Hydrogel adhesives for generalized wound treatment: Design and applications

Wound refers to the place where human body is injured and ruptured. So, wounds in a broad sense include not only skin wounds, but also damages of muscle, corneal, heart, and lung, etc. As “gold standard” of wound closure, suture and staple cause secondary damage to the tissue, and require professional skills and equipment, so noninvasive hydrogel adhesives have been developed as an alternative to close and treat different kinds of wounds. However, the existing reviews mainly discussed the research of hydrogel adhesives for skin wounds, and the focus is mostly on its types and adhesion mechanisms, but a review comprehensively discusses the design and application of hydrogel adhesives on generalized wounds for wound closure and wound healing and the unique needs of various wounds for hydrogel adhesives is still lacking. In this review, the types and adhesion mechanisms of hydrogel adhesives will be briefly described, then the research progress of hydrogel adhesives in wound treatment is reviewed in detail from two aspects: the comprehensive design principles and the unique requirements of different types of wounds. Overall, we expect that this review will provide guidance for the development of hydrogel adhesives as new avenues for generalized wound care and treatment.     

Protein‐based bioadhesives and bioglues

Bioadhesives and glues are widely used as an adjunct to conventional methods employed in healing the post‐surgical injuries and restoration of normal tissue functions. Protein‐based bioadhesives have been used for a long time, and they are a more biocompatible alternative compared with synthetic adhesives. They offer advantages such as ease of application, reduction in surgery time, improved quality and strength of the seal, and effective sealing. Also, bioadhesives are being exploited in different fields like controlled and site‐specific drug delivery systems, and in tissue engineering and regeneration. There are various marketed protein‐based glues that are available in different forms. Thus, all in all, it is a patient compliant system, thereby increasing its recent popularity. This article provides insight into different types and sources of protein‐based bioadhesives, their history of use, mechanism of adhesion. and various products that have been approved by the regulatory authorities for clinical use. It also includes information regarding the products in clinical trials and potential applications.     

Design Strategies and Applications of Tissue Bioadhesives

In the past two decades tissue adhesives and sealants have revolutionized bleeding control and wound healing. This paper focuses on existing tissue adhesive design, their structure, functioning mechanism, and their pros and cons in wound management. It also includes the latest advances in the development of new tissue adhesives as well as the emerging applications in regenerative medicine. We expect that this paper will provide insightful discussion on tissue bioadhesive design and lead to innovations for the development of the next generation of tissue bioadhesives and their related biomedical applications.

     

Fiber‐reinforced composite hydrogels for bioadhesive and sealant applications

The use of bioadhesives and sealants for wound closure and healing applications is becoming more and more popular, particularly when other techniques, such as stapling or suturing, are impractical or inefficient. Loading adhesives with fibers has tremendous potential for improving their mechanical properties. The concept of fiber‐reinforced bioadhesives and sealants is novel and has not been investigated to date. In the present study, natural cellulose fibers were selected for enhancement of bioadhesive properties. A bioadhesive formulation based on a combination of gelatin and alginate crosslinked with water‐soluble carbodiimide was used as a generic formulation for this study, on the basis of our previous studies. The polymeric matrix and the cellulose fibers showed high affinity, which resulted in a dramatic increase in the viscosity and in the burst strength. They moderately affected the curing time, swelling, and weight loss. A mixed response was found in the compression modulus and the bonding strength in lap shear. We demonstrated that fiber‐reinforced bioadhesives have a great potential for surgical sealant applications because of improvement in the cohesive strength of the composite hydrogel. This study presents proof of the concept of using fibers for the enhancement of bioadhesive properties as a result of fiber‐reinforcement and may comprise the basis for future studies in this field. Copyright © 2017 John Wiley & Sons, Ltd.     

