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Abstract
Rapid hemostasis, antibacterial effect and promotion of wound healing are the most important functions that wound dressings need to have. In this work, we designed and prepared a hydrogel with antibacterial effect, hemostatic ability and wound healing promotion using agar, polyvinyl alcohol (PVA) and tannic acid (TA). We performed a series of tests to characterize the structure and properties of AGAR@PVA-TA hydrogels. The results showed that the AGAR@PVA-TA hydrogels had good mechanical properties and excellent antibacterial ability as well as good hemocompatibility. The cytotoxicity results showed that the AGAR@PVA-TA hydrogels had good cytocompatibility. And the TA loaded hydrogels also presented some good performances in animal studies. In the liver hemostasis model, the AGAR@PVA-TA hydrogel showed good hemostatic ability. Also, the AGAR@PVA-TA hydrogel was able to promote wound healing in an S. aureus-infected rat wound model. More importantly, our research results demonstrated that compared to other polyphenols (such as proanthocyanidins), TA could better improve the mechanical properties, antibacterial ability and rapid hemostasis of hydrogels, which illustrated the uniqueness of TA. Therefore, the TA loaded hydrogel (AGAR@PVA-TA hydrogel) has the potential to be applied as a wound dressing.
... FA promotes the angiogenic pathway to stimulate neovascularization, increase granulation tissue formation, and remodel collagen, thus accelerating wound healing. In addition, the fabrication of AGAR@ PVA-TA hydrogels by mixing Agar and polyvinyl alcohol (PVA), followed by the subsequent introduction of tannic acid (TA) have been reported (Cheng et al., 2022). The use of TA improves the mechanical strength of the hydrogel owing to hydrogen bonding between the phenolic hydroxyl group of TA and the hydroxyl groups of Agar and PVA. ...
... The use of TA improves the mechanical strength of the hydrogel owing to hydrogen bonding between the phenolic hydroxyl group of TA and the hydroxyl groups of Agar and PVA. At the same time, it enhances the ability of the hydrogel to capture erythrocytes while absorbing bleeding from the wound and promotes the production of thrombin, which expedites the hemostatic process (Ge et al., 2019;He et al., 2020;Cheng et al., 2022). ...
Precise healing of wounds in the oral and maxillofacial regions is usually achieved by targeting the entire healing process. The rich blood circulation in the oral and maxillofacial regions promotes the rapid healing of wounds through the action of various growth factors. Correspondingly, their tissue engineering can aid in preventing wound infections, accelerate angiogenesis, and enhance the proliferation and migration of tissue cells during wound healing. Recent years, have witnessed an increase in the number of researchers focusing on tissue engineering, particularly for precise wound healing. In this context, hydrogels, which possess a soft viscoelastic nature and demonstrate exceptional biocompatibility and biodegradability, have emerged as the current research hotspot. Additionally, nanofibers, films, and foam sponges have been explored as some of the most viable materials for wound healing, with noted advantages and drawbacks. Accordingly, future research is highly likely to explore the application of these materials harboring enhanced mechanical properties, reduced susceptibility to external mechanical disturbances, and commendable water absorption and non-expansion attributes, for superior wound healing.
... TA increases the mechanical strength, decreases the excessive swelling rate, and promotes the adherence of the hydrogel to various substrates. According to Cheng et al., the combination of PVA and agar loaded with tannic acid presented promising characteristics in terms of hemostatic, antibacterial activity, cytocompatibility, and rapid wound healing [34]. Finally, the composite hydrogel developed in this study can effectively be applied in crucial areas such as artificial cartilage. ...
Hydrogels composed of natural and synthetic polymers have considerable potential for use in diverse areas such as biomedical applications and water purification. This is primarily because of their biocompatibility, biodegradability, and low toxicity. The widespread usage of composite hydrogels is hindered by a lack of simultaneous properties, such as high strength and low swelling rate. Herein, we report the preparation of novel hydrogels composed of polyvinyl alcohol (PVA)–intercalated agar polymer networks physically crosslinked with tannic acid. The hydrogel was subjected to multiple freeze/thaw (F/T) cycles (1, 3, and 5), and it was found to exhibit the highest strength after 5 F/T cycles. After 1 F/T cycle, the tensile strength of the composite hydrogel reached 1.56 MPa with a 1.0 wt% crosslinker, whereas after 5 F/T cycles, it increased to 3.77 MPa with a reduced amount (0.75 wt%) of the crosslinker. In addition, the swelling ability decreased upon increasing the crosslinker content and number of F/T cycles. Furthermore, the hydrogel demonstrated excellent water retention and a strong ability to adhere to different substrates. We have successfully implemented an innovative approach to improve the mechanical properties of PVA-based hydrogels by combining the use of tannic acid as a cross-linking agent and multiple F/T cycles. The developed hydrogels are expected to facilitate new developments in hydrogel technology, thus impacting diverse fields such as biomedical (wound dressing and artificial cartilage).
... Three-dimensional electrospun fiber membranes with a porous structure have a high absorptive capacity and can concentrate blood to promote coagulation, showing a tamponade effect. Therefore, based on the physical barrier effect, PVA/PLA fibrous membranes show a good hemostatic effect [12,49,50]. Plasma treatment generates the enhancements of wetting properties, mechanical performance, and adhesion capacity of the PVA/PLA fiber membrane, enhancing the physical barrier effect for hemostasis. ...
In this study, an improved PVA/PLA fibrous hemostatic membrane was prepared by electrospinning technology combined with air plasma modification. The plasma treatment was used to modify PLA to enhance the interlayer bonding between the PVA and PLA fibrous membranes first, then modify the PVA to improve the hemostatic capacity. The surfaces of the PLA and PVA were oxidized after air plasma treatment, the fibrous diameter was reduced, and roughness was increased. Plasma treatment enhanced the interfacial bond strength of PLA/PVA composite fibrous membrane, and PLA acted as a good mechanical support. Plasma-treated PVA/PLA composite membranes showed an increasing liquid-enrichment capacity of 350% and shortened the coagulation time to 258 s. The hemostatic model of the liver showed that the hemostatic ability of plasma-treated PVA/PLA composite membranes was enhanced by 79% compared to untreated PVA membranes, with a slight improvement over commercially available collagen. The results showed that the plasma-treated PVA/PLA fibers were able to achieve more effective hemostasis, which provides a new strategy for improving the hemostatic performance of hemostatic materials.
... For this reason, agar hydrogel can be streamlined with other versatile polymers, such as PVA, to obtain new functional structures. Studies on combining and characterizing functionalized PVA/A hydrogels with phytoextracts are not very numerous [44][45][46]. ...
In this study, the potential use of Artemisia dracunculus essential oil in bio-applications was investigated. Firstly, the phytochemicals from Artemisia dracunculus were analyzed by different methods. Secondly, the Artemisia dracunculus essential oil was incorporated into the hydrogel matrix based on poly(vinyl alcohol) (PVA) and agar (A). The structural, morphological, and physical properties of the hydrogel matrix loaded with different amounts of Artemisia dracunculus essential oil were thoroughly investigated. FTIR analysis revealed the successful loading of the essential oil Artemisia dracunculus into the PVA/A hydrogel matrix. The influence of the mechanical properties and antimicrobial activity of the PVA/A hydrogel matrix loaded with different amounts of Artemisia dracunculus was also assessed. The antimicrobial activity of Artemisia dracunculus (EO Artemisia dracunculus) essential oil was tested using the disk diffusion method and the time-kill assay method after entrapment in the PVA/A hydrogel matrices. The results showed that PVA/agar-based hydrogels loaded with EO Artemisia dracunculus exhibited significant antimicrobial activity (log reduction ratio in the range of 85.5111–100%) against nine pathogenic isolates, both Gram-positive (S. aureus, MRSA, E. faecalis, L. monocytogenes) and Gram-negative (E. coli, K. pneumoniae, S. enteritidis, S. typhimurium, and A. salmonicida). The resulted biocompatible polymers proved to have enhanced properties when functionalized with the essential oil of Artemisia dracunculus, offering opportunities and possibilities for novel applications.
... [40] NYS release in addition to TA would greatly benefit in wound healing which is why TA was not washed from the hydrogel. [41][42][43][44] ...
Biocompatible hydrogels of polyvinylpyrrolidone (PVP) with tannic acid (TA) in the weight ratios of 1 : 0.70 (70 %)–1 : 0.60 (60 %) were prepared and loaded with the antifungal drug, nystatin (NYS). The hydrogel is expected to exhibit a two‐fold (anti‐bacterial and anti‐fungal) characteristics. Infrared spectroscopy (IR), viscometry and differential scanning calorimetry (DSC) were used to investigate interactions between PVP and TA. In vitro release kinetics of NYS in simulated body fluid (SBF) and sweat (SS) were studied using ultra‐violet spectroscopy (UV) and high‐performance liquid chromatography (HPLC). An increase in the glass transition temperature (Tg) of PVP accompanied with changes observed in the OH stretching, C=O and the C−O−C regions in the IR spectrum in dried PVP/TA hydrogel suggested physical crosslinking. The swelling of the hydrogels in distilled deionized water (DDW), SBF and SS decreased with increasing TA concentration and showed pH sensitivity. TA release followed the Korsmeyer‐Peppas kinetic model regardless of swelling media while NYS followed the Korsmeyer‐Peppas and Hixson‐Crowell cube root law in SS and SBF respectively. TA was active against Escherichia coli and Staphylococcus aureus while NYS against Candida albicans. A topical patch was prepared by adhering the drug loaded PVP/TA hydrogel onto silicone strips.
