Assessment of reinforced poly(ethylene glycol) chitosan hydrogels as dressings in a mouse skin wound defect model

Wound dressings of chitosan are biocompatible, biodegradable, antibacterial and hemostatic biomaterials. However, applications for chitosan are limited due to its poor mechanical properties. Here, we conducted an in vivo mouse angiogenesis study on reinforced poly(ethylene glycol) (PEG)-chitosan (RPC) hydrogels. RPC hydrogels were formed by cross-linking chitosan with PEGs of different molecular weights at various PEG to chitosan ratios in our previous paper. These dressings can keep the wound moist, had good gas exchange capacity, and was capable of absorbing or removing the wound exudate. We examined the ability of these RPC hydrogels and neat chitosan to heal small cuts and full-thickness skin defects on the backs of male Balb/c mice. Histological examination revealed that chitosan suppressed the infiltration of inflammatory cells and accelerated fibroblast proliferation, while PEG enhanced epithelial migration. The RPC hydrogels promoted wound healing in the small cuts and full layer wounds. The optimal RPC hydrogel had a swelling ratio of 100% and a water vapor transmission rate (WVTR) of about 2000 g/m²/day. In addition, they possess good mechanical property and appropriate degradation rates. Thus, the optimal RPC hydrogel formulation functioned effectively as a wound dressing and promoted wound healing.     

Starch-based adhesive hydrogel with gel-point viscoelastic behavior and its application in wound sealing and hemostasis

Hydrogels with tissue adhesiveness have demonstrated great promise for wearable electronics,artificial skin,soft robotics,and tissue repair.Nevertheless,adhesive hydrogels that are capable of sealing and hemostasis of wound with severe hemorrhage still lack.For this purpose,a series ofionically crosslinked starch hydrogels were developed here.The viscoelastic properties and tissue adhesiveness of the starch hydrogels were investigated.It is shown that the starch and cross linkers had significant influence on the viscoelastic properties of the starch hydrogels,which further resulted in varied tissue adhesiveness.Among the starch gels,there was one exhibiting a unique and stable "Gel Point" viscoelastic characteristic and it was named as gel-point adhesive hydrogel (GPAH).GPAH showed electrical conductivity,high tissue adhesiveness,high stretch-ability,self-healing capability,injectability,and degradability.The GPAH also exhibited high cytocompatibility,low hemolysis risk,and strong antibacterial effect.The wound sealing and hemostatic performance of GPAH was further evaluated by a rat femoral artery injury model.The blood loss after the sealing of GPAH (2.4 ± 1.3 g) was significantly decreased compared to the group using gauze for sealing (6.3 ± 1.5g).Meanwhile,GPAH did not cause pathological changes of the soft tissues surrounding the wound.The above results indicate that GPAH,with high tissue adhesiveness,suitable viscoelastic property,strong antibacterial capacity,as well as electro-conductivity,bears great potential for the applications in smart wound management.     

An All-in-One “4A Hydrogel”: through First-Aid Hemostatic,Antibacterial, Antioxidant,and Angiogenic to Promoting Infected Wound Healing

Currently used wound dressings are ineffective. Hence, there is a need to develop introduce a high-performance medicament with multiple functions including rapid hemostasis and excellent antibacterial activity to meet the growing worldwide demand for wound healing products. Here, inspired by the strong adhesion of mussels and the enzyme-mimicking activity of nanometallic biomaterials, the authors developed an injectable hydrogel to overcome multiple limitations of current wound dressings. The hydrogel is synthesized via esterification reaction between poly(vinyl alcohol) (PVA) and 3,4-dihydroxyphenylalanine (DOPA), followed by catechol-metal coordination between Cu²⁺ and the catechol groups of DOPA to form a PVA-DOPA-Cu (PDPC) hydrogel. The PDPC hydrogel possesses excellent tissue adhesive, antioxidative, photothermal, antibacterial, and hemostatic properties. The hydrogel rapidly and efficiently stopped bleeding under different traumatic conditions, including otherwise-lethal liver injury, high-pressure carotid artery rupture, and even fatal cardiac penetration injuries in animal models. Furthermore, it is demonstrated that the PDPC hydrogel affected high-performance wound repair and tissue regeneration by accelerating re-epithelialization, promoting collagen deposition, regulating inflammation, and contributing to vascularization. The results show that PDPC hydrogel is a promising candidate for rapid hemorrhage control and efficient wound healing in multiple clinical applications.     

