functional analyses were performed for these newly identified proteins. We have identified previously unreported phosphorylation sites within the C. farreri byssus protein. The results show phosphorylation modifications in all parts of the byssus structure and four foot-specific phosphorylated proteins were verified by two types of mass spectrometry and staining. The annotation of biological functions, based on sequence alignments shows that the protein 40,215.25 is homologous with TIMP-2. Similar to the previously identified TIMP-2-like protein Sbp8-1 in the scallop byssus, it contains an abundance of phosphorylated Cys, which may promote protein polymerization. We speculate that protein 40,215.25 may play an important role in cross-linking and adhesion of the scallop byssus. The phosphorylated protein we have identified in the C. farreri byssus may be related to the formation of protein cross-linkings and adhesion of the scallop foot. Our study lays the groundwork for a better understanding of the adhesion mechanism of the scallop byssus.

Wet and Functional Adhesives from One-Step Aqueous Self-Assembly of Natural Amino Acids and Polyoxometalates.

Sessile organisms have undergone long-term evolution to develop the unique ability by positioning themselves on wet solid surface through secreting adhesive proteins. The present study reveals that natural amino acid monomers can also exhibit similar adhesion capacity. This kind of biomimetic adhesives were created by the one-step aqueous assembly of basic amino acids with assistance of anionic polyoxometalates. The polyoxometalates not only serve as multivalent scaffold to initiate the supramolecular cross-linking of amino acid molecules, but also function as a redox component, bestowing the wet adhesives with electrochromic features.

Intrinsic surface-drying properties of bioadhesive proteins.

Sessile marine mussels must "dry" underwater surfaces before adhering to them. Synthetic adhesives have yet to overcome this fundamental challenge. Previous studies of bioinspired adhesion have largely been performed under applied compressive forces, but such studies are poor predictors of the ability of an adhesive to spontaneously penetrate surface hydration layers. In a force-free approach to measuring molecular-level interaction through surface-water diffusivity, different mussel foot proteins were found to have different abilities to evict hydration layers from surfaces-a necessary step for adsorption and adhesion. It was anticipated that DOPA would mediate dehydration owing to its efficacy in bioinspired wet adhesion. Instead, hydrophobic side chains were found to be a critical component for protein-surface intimacy. This direct measurement of interfacial water dynamics during force-free adsorptive interactions at solid surfaces offers guidance for the engineering of wet adhesives and coatings.

Highly Adaptive Kirigami-Metastructure Adhesive with Vertically Self-Aligning Octopus-like 3D Suction Cups for Efficient Wet Adhesion to Complexly Curved Surfaces.

An essential requirement for biomedical devices is the capability of conformal adaptability on diverse irregular 3D (three-dimensional) nonflat surfaces in the human body that may be covered with liquids such as mucus or sweat. However, the development of reversible adhesive interface materials for biodevices that function on complex biological surfaces is challenging due to the wet, slippery, smooth, and curved surface properties. Herein, we present an ultra-adaptive bioadhesive for irregular 3D oral cavities covered with saliva by integrating a kirigami-metastructure and vertically self-aligning suction cups. The flared suction cup, inspired by octopus tentacles, allows adhesion to moist surfaces. Additionally, the kirigami-based auxetic metastructure with a negative Poisson's ratio relieves the stress caused by tensile strain, thereby mitigating the stress caused by curved surfaces and enabling conformal contact with the surface. As a result, the adhesive strength of the proposed auxetic adhesive is twice that of adhesives with a flat backbone on highly curved porcine palates. For potential application, the proposed auxetic adhesive is mounted on a denture and performs successfully in human subject feasibility evaluations. An integrated design of these two structures may provide functionality and potential for biomedical applications.

Bioactive citrate-based polyurethane tissue adhesive for fast sealing and promoted wound healing.

As a superior alternative to sutures, tissue adhesives have been developed significantly in recent years. However, existing tissue adhesives struggle to form fast and stable adhesion between tissue interfaces, bond weakly in wet environments and lack bioactivity. In this study, a degradable and bioactive citrate-based polyurethane adhesive is constructed to achieve rapid and strong tissue adhesion. The hydrophobic layer was created with polycaprolactone to overcome the bonding failure between tissue and adhesion layer in wet environments, which can effectively improve the wet bonding strength. This citrate-based polyurethane adhesive provides rapid, non-invasive, liquid-tight and seamless closure of skin incisions, overcoming the limitations of sutures and commercial tissue adhesives. In addition, it exhibits biocompatibility, biodegradability and hemostatic properties. The degradation product citrate could promote the process of angiogenesis and accelerate wound healing. This study provides a novel approach to the development of a fast-adhering wet tissue adhesive and provides a valuable contribution to the development of polyurethane-based tissue adhesives.

Laponite nanoparticle-crosslinked carboxymethyl cellulose-based injectable hydrogels with efficient underwater-specific adhesion for rapid hemostasis.

Tissue adhesives have attracted intense and increasing interest due to their multiple biomedical applications. Despite the rapid development of adhesive hydrogels, huge challenges remain for materials that can ensure strong adhesion and seal hemostasis in aqueous and blood environments. To address this issue, we have developed an innovative design of PAA-based coacervate hydrogel with strong wet adhesion capability through a simple mixture of PAA copolymers with oxidized-carboxymethylcellulose (OCMC), and tannic acid (TA) as the main components, and structurally enhanced with natural clays (Laponite XLG). The absorbed TA provides solid adhesion to dry and wet substrates via multiple interactions, which endows the XLG-enhanced coacervate with the desired underwater adhesive strength. More importantly, the dielectric constant is introduced to evaluate the polarity of the tested samples, which may be used as guidance for the design of mussel-inspired adhesives with even better underwater adhesive properties. In vivo hemorrhage experiments further confirmed that the hydrogel adhesive dramatically shortened the hemostatic time to tens of seconds. Overall, the persistent adhesion and acceptable cytocompatibility of the hydrogel nanocomposite make it a promising alternative suture-free approach for rapid hemostasis at different length scales and is expected to be extended to clinical application for other organ injuries.