... Using the method of counting live cells, it was shown that the biomaterial containing two compounds with antibacterial activity-chitosan and tannic acid-caused complete inhibition of the growth of Gram-negative E. coli bacteria. Cheng et al. [128] also incorporated tannic acid as an antibacterial agent into a PVA and agar-based hydrogel. In vitro tests proved that the biomaterial with the lowest tested concentration of TA (1%) revealed high antibacterial activity against S. aureus and E. coli. ...
Infections that occur during wound healing involve the most frequent complications in the field of wound care which not only inhibit the whole process but also lead to non-healing wound formation. The diversity of the skin microbiota and the wound microenvironment can favor the occurrence of skin infections, contributing to an increased level of morbidity and even mortality. As a consequence, immediate effective treatment is required to prevent such pathological conditions. Antimicrobial agents loaded into wound dressings have turned out to be a great option to reduce wound colonization and improve the healing process. In this review paper, the influence of bacterial infections on the wound-healing phases and promising modifications of dressing materials for accelerated healing of infected wounds are discussed. The review paper mainly focuses on the novel findings on the use of antibiotics, nanoparticles, cationic organic agents, and plant-derived natural compounds (essential oils and their components, polyphenols, and curcumin) to develop antimicrobial wound dressings. The review article was prepared on the basis of scientific contributions retrieved from the PubMed database (supported with Google Scholar searching) over the last 5 years.
... The improvement of the mechanical properties of the XG-based composite hydrogels is also due to the presence of intermolecular hydrogen bonding between the functional groups of XG, PVA, and resveratrol, which reinforced the whole cryogel network. Similar results have also been reported for agar/PVA hydrogels loaded with tannic acid [54]. linear part of the stress−strain curves ( Figure S2, supporting information), the elastic modulus (G, kPa) of the polyphenol-loaded XG/PVA composite hydrogels was determined, according to the standard procedure already established for macroporous hydrogel-based materials [33,52,53]. ...
This study aimed to evaluate the effect of the synthesis parameters and the incorporation of natural polyphenolic extract within hydrogel networks on the mechanical and morphological properties of physically cross-linked xanthan gum/poly(vinyl alcohol) (XG/PVA) composite hydrogels prepared by multiple cryo-structuration steps. In this context, the toughness, compressive strength, and viscoelasticity of polyphenol-loaded XG/PVA composite hydrogels in comparison with those of the neat polymer networks were investigated by uniaxial compression tests and steady and oscillatory measurements under small deformation conditions. The swelling behavior, the contact angle values, and the morphological features revealed by SEM and AFM analyses were well correlated with the uniaxial compression and rheological results. The compressive tests revealed an enhancement of the network rigidity by increasing the number of cryogenic cycles. On the other hand, tough and flexible polyphenol-loaded composite films were obtained for a weight ratio between XG and PVA of 1:1 and 10 v/v% polyphenol. The gel behavior was confirmed for all composite hydrogels, as the elastic modulus (G′) was significantly greater than the viscous modulus (G″) for the entire frequency range.
... Haidari et al. introduced multifunctional thermo-responsive hydrogels inspired by ultrasmall silver nanoparticles (size < 3 nm) as antibacterial and anti-inflammatory wound dressings, which frustrated the growth of different virulent bacteria and accelerated the wound healing process of infected wounds [24,25]. Cheng et al. fabricated an antibacterial wound dressing with high hemostatic efficacy using an agar-polyvinyl alcohol hydrogel inspired by tannic acid [26]. Additionally, previous studies presented antimicrobial, antioxidant, and hemostatic PVA and chitosan hydrogels with adhesive and self-healing potency for enhancing the restora-tion of wounded skin [27,28]. ...
Polyvinyl alcohol (PVA) is a safe and biodegradable polymer. Given the unique physical and chemical properties of PVA, we physically cross-linked PVA with kaolin (K) and cedar essential oil (Ced) using the freeze-thawing approach to fabricate PVA/Ced/K sponge hydrogels as hemostatic, antibacterial, and antioxidant wound healing materials. The physicochemical characteristics of PVA/Ced/K hydrogels, including water swelling profiles and gel fractions, were surveyed. Additionally, the functional groups of hydrogels were explored by Fourier transform infrared spectroscopy (FTIR), while their microstructures were studied using scanning electron microscopy (SEM). Furthermore, the thermal features of the hydrogels were probed by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Evidently, alterations in cedar concentrations resulted in significant variations in size, water uptake profiles, and hydrolytic degradation of the hydrogels. The incorporation of cedar into the PVA/K endowed the hydrogels with significantly improved antibacterial competency against Bacillus cereus (B. cereus) and Escherichia coli (E. coli). Moreover, PVA/Ced/K exhibited high scavenging capacities toward ABTS•+ and DPPH free radicals. Beyond that, PVA/Ced/K hydrogels demonstrated hemocompatibility and fast blood clotting performance in addition to biocompatibility toward fibroblasts. These findings accentuate the prospective implementation of PVA/Ced/K composite hydrogel as a wound dressing.
Calcium ions play a vital role in skeletal growth, muscle action and neural signalling. Thus, the level of calcium in the body is a crucial parameter in the diagnosis of muscle weakness and osteoporosis. Fluorescence conductive hydrogels are widely employed in electronic devices as they are able to monitor single or multiple parameters in synergistic optical and electrical modes. However, integrating optical and conductive modalities and synergizing their various functions to develop a wearable sensor is challenging. In this regard, a PVA–agar hydrogel (PAGH) cross-linked with copper-doped carbon dot (MCD) was fabricated. The developed MCD@PAGH addressed Ca²⁺ recognition through a change in ionic conductance and fluorescence. The hydrogel patch sensor was not cytotoxic, exhibited bactericidal activity, and monitored Ca²⁺ level in sweat in both the fluorescence and electrical modes. This work provides a strategy to design multifunctional materials to address prospective applications in wearable biosensors.
Unmet needs in controlling uncontrolled hemorrhage in emergency, surgical, and battlefield scenarios have sparked widespread interest in developing new hemostatic technologies. Despite the availability of a wide range of commercially available hemostats, sealants, and adhesives, the development of ideal hemostatic formulations with remarkable properties such as the ability to promptly staunch bleeding under wet and dynamic conditions remains a challenge. Injectable polymeric hydrogels with superior hemostatic qualities besides their irregular wound filling capability, and minimal invasiveness have received considerable interest in recent years because of their attractive properties particularly useful in bleeding management. In this article, the most recent advances in the fabrication of injectable hydrogel systems from natural polymers towards hemostatic applications are discussed based on an extensive review of the literature. Additionally, the inherent hemostatic attributes of each polymer have been highlighted alongwith a comprehensive overview of various mechanisms through which injectable hydrogels achieve hemostasis. Furthermore, the challenges that need to be tackled towards accelerating the translation of these novel hemostatic hydrogel systems to clinical practice are emphasized and future directions for research in the field are also presented.
The effective management of deep skin wounds remains a significant healthcare challenge that often deteriorates with bacterial infection, oxidative stress, tissue necrosis, and excessive production of wound exudate. Current medical approaches, including traditional wound dressing materials, cannot effectively address these issues. There is a great need to engineer advanced and multifunctional wound dressings to address this multifaceted problem effectively. Herein, a rationally designed composite cryogel composed of a Copper Metal-Organic Framework (Cu-MOF), tannic acid (TA), polyvinyl alcohol (PVA), and zein protein has been developed by freeze-thaw technique. Cryogels display a remarkable swelling capacity attributed to their interconnected microporous morphology. Moreover, dynamic mechanical behaviour with the characteristics of potent antimicrobial, antioxidant, and biodegradation makes it a desirable wound dressing material. It was further confirmed that the material is highly biocompatible and can release TA and copper ions in a controlled manner. In-vivo skin irritation in a rat model demonstrated that composite cryogel did not provoke any irritation/inflammation when applied to the skin of a healthy recipient. In a deep wound model, the composite cryogel significantly accelerates the wound healing rate. These findings highlight the multifunctional nature of composite cryogels and their promising potential for clinical applications as advanced wound dressings.
Effective wound treatment has become one of the most important challenges for healthcare as it continues to be one of the leading causes of death worldwide. Therefore, wound care technologies significantly evolved in order to provide a holistic approach based on various designs of functional wound dressings. Among them, hydrogels have been widely used for wound treatment due to their biocompatibility and similarity to the extracellular matrix. The hydrogel formula offers the control of an optimal wound moisture level due to its ability to absorb excess fluid from the wound or release moisture as needed. Additionally, hydrogels can be successfully integrated with a plethora of biologically active components (e.g., nanoparticles, pharmaceuticals, natural extracts, peptides), thus enhancing the performance of resulting composite hydrogels in wound healing applications. In this review, the-state-of-the-art discoveries related to stimuli-responsive hydrogel-based dressings have been summarized, taking into account their antimicrobial, anti-inflammatory, antioxidant, and hemostatic properties, as well as other effects (e.g., re-epithelialization, vascularization, and restoration of the tissue) resulting from their use.