Natural underwater adhesives

The general topic of this review is protein‐based underwater adhesives produced by aquatic organisms. The focus is on mechanisms of interfacial adhesion to native surfaces and controlled underwater solidification of natural water‐borne adhesives. Four genera that exemplify the broad range of function, general mechanistic features, and unique adaptations are discussed in detail: blue mussels, acorn barnacles, sandcastle worms, and freshwater caddisfly larva. Aquatic surfaces in nature are charged and in equilibrium with their environment, populated by an electrical double layer of ions as well as adsorbed natural polyelectrolytes and microbial biofilms. Surface adsorption of underwater bioadhesives likely occurs by exchange of surface bound ligands by amino acid sidechains, driven primarily by relative affinities and effective concentrations of polymeric functional groups. Most aquatic organisms exploit modified amino acid sidechains, in particular phosphorylated serines and hydroxylated tyrosines (dopa), with high‐surface affinity that form coordinative surface complexes. After delivery to the surfaces as a fluid, permanent natural adhesives solidify to bear sustained loads. Mussel plaques are assembled in a manner superficially reminiscent of in vitro layer‐by‐layer strategies, with sequentially delivered layers associated through Fe(dopa)₃ coordination bonds. The adhesives of sandcastle worms, caddisfly larva, and barnacles may be delivered in a form somewhat similar to in vitro complex coacervation. Marine adhesives are secreted, or excreted, into seawater that has a significantly higher pH and ionic strength than the internal environment. Empirical evidence suggests these environment triggers could provide minimalistic, fail‐safe timing mechanisms to prevent premature solidification (insolubilization) of the glue within the secretory system, yet allow rapid solidification after secretion. Underwater bioadhesives are further strengthened by secondary covalent curing. © 2011 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2011     

Recent progress in polymer hydrogel bioadhesives

Adhesive hydrogels have broad applications in tissue adhesives, hemostatic agents, and biomedical sensors. Various bio-inspired glues and synthetic adhesives are clinically used as conventional hemostatic agents and auxiliary tools for wound closure. Medical adhesives are needed to effectively and quickly control bleeding, thereby reducing the risk of complications caused by severe blood loss. Medical sensors need to have excellent skin compliance, mechanical properties, sensitivity, and biological safety. This review focuses on recent progress in adhesive hydrogel systems, their structures, adhesion mechanisms, construction strategies, and emerging applications in the biomedical field.     

A novel corneal adhesive based on functionally coupled PEG-lysozyme hydrogel for wound closure after surgical eye surgery

Corneal wound closure for surgical eye surgeries or accidents is typically performed to prevent pathogens from the sterile intraocular environment and avoid potential postoperative complications. Tissue adhesives are increasingly employed for corneal wound closure with superior treatment efficiency and less adverse effects. In this study, we successfully develop a novel corneal adhesive based on functionally coupled PEG-lysozyme (PEG-LZ) hydrogels for wound closure after surgical eye surgeries. PEG-LZ hydrogels have plenty of micropores and gradually decreased pore size with increasing concentration from 10%, 15% to 20% (w/v), in which PEG-LZ (15%) represents the suitable pH value, gelation time and elastic modulus. PEG-LZ hydrogels have no in vitro cytotoxicity and excellent ex vivo wound closure effectiveness in porcine eyes. The in vivo wound sealant in rabbit eyes by PEG-LZ hydrogels presents a superior therapeutic effect compared with the conventional methods of stromal hydration and suture, in terms of the wound closure percent, mean corneal thickness, percent of wound gaping, and the Descemet membrane detachment. PEG-LZ hydrogels do not induce obvious histological pathology changes. The PEG-LZ corneal adhesive is considered as a tissue adhesive alternative for wound closure after surgical eye surgeries.     