A Nature-Derived, Hetero-Structured, Pro-Healing Bioadhesive Patch for High-Performance Sealing of Wet Tissues.

Tissue adhesives are promising alternatives to sutures and staples to achieve wound closure and hemostasis. However, they often do not work well on tissues that are soaked in blood or other biological fluids, and organs that are typically exposed to a variety of harsh environments such as different pH values, nonhomogeneous distortions, continuous expansions and contractions, or high pressures. In this study, a nature-derived multilayered hetero-bioadhesive patch (skin secretion of Andrias davidianus (SSAD)-Patch) based on hydrophilic/hydrophobic pro-healing bioadhesives derived from the SSAD is developed, which is designed to form pressure-triggered strong adhesion with wet tissues. The SSAD-Patch is successfully applied for the sealing and healing of tissue defects within 10 s in diverse extreme injury scenarios in vivo including rat stomach perforation, small intestine perforation, fetal membrane defect, porcine carotid artery incision, and lung lobe laceration. The findings reveal a promising new type of self-adhesive regenerative SSAD-Patch, which is potentially adaptable to broad applications (under different pH values and air or liquid pressures) in sutureless wound sealing and healing.

Gluing blood into adhesive gel by oppositely charged polysaccharide dry powder inspired by fibrin fibers coagulation mediator.

Hemostatic powders that adapt to irregularly shaped wounds, allowing for easy application and stable storage, have gained popularity for first-aid hemorrhage control. However, traditional powders often provide weak thrombus support and exhibit limited tissue adhesion, making them susceptible to dislodgment by the bloodstream. Inspired by fibrin fibers coagulation mediator, we have developed a bi-component hemostatic powder composed of positively charged quaternized chitosan (QCS) and negatively charged catechol-modified alginate (Cat-SA). Upon application to the wound, the bi-component powders (QCS/Cat-SA) rapidly absorb plasma and dissolve into chains. These chains interact with each other to form a network, which can effectively bind and entraps clustered red blood cells and platelets, ultimately leading to the creation of a durable and robust thrombus. Significantly, these interconnected polymers adhere to the injury site, offering protection against thrombus disruption caused by the bloodstream. Benefiting from these synthetic properties, QCS/Cat-SA demonstrates superior hemostatic performance compared to commercial hemostatic powders like Celox™ in both arterial injuries and non-compressible liver puncture wounds. Importantly, QCS/Cat-SA exhibits excellent antibacterial activity, cytocompatibility, and hemocompatibility. These advantages of QCS/Cat-SA, including strong blood clotting, wet tissue adherence, antibacterial activity, biosafety, ease of use, and stable storage, make it a promising hemostatic agent for emergency situations.

A Self-Assembly Pro-Coagulant Powder Capable of Rapid Gelling Transformation and Wet Adhesion for the Efficient Control of Non-Compressible Hemorrhage.

Rapid and effective control of non-compressible massive hemorrhage poses a great challenge in first-aid and clinical settings. Herein, a biopolymer-based powder is developed for the control of non-compressible hemorrhage. The powder is designed to facilitate rapid hemostasis by its excellent hydrophilicity, great specific surface area, and adaptability to the shape of wound, enabling it to rapidly absorb fluid from the wound. Specifically, the powder can undergo sequential cross-linking based on "click" chemistry and Schiff base reaction upon contact with the blood, leading to rapid self-gelling. It also exhibits robust tissue adhesion through covalent/non-covalent interactions with the tissues (adhesive strength: 89.57 ± 6.62 KPa, which is 3.75 times that of fibrin glue). Collectively, this material leverages the fortes of powder and hydrogel. Experiments with animal models for severe bleeding have shown that it can reduce the blood loss by 48.9%. Studies on the hemostatic mechanism also revealed that, apart from its physical sealing effect, the powder can enhance blood cell adhesion, capture fibrinogen, and synergistically induce the formation of fibrin networks. Taken together, this hemostatic powder has the advantages for convenient preparation, sprayable use, and reliable hemostatic effect, conferring it with a great potential for the control of non-compressible hemorrhage.

Infant friendly adhesive film containing glucose for neonatal hypoglycemia.

Neonatal hypoglycemia is a common disease in newborns, which can precipitate energy shortage and follow by irreversible brain and neurological injury. Herein, we present a novel approach for treating neonatal hypoglycemia involving an adhesive polyvinylpyrrolidone/gallic acid (PVP/GA) film loading glucose. The PVP/GA film with loose cross-linking can be obtained by mixing their ethanol solution and drying complex. When depositing this soft film onto wet tissue, it can absorb interfacial water to form a hydrogel with a rough surface, which facilitates tight contact between the hydrogel and tissue. Meanwhile, the functional groups in the hydrogels and tissues establish both covalent and non-covalent bonds, leading to robust bioadhesion. Moreover, the adhered PVP/GA hydrogel can be detached without damaging tissue as needed. Furthermore, the PVP/GA films exhibit excellent antibacterial properties and biocompatibility. Notably, these films effectively load glucose and deliver it to the sublingual tissue of newborn rabbits, showcasing a compelling therapeutic effect against neonatal hypoglycemia. The strengths of the PVP/GA film encompass excellent wet adhesion in the wet and highly dynamic environment of the oral cavity, on-demand detachment, antibacterial efficacy, biocompatibility, and straightforward preparation. Consequently, this innovative film holds promise for diverse biomedical applications, including but not limited to wearable devices, sealants, and drug delivery systems.