Natural Carrier-Free Binary Small Molecule Self-Assembled Hydrogel Synergize Antibacterial Effects and Promote Wound Healing by Inhibiting Virulence Factors and Alleviating the Inflammatory Response

Methicillin-resistant Staphylococcus aureus (MRSA)-infected skin wounds have caused a variety of diseases and seriously endanger global public health. Therefore, multidimensional strategies are urgently to find antibacterial dressings to combat bacterial infections. Antibacterial hydrogels are considered potential wound dressing, while their clinical translation is limited due to the unpredictable risks and high costs of carrier excipients. it is found that the natural star antibacterial and anti-inflammatory phytochemicals baicalin (BA) and sanguinarine (SAN) can directly self-assemble through non-covalent bonds such as electrostatic attraction, π–π stacking, and hydrogen bonding to form carrier-free binary small molecule hydrogel. In addition, BA-SAN gel exhibited a synergistic inhibitory effect on MRSA. And its plasticity and injectability allowed it to be applied as a wound dressing. Due to the matched physicochemical properties and synergistic therapeutic effects, BA-SAN gel can inhibit bacterial virulence factors, alleviate wound inflammation, promote wound healing, and has good biocompatibility. The current study not only provided an antibacterial hydrogel with clinical value but also opened up new prospects that carrier-free hydrogels can be designed and originated from clinically used small-molecule phytochemicals.     

Preparation of green cellulose diacetate-based antibacterial wound dressings for wound healing

Managing wounds is a growing universal problem and developing effective wound dressings to staunch bleeding and protect wounds from bacterial infections is an increasingly serious challenge. In this work, a remolding electrospinning nanofiber three-dimensional structure wound dressing (CCP) was prepared with superhydrophilicity, high water absorption and absorbing capacity, excellent hemostatic capacity and antibacterial ability, and biocompatibility to promote wound healing. Polyhexamethylene guanidine hydrochloride (PHMG) was grafted to cellulose diacetate (CDA) wound dressing surface through an amide reaction. A water contact angle analysis demonstrated that CCP wound dressing could be beneficial to promote wound exudate management effectively with rapid absorption of water within 0.2 s. In vitro hemo- and cytocompatibility assay showed that a CCP wound dressing had no significant hemotoxicity or cytoxicity. Specifically, CCP wound dressings could be beneficial to accelerate wound hemostasis and further reduce mortality caused by uncontrolled bleeding. Furthermore, CCP wound dressings have an excellent antibacterial ability, which could be beneficial to inhibit wound inflammatory over-reaction and promote normal wound healing. Combined together, the prepared wound dressing in this research effort is expected to have high-potential in clinical applications.     

Radiation synthesis of PVP/alginate hydrogel containing nanosilver as wound dressing

Hydrogels with polyvinyl pyrrolidone (PVP) and alginate were synthesized and silver nanoparticles were incorporated in hydrogel network using gamma radiation. PVP (10?and 15?%) in combination with 0.5?and 1?% alginate was gamma irradiated at different doses of 25?and 40?kGy. Maximum gel percent was obtained with 15?% PVP in combination with 0.5?% alginate. The fluid absorption capacity for the PVP/alginate hydrogels was about 1881–2361?% at 24?h. Moisture vapour transmission rate (MVTR) of hydrogels containing nanosilver at 24?h was 278.44?g/(m²h). The absorption capacity and moisture permeability of the PVP/alginate–nanosilver composite hydrogel dressings show the ability of the hydrogels to prevent fluid accumulation in exudating wound. The hydrogels containing nanosilver demonstrated strong antimicrobial effect and complete inhibition of microbial growth was observed with 70?ppm nanosilver dressings. PVP/alginate hydrogels containing nanosilver with efficient fluid handling capacity and antimicrobial activity was found suitable for use as wound dressing.     

Adhesive Composite Microspheres with Dual Antibacterial Strategies for Infected Wound Healing

Skin damage and infection pose a severe challenge to human health. Construction of a novel versatile dressing with good anti-infection and healing-promoting abilities is greatly expected. In this paper, nature-source-based composite microspheres with dual antibacterial mechanisms and bioadhesive features by microfluidics electrospray for infected wound healing is developed. The microspheres enable sustained release of copper ions, which not only show long-term antibacterial properties, but also play important role in wound-healing-related angiogenesis. Additionally, the microspheres are coated with polydopamine via self-polymerization, which renders the microspheres adhesive to the wound surface, and further enhance the antibacterial ability through photothermal energy conversion. Based on the dual antibacterial strategies provided by copper ions and polydopamine as well as the bioadhesive property, the composite microspheres exhibit excellent anti-infection and wound healing performances in a rat wound model. These results, along with the nature-source-based composition and biocompatibility, indicate the great potential of the microspheres in clinical wound repair.     

Injectable hydrogel wound dressing based on strontium ion cross-linked starch

Severe skin wounds cause great problems and sufferings to patients. In this study, an injectable wound dressing based on strontium ion cross-linked starch hydrogel (SSH) was developed and evaluated. The good inject-ability of SSH made it easy to be delivered onto the wound surface. The good tissue adhesiveness of SSH ensured a firm protection of the wound. Besides, SSH supported the proliferation of NIH/3T3 fibroblasts and facilitated the migration of human umbilical vein endothelial cells (HUVECs). Importantly, SSH exhibited strong antibacterial effects on Staphylococcus aureus (S. aureus), which could prevent wound infection. These results demonstrate that SSH is a promising wound dressing material for promoting wound healing.     