Repairing articular cartilage defects is a great challenge due to the poor self-regenerative capability of cartilage. Inspired by active substances found in the natural cartilage extracellular matrix, we used methacrylated carboxymethyl chitosan (MA-CMCS) and oxidized locust bean gum (OLBG) as the hydrogel backbone, and prepared a photocrosslinked dual network hydrogel containing allicin and decellularized cartilage powder (DCP). The rheological, swelling and water retention capacities of MA-CMCS@OLBG-Allicin/DCP (MCOAC) hydrogels were investigated to confirm the successful preparation of hydrogels suitable for cartilage repair. The MCOAC hydrogels showed good antibacterial ability to kill S. aureus and E. coli and anti-inflammatory properties due to the introduction of allicin. Furthermore, MA-CMCS@OLBG-Allicin/DCP hydrogels presented good cytocompatibility due to the addition of DCP, which could promote chondrocyte proliferation and promote the differentiation of BMSCs to chondrocytes. Further studies in vivo demonstrated that the DCP-contained MCOAC hydrogel exhibited superior performance in promoting cartilage tissue growth and wound healing in articular cartilage defects. Thus, the MCOAC hydrogel is a promising cartilage repair hydrogel with potential for clinical use.
Tissue engineering and regenerative medicine is a highly sought-after field for researchers aiming to compensate and repair defective tissues. However, the design and development of suitable scaffold materials with bioactivity for application in tissue repair and regeneration has been a great challenge. In recent years, biomimetic hydrogels have shown great possibilities for use in tissue engineering, where they can tune mechanical properties and biological properties through functional chemical modifications. Also, biomimetic hydrogels provide three-dimensional (3D) network spatial structures that can imitate normal tissue microenvironments and integrate cells, scaffolds, and bioactive substances for tissue repair and regeneration. Despite the growing interest in various hydrogels for biomedical use in previous decades, there are still many aspects of biomimetic hydrogels that need to be understood for biomedical and clinical trial applications. This review systematically describes the preparation of biomimetic hydrogels and their characteristics, and it details the use of biomimetic hydrogels in bone, cartilage, and nerve tissue repair. In addition, this review outlines the application of biomimetic hydrogels in bone, cartilage, and neural tissues regarding drug delivery. In particular, the advantages and shortcomings of biomimetic hydrogels in biomaterial tissue engineering are highlighted, and future research directions are proposed.
The clinical treatment of infected skin injuries caused by exogenous bacteria faces great challenges. Conventional therapeutic approaches are difficult to achieve synergistic effects of infection control and induction of skin regeneration. In this study, a novel tannic acid-based physically cross-linked double network hydrogel (PDH gel) was prepared on demand by covalent cross-linking of tannic acid (TA) with polyvinyl alcohol (PVA) and chelating ligand of TA with Fe3+. The homogeneity of the hydrogel was achieved by the action of glycol dispersant. With the anti-inflammatory and antioxidant properties of Fe3+ and TA, this hydrogel exhibited excellent antibacterial properties by achieving 99.69% and 99.36% bacterial inhibition against E.coli and S. aureus, respectively. Moreover, the PDH gel exhibits good biocompatibility, stretchability (up to 200%) and skin-friendliness. After 14 days of PDH-1 gel implantation in a rat model infected by S. aureus, the wound healing rate was as high as 95.21%. PDH gel-1 showed more granulation tissue, more pronounced blood vessels, higher collagen fiber density and good collagen deposition, and its recovery effect was better than that of PSH gel and PDH gel-2 in vivo. Hence, this study provides a novel avenue for the design of future clinical infected wound healing dressings.
Agar is a sulfated polysaccharide extracted from certain marine red algae, and its gel properties depend on the seaweed source and extraction conditions. In the present study, the seaweed Gracilaria gracilis (Gracilariales, Rhodophyta) from Dakhla (Moroccan Atlantic Coast) was investigated for its agar content, structure, and gel properties. The agar yields of G. gracilis were 20.5% and 15.6% from alkaline pretreatment and native extraction, respectively. Agar with alkaline pre-treatment showed a better gelling property supported by higher gel strength (377 g·cm −2), gelling (35.4 °C), and melting (82.1 °C) temperatures with a notable increase in 3,6-anhydro-galactose (11.85%) and decrease in sulphate (0.32%) contents. The sulfate falling subsequent to alkaline pre-treatment was verified through FT-IR spectroscopy. The 13 C NMR spectroscopy showed that alkaline -pretreated agar has a typical unsubstituted agar pattern. However, native agar had a partially methylated agarose structure. Overall, this study suggested the possibility of the exploitation of G. gracilis to produce a fine-quality agar. Yet, further investigation may need to determine the seasonal variability of this biopolymer according to the life cycle of G. gracilis.
Wound dressings have become a crucial treatment for wound healing due to their convenience, low cost, and prolonged wound management. As cutting-edge biomaterials, marine polysaccharides are divided from most marine organisms. It possesses various bioactivities, which allowing them to be processed into various forms of wound dressings. Therefore, a comprehensive understanding of the application of marine polysaccharides in wound dressings is particularly important for the studies of wound therapy. In this review, we first introduce the wound healing process and describe the characteristics of modern commonly used dressings. Then, the properties of various marine polysaccharides and their application in wound dressing development are outlined. Finally, strategies for developing and enhancing marine polysaccharide wound dressings are described, and an outlook of these dressings is given. The diverse bioactivities of marine polysaccharides including antibacterial, anti-inflammatory, haemostatic properties, etc., providing excellent wound management and accelerate wound healing. Meanwhile, these biomaterials have higher biocompatibility and biodegradability compared to synthetic ones. On the other hand, marine polysaccharides can be combined with copolymers and active substances to prepare various forms of dressings. Among them, emerging types of dressings such as nanofibers, smart hydrogels and injectable hydrogels are at the research frontier of their development. Therefore, marine polysaccharides are essential materials in wound dressings fabrication and have a promising future.
Abstract：Due to its excellent biocompatibility and anti-inflammatory activity, amniotic membrane (AM) has attracted much attention from scholars. However, its clinical application in vascular reconstruction was limited for poor processability, rapid biodegradation, and insufficient hemocompatibility. A naturally extracted substance with good cytocompatibility, Phytic acid (PA), which can quickly form strong and stable hydrogen bonds on the tissue surface, was used to crosslink decellularized AM (DAM) to prepare a novel vascular replacement material. The results showed that PA-fixed AM had excellent mechanical strength and resistance to enzymatic degradation as well as appropriate surface hydrophilicity. Among all samples, 2% PA-fixed specimen showed excellent human umbilical vein endothelial cells (HUVECs)-cytocompatibility and hemocompatibility. It could also stimulate the secretion of vascular endothelial growth factor (VEGF) and Endothelin-1 (ET-1) from seeded HUVECs, indicating that PA might promote neovascularization after implantation of PA-fixed specimens. Also, 2% PA-fixed specimen could inhibit the secretion of tumor necrosis factor-α (TNF-α) from co-cultured macrophages, thus might reduce the inflammatory response after sample implantation. Finally, the results of ex vivo blood test and in vivo experiments confirmed our deduction that PA might promote neovascularization after implantation. All the results indicated that prepared.
The effectiveness of tannic acid as antimicrobial and wound healing for burns have been shown for a century; however, uncontrolled target dosage may result in undesirable side-effects. Remarkably, tannic acid polyphenols compounds crosslinked with polymeric materials produce a strong composite containing the beneficial properties of this tannin. However, investigation of the crosslink structure and its antibacterial and regenerative properties are still unknown when using nanocellulose by mechanical defibrillation; additionally, due to the potential crosslink structure with chitosan, its structure can be complex. Therefore, this work uses bleach kraft nanocellulose in order to investigate the effect on the physical and regenerative properties when incorporated with chitosan and tannic acid. This film results in increased rigidity with a lamellar structure when incorporated with tannic acid due to its strong hydrogen bonding. The release of tannic acid varied depending on the structure it was synthesised with, whereas with chitosan it presented good release model compared to pure cellulose. In addition, exhibiting similar thermal stability as pure cellulose films with antibacterial properties tested against S. aureus and E. coli with good metabolic cellular viability while also inhibiting NF-κB activity, a characteristic of tannic acid. Graphical Abstract 1 Introduction
Natural biopolymers, which are renewable, widely available, biodegradable, and biocompatible, have attracted huge interest in the development of biocomposite materials. Herein, formulation–property relationships for starch/agar composite films were investigated. First, rapid visco analysis was used to confirm the conditions needed for their gelation and to prepare filmogenic solutions. All the original crystalline and/or lamellar structures of starch and agar were destroyed, and films with cohesive and compact structures were formed, as shown by SEM, XRD, and SAXS. All the plasticized films were predominantly amorphous, and the polymorphs of the composite films were closer to that of the agar-only film. FTIR results suggest that the incorporation of agar restricted starch chain interaction and rearrangement. The addition of agar to starch increased both tensile strength and elongation at break, but the improvements were insignificant after the agar content was over 50 wt.%. Contact angle results indicate that compared with the other samples, the 4:6 (wt./wt.) starch/agar film was less hydrophilic. Thus, this work shows that agar dominates the structure and properties of starch/agar composites, and the best properties can be obtained with a certain starch/agar ratio. Such composite polysaccharide films with tailored mechanical properties and surface hydrophilicity could be useful in biodegradable packaging and biomedical applications (wound dressing and tissue scaffolding).