Investigation of Degradation of Structural Adhesives under Influence of Chemicals

Structural adhesives are used for joining materials also under conditions, where they through the application will be influenced by many different chemicals. The adhesives can – if not protected from the chemical influence – be degradated of the chemicals. The degradation can because of the different structures of the polymers in the adhesives result in lower strength of the joining area, but can also give higher strength but brittleness. Information of the structures of the structural adhesives used in the project have been taken from the data sheets from the manufacturers and have been compared with investigation of the structures by FTIR and DSC. In the laboratory the HSP's (Hansen Solubility Parameters) of the adhesives has been determined and compared with the theoretically estimated HSP's. The estimation has mainly been done by Lydersens group contribution method. The chemical resistance of the adhesives have been foreseen by using HSP's of the adheisves and compared them with the HSP's of the chemicals. The structural adhesives were most of the epoxy types and of the polyurethane types with different curing systems. The structural adhesives should all have high strength and an opening time of more than 30 minutes. They were in the laboratory cured up after the specifications from the manufacturer and were stored one week after curing before they were influenced by hte chosen chemicals. The chemicals were chosen from their functional groups. In the laboratory the adhesives were influenced by different chemicals at room temperarture and under elevated temperature and under different periods to develope the degradation curves for the different chemicals and to foresee the degradation time of the adhesives before their properties were not acceptable any more. The structure after influence of the chemicals is studied by FTIR. The results of the investigations have been that it is possible to estimate the degradation by using the HSP's of the adhesives and the chemicals, but to estimate the time before degradation has been so serious that the properties of the adhesives are not acceptable any more, it is necessary to add laboratory investigations to the HSP comparisons of adhesives and chemicals. The comparison of the HSP and of the chemicals by which the adhesives can be in its lifetime has seen to be usefull especially if the chemicals are pesticides.     

POSS-modified PEG adhesives for wound closure

PEG-related adhesives are limited in clinical use because they are easy to swell and cannot support the cell growth.In this study,we produced a series of POSS-modified PEG adhesives with high adhesive strength.Introduction of inorganic hydrophobic POSS units decreased the swelling of the adhesives and enhanced cell adhesion and growth.The in vitro cytotoxicity and in vivo inflammatory response experiments clearly demonstrated that the adhesives were nontoxic and possessed excellent biocompatibility.Compared with the sutured wounds,the adhesive-treated wounds showed an accelerated healing process in wounded skin model of the Bama miniature pig,demonstrating that the POSS-modified PEG adhesive is a promising candidate for wound closure.     

Dynamic Interfacial Adhesion through Cucurbit[n]uril Molecular Recognition

Supramolecular building blocks, such as cucurbit[n]uril (CB[n])‐based host–guest complexes, have been extensively studied at the nano‐ and microscale as adhesion promoters. Herein, we exploit a new class of CB[n]‐threaded highly branched polyrotaxanes (HBP‐CB[n]) as aqueous adhesives to macroscopically bond two wet surfaces, including biological tissue, through the formation of CB[8] heteroternary complexes. The dynamic nature of these complexes gives rise to adhesion with remarkable toughness, displaying recovery and reversible adhesion upon mechanical failure at the interface. Incorporation of functional guests, such as azobenzene moieties, allows for stimuli‐activated on‐demand adhesion/de‐adhesion. Macroscopic interfacial adhesion through dynamic host–guest molecular recognition represents an innovative strategy for designing the next generation of functional interfaces, biomedical devices, tissue adhesives, and wound dressings.     

Recent advances on herb‐derived constituents‐incorporated wound‐dressing materials: A review

Since ancient times, wound dressings have evolved with persistent and substantial changes. Several efforts have been made toward the development of new dressing materials, which can meet the demanding conditions for the treatment of skin wounds. Currently, many studies have been focused on the production and designing of herb‐incorporated wound dressings. Herb‐derived constituents are more effective than conventional medicines because of their nontoxic nature and can be administered over long periods. Herbal medicines in wound healing provide a suitable environment for aiding the natural course of healing. This review mainly focuses on the diverse approaches that have been developed to produce a wound dressing material, which can deliver herb‐derived bioactive constituents in a controlled manner. This review also discusses the common wound‐dressing materials available, basic principles of wound healing, and wound‐healing agents from medicinal plants.     