Developing physical double‐network (DN) removable hydrogel adhesives with both high healing efficiency and photothermal antibacterial activities to cope with multidrug‐resistant bacterial infection, wound closure, and wound healing remains an ongoing challenge. An injectable physical DN self‐healing hydrogel adhesive under physiological conditions is designed to treat multidrug‐resistant bacteria infection and full‐thickness skin incision/defect repair. The hydrogel adhesive consists of catechol–Fe³⁺ coordination cross‐linked poly(glycerol sebacate)‐co‐poly(ethylene glycol)‐g‐catechol and quadruple hydrogen bonding cross‐linked ureido‐pyrimidinone modified gelatin. It possesses excellent anti‐oxidation, NIR/pH responsiveness, and shape adaptation. Additionally, the hydrogel presents rapid self‐healing, good tissue adhesion, degradability, photothermal antibacterial activity, and NIR irradiation and/or acidic solution washing‐assisted removability. In vivo experiments prove that the hydrogels have good hemostasis of skin trauma and high killing ratio for methicillin‐resistant staphylococcus aureus (MRSA) and achieve better wound closure and healing of skin incision than medical glue and surgical suture. In particular, they can significantly promote full‐thickness skin defect wound healing by regulating inflammation, accelerating collagen deposition, promoting granulation tissue formation, and vascularization. These on‐demand dissolvable and antioxidant physical double‐network hydrogel adhesives are excellent multifunctional dressings for treating in vivo MRSA infection, wound closure, and wound healing.
Hydrogel‐based drug depot formulations are of great interest for therapeutic applications. While the biological activity of such drug depots is often characterized well, the influence of incorporated drug or drug‐loaded micelles on the gelation properties of the hydrogel matrix is less investigated. However, the latter is of great importance from fundamental and application points of view as it informs on the physicochemical interactions of drugs and water‐swollen polymer networks and it determines injectability, depot stability, as well as drug‐release kinetics. Here, the impact of incorporated drug, neat polymer micelles, and drug‐loaded micelles on the viscoelastic properties of a cytocompatible hydrogel is investigated systematically. To challenge the hydrogel with regard to the desired application as injectable drug depot, curcumin (CUR) is chosen as a model compound due to its very low‐water solubility and limited stability. CUR is either directly solubilized by the hydrogel or pre‐incorporated into polymer micelles. Interference of CUR with the temperature‐induced gelation process can be suppressed by pre‐incorporation into polymer micelles forming a binary drug delivery system. Drug release from a collagen matrix is studied in a trans‐well setup. Compared to direct injection of drug formulations, the hydrogel‐based systems show improved and extended drug release over 10 weeks. While the biological activity of hydrogel‐based drug depot formulations is often characterized well, the influence of incorporated drug or drug‐loaded micelles on the gelation properties of the hydrogel matrix is less investigated. Here, the impact of incorporated drug, neat polymer micelles, and drug‐loaded micelles on the viscoelastic properties of a cytocompatible hydrogel is investigated systematically.
Antibacterial hydrogel has received extensive attention in soft tissue repair, especially preventing infections those associated with impaired wound healing. However, it is challenging in developing an inherent antibacterial hydrogel integrating with excellent cell affinity and superior mechanical properties. Inspired by the mussel adhesion chemistry, a contact‐active antibacterial hydrogel is proposed by copolymerization of methacrylamide dopamine (MADA) and 2‐(dimethylamino)ethyl methacrylate and forming an interpenetrated network with quaternized chitosan. The reactive catechol groups of MADA endow the hydrogel with contact intensified bactericidal activity, because it increases the exposure of bacterial cells to the positively charged groups of the hydrogel and strengthens the bactericidal effect. MADA also maintains the good adhesion of fibroblasts to the hydrogel. Moreover, the hybrid chemical and physical cross‐links inner the hydrogel network makes the hydrogel strong and tough with good recoverability. In vitro and in vivo tests demonstrate that this tough and contact‐active antibacterial hydrogel is a promising material to fulfill the dual functions of promoting tissue regeneration and preventing bacterial infection for wound‐healing applications.
This review presents the past and current efforts with a brief description on the featured properties of hydrogel membranes fabricated from biopolymers and synthetic ones for wound dressing applications. Many endeavors have been exerted during past ten years for developing new artificial polymeric membranes which fulfill the demanded conditions for the treatment of skin wounds. This review mainly focuses on representing specifications of ideal polymeric wound dressing membranes, such as crosslinked hydrogels compatible with wound dressing purposes. But as the hydrogels with single component have low mechanical strength, recent trends have offered composite or hybrid hydrogel membranes to achieve the typical wound dressing requirements.
Polyphenolic compounds are plant nutraceuticals showing a huge structural diversity, including chlorogenic acids, hydrolyzable tannins, and flavonoids (flavonols, flavanones, flavan-3-ols, anthocyanidins, isoflavones, and flavones). Most of them occur as glycosylated derivatives in plants and foods.
In order to become bioactive at human body, these polyphenols must undergo diverse intestinal transformations, due to the action of digestive enzymes, but also by the action of microbiota metabolism. After elimination of sugar tailoring (generating the corresponding aglycons) and diverse hydroxyl moieties, as well as further backbone reorganizations, the final absorbed compounds enter the portal vein circulation towards liver (where other enzymatic transformations take place) and from there to other organs, including behind the digestive tract or via blood towards urine excretion. During this transit along diverse tissues and organs, they are able to carry out strong antiviral, antibacterial, and antiparasitic activities. This paper revises and discusses these antimicrobial activities of dietary polyphenols and their relevance for human health, shedding light on the importance of polyphenols structure recognition by specific enzymes produced by intestinal microbial taxa.
The development of compressible, stretchable and self-healing hydrogel dressings with good adhesive, antibacterial and angiogenesis properties is needed to promote the regeneration of diabetic wounds in clinical applications. In this work, a series of self-healing, adhesive and antibacterial hydrogels based on gelatin methacrylate (GelMA), adenine acrylate (AA), and CuCl2 were designed through covalent bonding, coordination complexation of Cu²⁺ and carboxyl groups and hydrogen bonding to promote diabetic wound healing. These hydrogels exhibit efficient self-healing properties, remarkable fatigue resistance, and good adhesive properties due to the hydrogen bond and the metal-ligand coordination provided by the Cu²⁺ and the carboxyl group. The GelMA/AA/Cu1.0 hydrogel (containing 1.0 mg/mL Cu²⁺) with well-balanced biocompatibility and antibacterial properties exhibited efficient hemostatic performance in a mouse liver trauma model and significantly promoted the healing process in a full-thickness skin diabetic wound model. The immunohistochemistry results showed that the GelMA/AA/Cu1.0 hydrogel can promote regular epithelialization and collagen deposition when compared to the TegadermTM Film, GelMA hydrogel, and GelMA/AA/Cu0 hydrogel. The immunofluorescence results confirmed that the GelMA/AA/Cu1.0 hydrogel can reduce the expression of proinflammatory factors and promote angiogenesis. In conclusion, the GelMA/AA/Cu hydrogel is an effective wound dressing to promote the healing process of diabetic skin wounds.
Statement of Significance
Diabetic wounds exhibit an extremely high risk of bacterial infection and poor angiogenesis in a high-sugar environment, hindering their healing process. Hydrogel wound dressings are a promising wound care material that need to have stable and long-lasting adhesive properties, avoid shedding, provide lasting protection to wounds, antibacterial properties and promote angiogenesis. In this study, a series of self-healing, adhesive, and antibacterial hydrogels based on gelatin methacrylate (GelMA), acrylated adenine (AA), and CuCl2 were designed and synthesized via free radical polymerization, hydrogen bond, and ionic bond to promote diabetic wound healing. Overall, GelMA/AA/Cu hydrogels are promising materials to promote diabetic wound healing.
A novel agarose/Ti3C2Tx-crosslinked-polyacrylamide (AG/T-PAM) double-network (DN) hydrogel is synthesized by combining heating-cooling and γ-ray radiation-induced polymerization. The AG/T-PAM DN hydrogel possesses excellent mechanical properties with 4250% stretchability, and good adhesion to different substrates, such as an adhesive strength of 1148 kPa to copper at 30 °C. The resultant hydrogel also exhibits excellent tensile and compression sensing properties due to the variation of conductive network within hydrogel. The flexible and wearable strain sensor composed of the AG/T-PAM DN hydrogel presents rapid response to strain withstand 1000 cycles, and can monitor various movements of human body with a high sensibility. The AG/T-PAM DN hydrogel-based strain sensor will have broad application in large-scale strain detection scenarios requiring high sensitivity and adhesion.
Trauma-related excessive bleeding is one of the leading causes of death. CS sponges have unique advantages in the treatment of massive bleeding, but their application is limited by poor stability and toxic crosslinking agent. In this work, chitosan/polyvinylpyrrolidone/zein (CS/PVP/Zein) sponges as efficient hemostatic materials were prepared. The CS/PVP/Zein sponges with macroporous structure exhibited rapid water absorption capacity and water-triggered expanding property with low cytotoxicity and low hemolysis ratio. In vitro blood coagulation experimentsshowed that CS/PVP/Zein sponges could clot blood significantly faster than commercial surgical gauze. Further investigation of the hemostatic mechanism suggested that the CS/PVP/Zein sponges could accelerate coagulation by promoting attachment of erythrocytes, activation of platelets, and rapid plasma protein absorption. Prepared sponges were also found effective in the rat femoral artery transection model to control bleeding. Overall, the CS/PVP/Zein sponges exhibited the potential to control trauma-related hemorrhage.
Bacterial induced wound infection is very common in real life, but the abuse of antibiotics means that is poses a potential threat to human health. The development of non-antibiotic type antibacterial materials appears to be of importance. Herein, a microenvironment-responsive and biodegradable hydrogel complex, consisting of an acid-degradable antibacterial hydrogel and a hydrogen peroxide (H2O2)-responsive polymer/gold hybrid film with photothermal conversion ability was constructed based on polyethylenimine (PEI), polyethylene glycol (PEG), hexachlorocyclic triphosphonitrile (HCCP), and gold nanoparticles. The resultant hydrogel showed excellent adhesion to various surfaces, whether in air or underwater. However, a simple glycerine and water (v/v = 1/1) mixed solution could rapidly promote the detachment of the hydrogel from skin automatically, without any external force and no residue was left, exhibiting a manmade controllable flexible feature. Moreover, the in vitro antibacterial performance against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus (S. aureus), as well as wound healing investigations conducted in living mice confirmed that these hydrogels possessed excellent antibacterial, antioxidative, and wound healing abilities. We believe this proof of concept could create a novel pathway for the design and construction of highly efficient hydrogel dressings using readily available polymeric materials and that the resulting dressing have potential for clinical applications.
Hydroxypropylation is effective in modifying the structure and properties of agar. So far, the industrial scale-up production of hydroxypropylated agar has not been evaluated. Therefore, the large-scale production of the hydroxypropylation of agar using a heterogeneous reaction system was evaluated in the present this study. The structures and properties of the hydroxypropyl agar (HPA) product were measured and the intrinsic kinetics of the heterogeneous reaction were determined and analyzed. The results showed that the large-scale HPA had good thermal stability, and lower viscosity, gelling temperature and melting temperature compared with those of agar. The SEM indicated that the improvement of solubility of HPA was not only due to the hydrophilic effect of hydroxypropyl group, but also due to the formation of cluster structure and grid structure. The characteristic of heterogeneous hydroxypropylation reaction were determined by preliminary kinetic experiments, which demonstrated that the reaction order of propylene oxide was 2, while that for agar was approximately 0. The reaction activation energy of heterogeneous hydroxypropylation reaction was calculated to be 83.50 kJ/mol using the Arrhenius formula. Taken together, the results would provide guidances for the industrialization of hydroxypropyl agar.
Chitin (CT) is widely used as a hemostatic material in surgical sponges, although its efficacy needs improvement to promote the clotting process. In this study, another green biomass, corn stalk pith (CSP), was incorporated into CT through ball milling to fabricate CT-CSP composite hemostatic sponges to enhance erythrocyte absorption, platelet activation, and clotting factor accumulation (Ca²⁺). In vitro hemostatic analysis indicated that CSP incorporation greatly promoted the coagulation process, with a much lower blood clot index and higher blood clot stability. In addition, the composite sponge promoted more platelet adhesion and activation, and the composite sponge demonstrated a greater ability to bind clotting factors (Ca²⁺). Consistently, it achieved complete hemostasis with less blood loss and a shorter hemostatic time in a rat liver injury-model. This composite hemostatic sponge is sustainable, cost-efficient, and biocompatible, which highlight the excellent translational potential in clinical settings.
Stanching severe traumatic bleeding requires hemostatic materials that can provide rapid and efficient hemostasis. However, most currently available hemostatic agents exhibit low efficiency and poor biocompatibility. In this study, a novel carboxymethyl chitosan modified with methacrylic anhydride (double-bonded carboxymethyl chitosan)/cysteamine-modified chondroitin sulfate (Me-CMC/CSS) rapid hemostatic dressing was developed using thiol-ene click chemistry. The freeze-dried Me-CMC/CSS dressings absorbed water rapidly and transformed into soft hydrogels that could seal wounds, achieving good hemostasis. The relative blood clotting index of the optimal Me-CMC/CSS dressing was decreased by 53% (p < 0.001) and 29% compared with a pure Me-CMC dressing and a commercial hemostatic gelatin sponge, respectively. In a rat liver hemorrhage model, the Me-CMC/CSS dressing stopped bleeding rapidly, and the total blood loss was significantly decreased by 92% (p < 0.0001) compared with the untreated group and was lower than that with gelatin sponge treatment. The Me-CMC/CSS dressing also exhibited a higher ability to adhere to platelets than the gelatin sponge. Furthermore, the Me-CMC/CSS dressing exhibited good hemocompatibility and cytocompatibility. The results indicate that the composite dressings can be potentially applied as rapid hemostatic materials.
Multifunctional wound dressings urgently need to be developed to meet the various needs of wound healing. In this work, we first proposed a new method about modifying the guar gum (GG) by performing a quaternization graft reaction and then oxidation. The obtained oxidized quaternized guar gum (OQGG) not only has antibacterial function due to the introduction of quaternary ammonium groups, but also can become one of the components of Schiff base hydrogels due to the presence of aldehyde groups. Therefore, we used it and carboxymethyl chitosan (CMCS) to design a hydrogel with antibacterial, hemostatic, self-repairing and injectable properties. We characterized the structure of OQGG and [email protected] hydrogels, but also evaluated the performance of the hydrogels. The results showed that GG was successfully modified to OQGG and [email protected] hydrogel was successfully prepared, and the obtained [email protected] hydrogel showed excellent antibacterial and hemostatic properties, and exhibited self-healing and injectability. In addition, cytotoxicity tests demonstrated that the [email protected] hydrogels presented good cytocompatibility. Further, the [email protected] hydrogel significantly promoted wound healing in an S. aureus-infected rat wound model. Therefore, the hydrogel has the potential to be applied as a wound dressing.
Antibacterial photocatalytic therapy (APCT) is a promising therapeutic approach for wound disinfection, which employs controllable light to activate photocatalysts and generate reactive oxygen species (ROS) for the destruction of bacteria. However, preventing bacterial growth and overcoming the difficulty in wound healing after stopping the excitation are the main challenges in APCT. Herein, a new antibacterial photocatalyst, LiLuGeO4:Bi³⁺/TiO2 (LGG/T), with persistent APCT activity was synthesized by loading titanium dioxide (TiO2) on the surface of an ultraviolet (UV) persistent luminescent material, LGG. After excitation by a 254 nm UV lamp, UV persistent luminescence (PersL) (∼350 nm) from LGG is efficiently absorbed by TiO2, which drives TiO2 to continuously produce ROS. In vitro antibacterial assay results show that LGG/T kills and inhibits the growth of the gram-negative and gram-positive bacteria surviving after stopping the excitation, owing to its continuous ROS generation ability. Furthermore, thermo-responsive hydrogel-loaded LGG/T ([email protected]/T) with sol–gel transition ability at body temperature was prepared and used for the treatment of bacteria-infected wounds. Because of the persistent antibacterial ability of LGG/T, [email protected]/T effectively promoted wound repair in mice with Staphylococcus aureus-infected dermal wounds, while demonstrating appropriate biosafety. Thus, [email protected]/T shows great potential for use in persistent wound disinfection.
Burn wounds are susceptible to bacterial infections and are usually accompanied by a large amount of exudate, making the treatment of burn wounds a challenge in the clinic. Here, we developed a biodegradable cryogel with high water absorption and good antibacterial and antibiofilm activity based on gelatin (GT) and silver nanoparticles (Ag NPs) to promote burn wound healing. The porous GT/Ag cryogel had a swelling ratio of up to 4000%, effectively absorbing wound exudate and allowing for gas exchange. Moreover, the GT/Ag cryogel had an excellent killing effect on methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PA), which burn wounds are susceptible to, and can effectively remove mature biofilms. In the rat liver defect noncompressible hemorrhage model, GT/Ag cryogels with shape memory performance showed better hemostatic ability than commercial gelatin sponges. Most importantly, the GT/Ag cryogel was more effective than the TegadermTM dressing and GT cryogel in promoting wound contraction, collagen deposition, and angiogenesis and reducing inflammation in a PA-infected burn wound model. In addition, GT/Ag cryogels degraded in the body within 4 weeks, which alleviated the pain of peeling the dressing from the wound. Therefore, GT/Ag cryogels with outstanding antibacterial properties and effective absorption of wound exudates are excellent candidates for wound dressings to promote burn wound repair.
Wounds are one of the most common health issues, and the cost of wound care and healing has continued to increase over the past decade. The first step in wound healing is haemostasis, and the development of haemostatic materials that aid wound healing has accelerated in the past 5 years. Numerous haemostatic materials have been fabricated, composed of different active components (including natural polymers, synthetic polymers, silicon-based materials and metal-containing materials) and in various forms (including sponges, hydrogels, nanofibres and particles). In this Review, we provide an overview of haemostatic materials in wound healing, focusing on their chemical design and operation. We describe the physiological process of haemostasis to elucidate the principles that underpin the design of haemostatic wound dressings. We also highlight the advantages and limitations of the different active components and forms of haemostatic materials. The main challenges and future directions in the development of haemostatic materials for wound healing are proposed. Uncontrolled bleeding is a major cause of death, incentivizing the development of biomaterials that aid haemostasis and wound healing. This Review highlights the active components and forms of haemostatic materials, with a focus on their chemical design, and considers future trends in their development.