Recent Advances on the Development of Protein-Based Adhesives for Wood Composite Materials—A Review

The industrial market depends intensely on wood-based composites for buildings, furniture, and construction, involving significant developments in wood glues since 80% of wood-based products use adhesives. Although biobased glues have been used for many years, notably proteins, they were replaced by synthetic ones at the beginning of the 20th century, mainly due to their better moisture resistance. Currently, most wood adhesives are based on petroleum-derived products, especially formaldehyde resins commonly used in the particleboard industry due to their high adhesive performance. However, formaldehyde has been subjected to strong regulation, and projections aim for further restrictions within wood-based panels from the European market, due to its harmful emissions. From this perspective, concerns about environmental footprint and the toxicity of these formulations have prompted researchers to re-investigate the utilization of biobased materials to formulate safer alternatives. In this regard, proteins have sparked a new and growing interest in the potential development of industrial adhesives for wood due to their advantages, such as lower toxicity, renewable sourcing, and reduced environmental footprint. This work presents the recent developments in the use of proteins to formulate new wood adhesives. Herein, it includes the historical development of wood adhesives, adhesion mechanism, and the current hotspots and recent progress of potential proteinaceous feedstock resources for adhesive preparation.     

Strategies Using Gelatin Microparticles for Regenerative Therapy and Drug Screening Applications

Gelatin, a denatured form of collagen, is an attractive biomaterial for biotechnology. In particular, gelatin particles have been noted due to their attractive properties as drug carriers. The drug release from gelatin particles can be easily controlled by the crosslinking degree of gelatin molecule, responding to the purpose of the research. The gelatin particles capable of drug release are effective in wound healing, drug screening models. For example, a sustained release of growth factors for tissue regeneration at the injured sites can heal a wound. In the case of the drug screening model, a tissue-like model composed of cells with high activity by the sustained release of drug or growth factor provides reliable results of drug effects. Gelatin particles are effective in drug delivery and the culture of spheroids or cell sheets because the particles prevent hypoxia-derived cell death. This review introduces recent research on gelatin microparticles-based strategies for regenerative therapy and drug screening models.     

Specific oxidants improve the wood bonding strength of soy and other plant flours

To meet newer environmental standards, modified plant proteins have been studied as no‐added formaldehyde wood adhesives for interior applications. Many methods have been developed to increase the wet strength of wood products bonded with soy adhesives. These methods involve modifying the soy in separate steps prior to formulating the adhesive or adding a polymerizable co‐reactant to the soy. We show that adding periodate, permanganate, or iodate to soy flour improved the strength of soy adhesive bonds in small‐scale testing and in plywood shear, especially when tested under wet conditions. Periodate improved the bond strength of other plant materials (lupine, canola, and cottonseed) but none of these produced as high of a wet strength as the soy flour. We investigated other oxidants with plant proteins. Permanganate was quite effective and iodate was somewhat effective, whereas nitric acid, chlorate, perchlorate, and bromate were not effective in increasing wet strength. The available data are consistent with oxidation of the carbohydrate–protein mixture in plant flours to provide adhesives with increased wet strength in wood bonds. This mechanism was also supported by the improved wet strength with the addition of dialdehydes (glyoxal and glutaraldehyde). The purified soy protein also gave strength improvement with periodate. Published 2019. This article is a U.S. Government work and is in the public domain in the USA. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 1017–1023     

Paradoxical effects of elastase inhibitor guamerin on the tissue repair of two different wound models: sealed cutaneous and exposed tongue wounds