Porous cryogel with its poor mechanical properties greatly limit its application for lethal non-compressible bleeding from deep wounds. Here, we creatively combined foaming reaction and cryo-polymerization reaction to prepare a series of high-strength composite cryogel hemostatic agents based on poly(vinyl alcohol) (PVA), carboxymethyl chitosan (CMCS) and dopamine (DA) to cope with lethal noncompressible bleeding. The optimized PVA/CMCS-DA6 cryogel (1 mL prepolymer solution contains 6 mg DA) exhibited compression stress higher than 125 kPa at 80% compression strain and tensile stress-at-break higher than 155 kPa which are much higher than that of traditional cryogels. The hemostatic material with shape memory behavior and high compression strength can effectively stop lethal non-compressible bleeding, which has a good physical hemostatic effect, and the hemostat is easy to be removed after hemostasis. In addition, PVA/CMCS-DA6 cryogel showed better whole blood clotting ability, platelets and blood cells activation ability than commercial gelatin sponge and medical gauze, which has a good chemical hemostatic effect. PVA/CMCS-DA6 cryogel with synergistic chemical hemostasis and physical hemostasis showed outstanding hemostatic capacity in the rabbit liver defect non-compressible hemorrhage model and lethal coagulopathic rabbit liver defect bleeding model. Therefore, high-strength PVA/CMCS-DA cryogels have great potential as a new hemostatic agent for controlling lethal bleeding and providing a new idea for the design of efficient hemostatic materials.
The design of bioactive plasters is of major interest for the amelioration of dental and bone cements. In this article, a one pot and environmentally friendly strategy based on the addition of a cheap polyphenol-tannic acid (TA) or the main phenolic constituent of TA, namely pyrogallol (PY)- able to interact with calcium sulfate is proposed. Tannic acid and pyrogallol not only modify the morphology of the obtained plaster+TA/PY composites but a part of it is released and provides strong-up to twenty fold- antibacterial effect against Staphylococcus aureus. It is shown that the higher antibacterial efficiency of PY is related to a greater release compared to TA even if in solution the antibacterial effect of PY is lower than that of TA when reported on the basis of the molar concentration in PY units.
The present work reports a versatile approach to the manufacture of chitosan beads with tunable pore size and targeted properties. To achieve this, the as prepared chitosan beads were allowed to interact with aqueous solutions of two types of oxidized pullulan derivatives. Depending on the functional groups present on the pullulan structure after oxidation, i.e., carboxyl or aldehyde, covalent or physical hybrid hydrogels could be prepared. The attachment of oxidized pullulan onto chitosan structure was checked by FTIR, RMN, XPS and thermal analysis. The morphology of the hybrid structures was evaluated by using Scanning Electron Microscopy (SEM). After structural evaluations, all the prepared hydrogels were characterized by means of dynamic vapor sorption and swelling degree studies, exhibiting a Case-II swelling mechanism. Drug model compounds, such as ibuprofen, bacitracin and neomycin were used for drug loading and release assays, proving high drug loading capacity and tunable release behavior. Drug loaded beads exhibited antibacterial activity and hemocompatibility experiments indicated no coagulation phenomena.
The chronic wounds often hinder wound healing resulting from infection; thus, an ideal wound dressing should be able to maintain a healthy wound microenvironment. Herein, peptide modified nanofibers reinforced hydrogel has been designed by Schiff base dynamic crosslinking. The incorporation of the nanofibers into the hydrogel extremely enhances the stability and mechanical strength of the hydrogel. Taking advantage of the feature, the reinforced hydrogel can restore its original shape while suffering the various external forces on the hydrogel-covered irregular shape wounds. The peptide modified nanofibers reinforced hydrogel (NFRH) not only possesses injectable and self-healing properties, but also inherent antibacterial and hemostatic properties, which can eradicate the bacterial biofilms and induce blood cells and platelets aggregation and finally accelerate the chronic wound healing process. The peptide modified nanofibers reinforced hydrogel has enormous potential to be novel dressing for chronic wounds healing clinically.
In this study, a photocurable hydrogel based on an ε-poly-l-lysine (EPL) composite was fabricated by a grafting reaction using glycidyl methacrylate and then complexed with tannic acid (TA) to improve the mechanical stability and antibacterial performance of the EPL hydrogels. UV-visible spectrophotometry, nuclear magnetic resonance, and Fourier transform infrared spectroscopy were introduced to characterize the chemical construction. The obtained EPLMA hydrogel was immersed into TA solution to induce the forming of the H-bond between EPL and TA, resulting in double networks in the composite hydrogel (EPLMA-TA). Due to the additional hydrogen-bond interaction between TA and EPLMA, the mechanical properties of hydrogels were improved and supported cell growth and proliferation. In addition, the antibacterial properties and antioxidant activities of the EPLMA-TA hydrogels were greatly enhanced due to the addition of TA. All the findings indicate that the EPLMA-TA hydrogels with multiple properties show great potential for biomedicine applications.
Wound management poses a considerable economic burden on the global healthcare system, considering the impacts of wound infection, delayed healing and scar formation. To this end, multifunctional dressings based on hydrogels have been developed to stimulate skin healing. Herein, we describe the design, fabrication, and characterization of a sprayable hydrogel-based wound dressing loaded with cerium oxide nanoparticles (CeONs) and an antimicrobial peptide (AMP), for combined reactive oxygen species (ROS)-scavenging and antibacterial properties. We adopted a mussel-inspired strategy to chemically conjugate gelatin with dopamine motifs and prepared a hydrogel dressing with improved binding affinity to wet skin surfaces. Additionally, the release of AMP from the hydrogel demonstrated rapid release ablation and contact ablation against four representative bacterial strains, confirming the desired antimicrobial activities. Moreover, the CeONs-loaded hydrogel dressing exhibited favorable ROS-scavenging abilities. The biocompatibility of the multifunctional hydrogel dressing was further proven in vitro by culturing with HaCaT cells. Overall, the benefits of the developed hydrogel wound dressing, including sprayability, adhesiveness, antimicrobial activity, as well as ROS-scavenging and skin-remodeling ability, highlight its promissing translational potentials in wound management.
Statement of Significance
Various hydrogel-based wound-dressing materials have been developed to stimulate wound healing. However, from the clinical perspective, few of the current wound dressings meet all the intended multifunctional requirements of preventing infection, promoting rapid wound closure, and minimizing scar formation, while simultaneously offering the convenience of application. In the current study, we adopted a mussel-inspired strategy to functionalize the GelMA hydrogels with DOPA to fabricate GelMA-DOPA hydrogel which exhibited an enhanced binding affinity for wound surfaces, AMP HHC-36 and CeONs are further encapsulated into the GelMA-DOPA hydrogel to confer the hydrogel wound dressing with antimicrobial and ROS-scavenging abilities. The GelMA-DOPA-AMP-CeONs dressing offered the benefits of sprayability, adhesiveness, antimicrobial activity, as well as ROS-scavenging and skin-remodeling ability, which might address the therapeutic and economic burdens associated with chronic wound treatment and management.
Self-healing hydrogel systems usually suffer from poor mechanical performance stemmed from weaker and reversible non-covalent interactions or dynamic chemical bonds, which hamper their practical applications. This issue is addressed by adopting a double-crosslinking design involving both dynamic Schiff base bonds and non-dynamic photo-induced crosslinking. This leads to the formation of a special topological structure which simultaneously provide good self-healing capability and enhanced mechanical performance (elastic recovery and tensile modulus of 157.4 kPa, close to modulus of native skin). The quaternary ammonium and protonated amino groups can provide superior antibacterial capability; and Schiff base formation between residual aldehyde groups and amino groups on tissue surface contribute to hydrogel's adhesion to tissues (5.9 kPa). Furthermore, the multifunctional hydrogels with desirable mechanical performance, self-healing capability, superior antibacterial capability and tissue adhesion can significantly promote healing of infectious cutaneous wound, tissue remodeling and regeneration.
Diabetic wound healing remains a major challenge due to its vulnerability to bacterial infection, as well as the less vascularization and prolonged inflammatory phase. In this study, we developed a hydrogel system for the treatment of chronic infected wounds, which can regulate inflammatory (through the use of antimicrobial peptides) and enhance collagen deposition and angiogenesis (through the addition of platelet-rich plasma (PRP)). Based on the formation of Schiff base linkage, the ODEX/HA-AMP/PRP hydrogel was prepared by mixing oxidized dextran (ODEX), antimicrobial peptide-modified hyaluronic acid (HA-AMP) and PRP under physiological conditions, which exhibited obvious inhibition zones against three pathogenic bacterial strains (E. coli, S. aureus and P. aeruginosa) and slow release ability of antimicrobials and growth factors. Moreover, CCK-8, live/dead fluorescent staining and scratch test confirmed that ODEX/HA-AMP/PRP hydrogel could facilitate the proliferation and migration of L929 fibroblast cells. More importantly, in vivo experiments further demonstrated that the prepared hydrogels could significantly improve wound healing in a diabetic mouse infection by regulating inflammation, accelerating collagen deposition and angiogenesis. In addition, prepared hydrogel showed a significant antibacterial activity against S. aureus and P. aeruginosa, inhibited pro-inflammatory factors (TNF-α, IL-1β and IL-6), enhanced anti-inflammatory factors (TGF-β1) and vascular endothelial growth factor (VEGF) production. The findings of this study suggested that the composite hydrogel with AMP and PRP controlled release ability could be used as a promising candidate for chronic wound healing and infection-related wound healing.