Innate elastase inhibitors are known to be putatively involved in the regulation of tissue inflammation by inhibiting polymorphonuclear leukocyte (PMN) derived proteinases. The aim of this study was to evaluate affects of leukocyte elastase suppression and PMN infiltration on wound healing in mouse by administering the recombinant elastase inhibitor guamerin (rEIG) in two different wound models; 1) impaired pin-punctured dorsal mucosa of anterior tongue wound, 60 mice, treated with saline containing rEIG that were fed ad libitum and 2) stable linear excisional cutaneous wound, 40 mice, covered with fibrin sealant containing rEIG. The progress of healing was analyzed by histological methods. The tongue wounds treated with rEIG became edematous around the pin-punctured tongue wound, and influx of inflammatory cells and PMN into the underlying stromal tissue were seen rapidly after wounding and peaked between 2-4 days. Whereas the control mice showed almost no wheal formation in the pin-punctured wound, a far lesser levels of PMN infiltration, and almost complete wound closure in 4 days. In the other model, the liner excisional cutaneous wound treated with fibrin sealant containing rEIG showed early wound constriction, lesser degree of inflammatory cells influx, and complete reepithelialization in 4-5 days, whereas the wound of control mice with the fibrin sealant alone showed contrary delayed reepithelialization, greater degree of inflammatory cell infiltration, and consequencial formation of greater granulation tissue at wound site. Taken together, these data suggest paradoxical effects of rEIG on the wound healing where in the wound exposed to infiltrating milieu of microorganisms in the oral cavity, the rEIG aggravates the wound healing by interfering with other innate defensive factors and extended greater flux of PMNs to inflamed wound site, while in the wound enclosed by fibrin, the rEIG accelerated wound healing by inhibiting the inflammation-generated proteases and the acute inflammatory reaction.     

Thermo-reversible MWCNTs/epoxy polymer for use in self-healing and recyclable epoxy adhesive

A self-healing and recyclable carbon tube/epoxy adhesive was prepared by epoxy monomer with Diels-Alder(DA) bonds, diethylenetriamine and polyethyleneimine modified multi-wall carbon nanotubes(MWCNTs). The self-healing and recyclable ability was attained by thermally reversible Diels-Alder reaction between furan and maleimide in the epoxy monomer. By controlling the molar ratio of furfuryl glycidyl ether and 4,4′-methylenebis(N-phenylmaleimide), the glass transition temperature and mechanical properties of MWCNTs/epoxy adhesives were varied. The self-healing properties of MWCNTs/epoxy polymers were evaluated by lap shear experiment and the results showed that the MWCNTs/epoxy adhesives exhibited enhanced mechanical properties and excellent self-healing ability under heat stimulus. The healing efficiency was related to the molecule mobility and the conversion of DA reaction between furan and maleimide. The MWCNTs/epoxy adhesives also displayed excellent recyclable ability by transforming into soluble polymer under heating. These materials offer a wide range of possibilities to produce materials with healing and recyclable ability and have the potential to bring great benefits to our daily lives by enhancing the safety, performance, and lifetime of products.     

Breathable rubbery skin protectors: Design,synthesis, characterization,and properties of cyanoacrylated silicone rubber networks

We extended our investigations of rubbery wound closure adhesives and created novel flexible networks by crosslinking cyanoacrylated silicone rubbers (i.e., commercial methylhydrosiloxane‐dimethylsiloxane copolymers, PMHS‐co‐PDMS) with N,N‐dimethyl‐p‐toluidine in tetrahydrofuran and hexamethyldisiloxane solvents at room temperature. Cyanoacrylation was achieved by hydrosilating (anthracene‐protected) allyl cyanoacrylate with PMHS‐co‐PDMS. Steric hindrance and the molecular weight of the copolymer strongly affect the extent of hydrosilation. The rate of crosslinking is proportional with the number of cyanoacrylate groups in the copolymer and networks form in seconds with appropriate amounts of initiator. Networks on porcine skin yield well‐adhering flexible optically‐transparent colorless conformal coatings of good “feel” appropriate for clinically useful non‐occlusive “breathable” skin or wound protectors. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1367‐1372     

Titanium Nanorods Loaded PCL Meshes with Enhanced Blood Vessel Formation and Cell Migration for Wound Dressing Applications

Proper management of nonhealing wounds is an imperative clinical challenge. For the effective healing of chronic wounds, suitable wound coverage materials with the capability to accelerate cell migration, cell proliferation, angiogenesis, and wound healing are required to protect the healing wound bed. Biodegradable polymeric meshes are utilized as effective wound coverage materials to protect the wounds from the external environment and prevent infections. Among them, electrospun biopolymeric meshes have got much attention due to their extracellular matrix mimicking morphology, ability to support cell adhesion, and cell proliferation. Herein, electrospun nanocomposite meshes based on polycaprolactone (PCL) and titanium dioxide nanorods (TNR) are developed. TNR incorporated PCL meshes are fabricated by electrospinning technique and characterized by scanning electron microscopy, energy dispersive X‐ray spectroscopy, Fourier transform infrared spectroscopy (FTIR) analysis, and X‐Ray diffraction (XRD) analysis. In vitro cell culture studies, in ovo angiogenesis assay, in vivo implantation study, and in vivo wound healing study are performed. Interestingly, obtained in vitro and in vivo results demonstrated that the presence of TNR in the PCL meshes greatly improved the cell migration, proliferation, angiogenesis, and wound healing. Owing to the above superior properties, they can be used as excellent biomaterials in wound healing and tissue regeneration applications.     

Effects of Alcell Lignin Methylolation and Lignin Adding Stage on Lignin-Based Phenolic Adhesives

To investigate the effects of lignin methylolation and lignin adding stage on the resulted lignin-based phenolic adhesives, Alcell lignin activated with NaOH (AL) or methylolation (ML) was integrated into the phenolic adhesives system by replacing phenol at various adhesive synthesis stages or directly co-polymerizing with phenolic adhesives. Lignin integration into phenolic adhesives greatly increased the viscosity of the resultant adhesives, regardless of lignin methylolation or adding stage. ML introduction at the second stage of adhesive synthesis led to much bigger viscosity than ML or AL introduction into phenolic adhesives at any other stages. Lignin methylolation and lignin adding stage did not affect the thermal stability of lignin based phenolic adhesives, even though lignin-based adhesives were less thermally stable than NPF. Typical three-stage degradation characteristics were also observed on all the lignin-based phenolic adhesives. Three-ply plywoods can be successfully laminated with lignin based adhesives, and it was interesting that after 3 h of cooking in boiling water, the plywoods specimens bonded with lignin-based phenolic adhesives displayed higher bonding strength than the corresponding dry strength obtained after direct conditioning at 20 °C and 65% RH. Compared with NPF, lignin introduction significantly reduced the bonding strength of lignin based phenolic adhesives when applied for plywood lamination. However, no significant variation of bonding strength was detected among the lignin based phenolic adhesives, regardless of lignin methylolation or adding stages.     

Skin Wound Healing: Normal Macrophage Function and Macrophage Dysfunction in Diabetic Wounds

Macrophages play a prominent role in wound healing. In the early stages, they promote inflammation and remove pathogens, wound debris, and cells that have apoptosed. Later in the repair process, they dampen inflammation and secrete factors that regulate the proliferation, differentiation, and migration of keratinocytes, fibroblasts, and endothelial cells, leading to neovascularisation and wound closure. The macrophages that coordinate this repair process are complex: they originate from different sources and have distinct phenotypes with diverse functions that act at various times in the repair process. Macrophages in individuals with diabetes are altered, displaying hyperresponsiveness to inflammatory stimulants and increased secretion of pro-inflammatory cytokines. They also have a reduced ability to phagocytose pathogens and efferocytose cells that have undergone apoptosis. This leads to a reduced capacity to remove pathogens and, as efferocytosis is a trigger for their phenotypic switch, it reduces the number of M2 reparative macrophages in the wound. This can lead to diabetic foot ulcers (DFUs) forming and contributes to their increased risk of not healing and becoming infected, and potentially, amputation. Understanding macrophage dysregulation in DFUs and how these cells might be altered, along with the associated inflammation, will ultimately allow for better therapies that might complement current treatment and increase DFU’s healing rates.