Agar that has been extracted via traditional alkaline pretreatment always appears yellowish because it contains pigments. This characteristic adversely affects the food and biotechnological applications of agar. In this work, agar was bleached with hydrogen peroxide. The whiteness of high-whiteness agar reached 74.4%, which was 32% higher than that of raw agar (56.48%). The high-whiteness agar bleached with hydrogen peroxide exhibited several other excellent qualities over raw agar. These characteristics included, low sulfate content (0.67%), low ash content (1.01%), and high transparency (64.4%). In particular, the transparency of the high-whiteness agar was 13% higher than that of raw agar (56.8%). By contrast, the gel strengths of the two agars did not significantly differ. The structures of raw and high-whiteness agar were characterized by using thermogravimetric (TG)–differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). TG–DSC analysis indicated that the high-whiteness agar had better thermal stability, hygroscopicity, and water-holding capacity than raw agar. SEM images showed that the surface of the high-whiteness agar had imperfections or fissures that were caused by the oxidative degradation of hydrogen peroxide. The diversified application of the high-whiteness agar was explored on the basis of the promotion of agar quality. Results indicated that the visual appearance of the jelly prepared with the high-whiteness agar was better than that of the jelly prepared with raw agar. Moreover, the high-whiteness agar medium was easier to observe and use for colony counting than biochemical medium.
Bioinspired underwater adhesives with tough and stable performance are increasingly in demand for biomedical and engineering applications. However, the current methods of synthesizing them usually require sophisticated chemical conjugation or modification and expensive adhesive building blocks. Here, by taking advantage of the catecholic and polyelectrolyte features of mussel foot proteins, we report a facile yet powerful strategy to the development of a strong and cost-effective self-coacervating adhesive based on a coacervation-induced adhesion mechanism. The adhesive comprises a low-cost, commercially available cationic polyelectrolyte—polyamidoamine-epichlorohydrin (PAE)—that is crosslinked in situ by naturally occurring dendritic molecules of tannic acid (TA). A complex coacervate gel (TAPA) is formed after directly mixing pyrogallol-containing TA with PAE polycation. With the gel matrix serving as a robust adhesive when applied underwater to various substrates owing to its synergistic azetidinium–phenolic electrostatic and hydrogen bonding interactions. Compared to previously reported catechol-based adhesives, the polyelectrolyte coacervate gel has a widely tunable underwater adhesive strength (50.8 ± 6.8 to 604.8 ± 9.5 kPa) in wide ranges of pH (3–11) and ionic strength (0–1 M NaCl) and displays reusable adhesiveness (<10 cycles). This adhesive strength increases substantially in basic conditions (pH > 9), which trigger the self-crosslinking of PAE chains. By synergistically combining electrostatic adsorption and macroscopic-scale interactions, the incorporated nanocellulose fillers further contribute to the strong cohesion of coacervate adhesives. The easy-to-prepare TAPA adhesive also has excellent antibacterial activity. This in-situ formation strategy opens an innovative and facile route to mimic the self-coacervation and adhesion stability of biomimetic source, leading to a multifunctional bonding solution for biological/engineering adhesive applications.
Trees are made of cellulose, hemicellulose and lignin linked by covalent bonds and supramolecular interactions. Among them, the lignin with three-dimensional structure plays a role in supporting the structure of the tree. Inspired by the nature of the tree, we have designed and synthesized a novel lignin/poly(ionic liquids) composite hydrogel dressing with excellent mechanical strength, self-healing properties, bactericidal activity, and antioxidant activity. This self-healing hydrogel dressing is obtained by the supramolecular interactions between the lignin/poly(ionic liquids) compounds. The introduction of lignin can effectively improve the mechanical properties of the hydrogel dressing. And the bactericidal poly (ionic liquid) modified on the lignin surface through covalent bonds endows this hydrogel dressing good antibacterial activity and self-healing properties. Wound healing model of rats and histomorphological evaluation results suggest that this hydrogel dressing promotes wound healing. Furthermore, the hydrogel dressing still maintains its excellent performances after simple high-temperature disinfection, and can be reused for many times.
The surface area is the most important aspect when considering the interactions between a material and the surrounding environment. Chitosan (CTS) and tannic acid (TA) were previously successfully tested by us to obtain thin films to serve as wound dressings or food packaging materials. However, surface properties as well as the antimicrobial activity of the material were not considered. They are important if the material is likely to find application in biomedical or food packaging application. Thereby, this study is a further investigation of chitosan/tannic acid films surface properties.
The results showed that higher content of tannic acid increases the surface free energy and roughness, which is beneficial when considering the application of the materials as wound dressings. However, higher content of chitosan provides better antibacterial properties. Hence, the most optimal complex of chitosan and tannic acid for proposed application is the ratio 80/20.
High transparent and biocompatible hydrogel dressing with bioactivity is attractive for clinical skin repair. Here we report a high optically transparent interpenetrating network (IPN) hydrogel that was fabricated by sericin and polyacrylamide. The hydrogels possess pH-dependent degradation as well as high porosity and porous structures with different sized diameters and distribution. Moreover, the swelling behaviors, degradation dynamics, and mechanical strength can be flexibly regulated by adjusting the content of sericin. In addition, the hydrogel system is compatible with hosting cells owing to its excellent cell-adhesive capability, effectively promoting cell attachment, proliferation and long-term survival. Together, our study demonstrates that the sericin-polyacrylamide interpenetrating network hydrogel may serve as a visualized dressing material for real-time monitoring of wounds.
Native tissues orchestrate their functions by complex interdependent cascades of biochemical and biophysical cues that vary spatially and temporally during cellular processes. Scaffolds with well-tuned structural, mechanical, and biochemical properties have been developed to guide cell behavior and provide insight on cell-matrix interaction. However, static scaffolds very often fail to mimic the dynamicity of native extracellular matrices. Stimuli-responsive scaffolds have emerged as powerful platforms that capture vital features of native tissues owing to their ability to change chemical and physical properties in response to cytocompatible stimuli, thus enabling on-demand manipulation of cell microenvironment. The vast expansion in biorthogonal chemistries and stimuli-responsive functionalities has fuelled further the development of new smart scaffolds that can permit multiple irreversible or reversible spatiotemporal modulation of cell-directing cues, thereby prompting in-depth studies to interpret the decisive elements that regulate cell behavior. Integration of stimuli-responsive hydrogels with current biofabrication technologies has allowed the development of dynamic scaffolds with organizational features and hierarchical architectures similar to native tissues. This review highlights the progress achieved using stimuli-responsive hydrogels in fundamental cell biology studies, with particular emphasis on the interplay between chemistry, biomaterials design, and biofabrication technologies for manipulation of cell microenvironment.
Although PVA-chitosan composite hydrogel has excellent biocompatibility and antibacterial ability, its poor mechanical strength limits its application for wound dressings. Furthermore, PVA-chitosan composite hydrogel cannot satisfy the requirements of wound dressing as an environmental conditioner to accelerate wound healing. In this work, a novel lignin-chitosan-PVA composite hydrogel was prepared as wound dressing. The introduction of lignin effectively improved the mechanical strength (tensile stress is up to 46.87 MPa), protein adsorption capacity, and wound environmental regulation ability of the hydrogel. In a murine wound model, the lignin-chitosan-PVA composite hydrogel significantly accelerated wound healing. The developed hydrogel provides new opportunities for highly efficient skin wound care and management.
As materials for the promotion of wound healing, hydrogel dressings must be usable for a long time or under extreme conditions. Traditional hydrogel dressings are often used for a short time mainly due to water loss at high temperature or water freezing at low temperature. This paper reports a facile approach to synthesize a novel antibacterial hydrogel wound dressing based on polyvinylpyrrolidone acrylamide 1-vinyl-3-butylimidazolium and polyethylene glycol dimethacrylate via one-pot method. This hydrogel has cationic groups in the polymer chains and exhibits effective antibacterial and antifungal activity. Furthermore, this hydrogel has anti-freezing, non-drying, and self-healing properties because of its unique molecular structure. Results of wound closure and histopathological examinations demonstrate that the fabricated hydrogel wound dressing effectively promotes the wound healing process in a full-thickness skin defect model. Therefore, this antibacterial hydrogel may be used as a wound healing dressing, even under extreme conditions.
A novel multifunctional poly(γ-glutamic acid) (γ-PGA)/gelatin hydrogel has been developed and used as a wound dressing. An ideal wound dressing should effectively provide a moist environment, absorb wound exudates and protect the wound from foreign microbes. Water soluble γ-PGA salts of sodium and calcium forms were chosen for their good biocompatibility, biodegradability and water absorption capacity. Oligomeric proanthocyanidins (OPCs), naturally occurring plant metabolites and potent antioxidants, were investigated as a non-toxic crosslinking agent in this study. The effects of hydrogels on the degree of crosslinking, swelling, in vitro degradation, mechanical properties and radical scavenging activity were systemically evaluated. A cell viability assay demonstrated that these OPCs crosslinked γ-PGA/gelatin (PGO) hydrogels were not cytotoxic to L929 fibroblasts. Dermal irritation and skin sensitization tests were examined using a guinea pig model; the hydrogels were considered to be neither allergic nor a dermal sensitizer in guinea pigs. Lastly, an in vivo wound healing model in rats was used to study the effects of the hydrogels on wound healing for 21 days. PGO hydrogels formed by both Na and Ca salts could accelerate wound contraction and re-epithelialization, in which Na-PGO hydrogel was significantly better than the untreated control group. The findings suggest that PGO hydrogels are promising wound dressing materials for the treatment for wound healing.
Poly(vinyl alcohol) (PVA) has attracted considerable research interest and is recognized among the largest volume of synthetic polymers that have been produced worldwide for almost one century. This is due to its exceptional properties which dictated its extensive use in a wide variety of applications, especially in medical and pharmaceutical fields. However, studies revealed that PVA-based biomaterials present some limitations that can restrict their use or performances. To overcome these limitations, various methods have been reported, among which blending with poly(vinylpyrrolidone) (PVP) showed promising results. Thus, our aim was to offer a systematic overview on the current state concerning the preparation, properties and various applications of biomaterials based on synergistic effect of mixtures between PVA and PVP. Future trends towards where the biomaterials research is headed were discussed, showing the promising opportunities that PVA and PVP can offer.
Electrospinning is widely used to fabricate nanoscale fibers from natural and synthetic polymers. Electrospun fibers have potential application in tissue engineering as well as in the design of catalysts, batteries, electronic sensors, packages, filtration membranes, medical implants, wound dressings, and medical fabrics, and drug delivery systems. Fibers offer a porous structure with a high surface area to volume ratio, which is a highly desired property in various applications. Integrating other materials such as metals nanoparticles or ceramics in electrospun fibers is emerging as a route to new nanoscale composites materials with enhanced functional properties. Incorporating nanoparticles on or within the nanofibrous scaffold impart functional properties with implication for catalysis, optoelectronics, and biomedicine. Indeed, these electrospun polymer-nanoparticles composites are a new frontier in biomedicine, where their relevance to tissue engineering, wound dressing, drug delivery is emerging. Here, we summarise advances in electrospun tissue engineering and wound dressing platforms developed from polymer-titanium dioxide nanocomposites.
Tannic acid (TA) is a polyphenol‐rich compound found in many natural plants. There are large numbers of phenolic hydroxyls at the terminal of the TA molecule, being capable of forming hydrogen bonds with hydrogen‐bonding donating polymers such as polyvinylpyrrolidone (PVP) and then engineering a hydrogel network. The reversible switch between phenolic hydroxyls and quinones tuned by pH affords the dynamic nature of the resultant hydrogen bonds. The gels exhibit excellent shear‐thinning and self‐recovery properties. Moreover, the polyphenols can form coordinates with Fe(III) that link different TAs to form a hydrogel network. Hence, adding Fe(III) solution to the TA‐PVP sol can form additional interactions inside the TA‐PVP gel. The easy preparation of the dual‐responsive gels with nontoxic raw materials may allow for its application in the biomedical field.
We demonstrate a facile and universal strategy in the fabrication of dual-cross-linked (DC) single network hydrogels with high toughness, “nonswellability”, rapid self-healing, and versatile adhesiveness based on polymer–tannic acid (TA) multiple hydrogen bonds. Two widely used hydrogels, physically cross-linked poly(vinyl alcohol) and chemically cross-linked polyacrylamide, have been transformed to TA-based DC hydrogels by dipping the corresponding aerogels into TA solution. The second cross-link via multiple polymer–TA hydrogen bonds effectively suppresses the crack propagation, resulting in both DC gels with high mechanical strength. But these two TA-based DC hydrogels go through different deformation mechanisms during the stretching based on analyzing their stress–strain curves using the Mooney–Rivlin equation. Moreover, these DC hydrogels are swelling-resistant, with strong toughness, good self-recoverability, rapid self-healing, and versatile adhesiveness. This work provides a simple route to fabricate multifunctional DC hydrogels, hopefully promoting their applications as biomedical materials.
Preventing bacterial contamination, treating wound infection and promoting wound healing have been major challenges in wound care management. In this work, a novel wound dressing based on zwitterionic poly-carboxybetaine (PCB) hydrogel and antibacterial silver nanoparticles (AgNPs) is developed via a one-step method for efficient treatment of infected wounds. The PCB-AgNPs hydrogel exhibits effective antibacterial ability against both Gram positive bacteria (Saphylococcus aureus) and Gram negative bacteria (Escherichia coli). Furthermore, in a murine model, the PCB-AgNPs hydrogel is found to efficiently treat the S.aureus infection and accelerate the cutaneous wound healing. After a two-week healing process, histological tests indicate that it can promote the reconstruction of intact epidermis, which is much faster than those treated with commercial wound dressing (Duoderm® film). This new bifunctional wound dressing provides new opportunities for highly efficient skin wounds care and management.
Intelligent hydrogels have promising applications in a wide variety of fields. Here, a transparent luminous hydrogel with self-healing property was formed from a novel Eu-containing PVA which was designed and synthesized by free radical copolymerization and ester hydrolysis. Fluorescence behavior of the Eu-PVA hydrogel depended on the Eu organic complex in Eu-PVA. The water content of the hydrogel depended on the concentration of PVA water solution. The strength of the Eu-PVA hydrogel was affected by the concentration of cross-linking agent (boric acid) and the content of Eu-PVA. Eu-containing organic complex which had good UV photoluminescence was stabilized in hydrogels without diffusion. The spectroscopic properties of Eu-containing polymers were investigated in detail. And the Eu-PVA hydrogel exhibited strong visible fluorescence and excellent self-healing property. Furthermore, Eu-PVA hydrogel had excellent biocompatibility as mouse osteoblasts could grow well on its surface. Approach in this study provided new insights in designing and fabricating multifunctional intelligent soft materials for biomedical applications.
Pyrrolidinium-type small molecule ionic liquids (ILs), poly(ionic liquid) (PIL) homopolymers, and their corresponding PIL membranes were synthesized and used for antibacterial applications. The influences of substitutions at the N position of pyrrolidinium cation on the antimicrobial activities against both Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) were studied by minimum inhibitory concentration (MIC). The antibacterial efficiency of both the small molecule ILs and PIL homopolymers increased with the increase of the alkyl chain length of substitutions. Furthermore, PIL homopolymers show relatively lower MIC values, indicating better antimicrobial activities than those of corresponding small molecule ILs. However, the antibacterial properties of the PIL membranes are contrary to corresponding ILs and PIL homopolymers, which reducing with the increase of alkyl chain length. Furthermore, the resultant PIL membranes show excellent hemocompatibility and low cytotoxicity towards human cells, demonstrating clinical feasibility in topical applications.
There is a significant cost to mitigate the infection and inflammation associated with the implantable medical devices. The development of effective antibacterial and anti-inflammatory biomaterials with novel mechanism of action has become an urgent task. In this study, a supramolecular polymer hydrogel is synthesized by the copolymerization of N-acryloyl glycinamide and 1-vinyl-1,2,4-triazole in the absence of any chemical crosslinker. The hydrogel network is crosslinked through the hydrogen bond interactions between dual amide motifs in the side chain of N-acryloyl glycinamide. The prepared hydrogels demonstrate excellent mechanical properties-high tensile strength (≈1.2 MPa), large stretchability (≈1300%), and outstanding compressive strength (≈11 MPa) at swelling equilibrium state. A simulation study elaborates the changes of hydrogen bond interactions when 1-vinyl-1,2,4-triazole is introduced into the gel network. It is demonstrated that the introduction of 1-vinyl-1,2,4-triazole endowes the supramolecular hydrogels with self-repairability, thermoplasticity, and reprocessability over a lower temperature range for 3D printing of different shapes and patterns under simplified thermomelting extrusion condition. In addition, these hydrogels exhibit antimicrobial and anti-inflammatory activities, and in vitro cytotoxicity assay and histological staining following in vivo implantation confirm the biocompatibility of the hydrogel. These hydrogels with integrated multifunctions hold promising potential as an injectable biomaterial for treating degenerated soft supporting tissues.
pH-sensitive hydrogels play an important role in controlled drug release applications and have the potential to impact the management of wounds. In this study, we report the fabrication of novel carboxylated agarose/tannic acid hydrogel scaffolds cross-linked with zinc ions for the pH-controlled release of tannic acid. The resulting hydrogels exhibited negligible release of tannic acid at neutral and alkaline pH and sustained release at acidic pH, where they also displayed maximum swelling. The hydrogels also displayed favourable anti-bacterial and anti-inflammatory properties, and a lack of cytotoxicity towards 3T3 fibroblast cell lines. In simulated wound assays, significantly greater cell migration and proliferation was observed for cells exposed to tannic acid hydrogel extracts. In addition, the tannic acid hydrogels were able to suppress NO production in stimulated human macrophages in a concentration-dependent manner, indicating effective anti-inflammatory activity. Taken together, the cytocompatibility, anti-bacterial and anti-inflammatory characteristics of these novel pH-sensitive hydrogels make them promising candidates for wound dressings.
Chitosan (CS)/Gelatin (Gel)/Polyvinyl alcohol (PVA) hydrogels were prepared by the gamma irradiation method for usage in wound dressing applications. Chitosan and gelatin solution was mixed with poly(vinyl alcohol) (PVA) solution at different weight ratios of CS/Gel of 1:3, 1:2, 1:1, 2:1and 3:1. The hydrogels irradiated at 40 kGy. The structure of the hydrogels was characterized by using FT-IR and SEM. The CS/Gel/PVA hydrogels were characterized for physical properties and blood clotting activity. The tensile strength of CS/Gel/PVA hydrogel enhanced than on the basis of the Gel/PVA hydrogel. The highest tensile strength reached the 2.2 Mpa. All hydrogels have shown a good coagulation effect. It takes only 5 minutes for the BCI index to reached 0.032 only 5 minutes when the weight ratio of CS/Gel was 1:1. It means that the hemostatic effect of hydrogels were optimal. And the hydrogrls also showed good pH-sensitivity, swelling ability and water evaporation rate. Therefore, this hydrogel showed a promising potential to be applied as wound dressing.