Multifunctional Hydrophobized Microparticles for Accelerated Wound Healing after Endoscopic Submucosal Dissection

Endoscopic submucosal dissection (ESD) provides strong therapeutic benefits for early gastrointestinal cancer as a minimally invasive treatment. However, there is currently no reliable treatment to prevent scar contracture resulting from ESD which may lead to cicatricial stricture. Herein, a multifunctional colloidal wound dressing to promote tissue regeneration after ESD is demonstrated. This sprayable wound dressing, composed of hydrophobized microparticles, exhibits the multifunctionality necessary for wound healing including tissue adhesiveness, blood coagulation, re‐epithelialization, angiogenesis, and controlled inflammation based on hydrophobic interaction with biological systems. An in vivo feasibility study using swine gastric ESD models reveals that this colloidal wound dressing suppresses fibrosis and accelerates wound healing. Multifunctional colloidal and sprayable wound dressings have an enormous therapeutic potential for use in a wide range of biomedical applications including accelerated wound healing after ESD, prevention of perforation, and the treatment of inflammatory diseases.     

Biofriendly,Stretchable, and Reusable Hydrogel Electronics as Wearable Force Sensors

The ever‐growing overlap between stretchable electronic devices and wearable healthcare applications is igniting the discovery of novel biocompatible and skin‐like materials for human‐friendly stretchable electronics fabrication. Amongst all potential candidates, hydrogels with excellent biocompatibility and mechanical features close to human tissues are constituting a promising troop for realizing healthcare‐oriented electronic functionalities. In this work, based on biocompatible and stretchable hydrogels, a simple paradigm to prototype stretchable electronics with an embedded three‐dimensional (3D) helical conductive layout is proposed. Thanks to the 3D helical structure, the hydrogel electronics present satisfactory mechanical and electrical robustness under stretch. In addition, reusability of stretchable electronics is realized with the proposed scenario benefiting from the swelling property of hydrogel. Although losing water would induce structure shrinkage of the hydrogel network and further undermine the function of hydrogel in various applications, the worn‐out hydrogel electronics can be reused by simply casting it in water. Through such a rehydration procedure, the dehydrated hydrogel can absorb water from the surrounding and then the hydrogel electronics can achieve resilience in mechanical stretchability and electronic functionality. Also, the ability to reflect pressure and strain changes has revealed the hydrogel electronics to be promising for advanced wearable sensing applications.     

Evaluation of hydrogels for soft tissue adhesives <Emphasis Type="Italic">in vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis> analyses

In this study, natural materials (sodium alginate, dextran, gelatin and carboxymethyl chitosan) were modified to get aldehyde components and amino components. Upon mixing the two-component solutions together, four kinds of Schiff base hydrogels formed successfully within 5-300 s and could seal the wound tissue. The cytotoxicity tests of hydrogel extraction solution confirmed that the hydrogels are nontoxic materials. The adhesive ability was evaluated in vivo by measuring the adhesive strength after sealing the skin incisions on the back of rats. All the hydrogels showed higher adhesive strength than that of commercial fibrin glue and the blank control. The histological staining observation by hematoxylin and eosin staining (HE) and Masson’s trichrome staining (MTC) methods suggested that the hydrogels had good biocompatibility and biodegradation in vivo. They have only normal initial inflammation to skin tissue and could improve the formation of new collagen in the incision section. So, the prepared hydrogels were both safe and effective tissue adhesive, which had the great potentials to be used as skin tissue adhesive.     

Heat preservation,antifouling, hemostatic and antibacterial aerogel wound dressings for emergency treatment

Hemostatic dressings with multiple functions are superior to current hemostatic dressings for use in the complex situation of emergency accidents. In particular, the existing dressings lack consideration for the prevention of hypothermic shock after massive hemorrhage. In this study, gelatin (GN) and oxidized pectin (OP) were used for Schiff base cross-linking, and then polyvinyl alcohol (PVA) solution mixed with hemostatic caffeic acid (CA) was introduced to obtain aerogel substrate material (CB) after lyophilization. Polydimethylsiloxane (PDMS) and silver nanowires (Ag NWs) were used to construct a hydrophobic layer, an antibacterial layer and an infrared reflective layer on both sides of CB to prepare a multifunctional aerogel wound dressing with heat preservation, antifouling, hemostasis and antibacterial properties (PDMS-Ag NW-CB). The results showed that the infrared transmittance of PDMS-Ag NW-CB is almost 0, so that thermal energy loss from the body is minimized. The contact angles with water and blood are 129° and 120°, respectively, which have the effect of antifouling. This dressing can absorb blood quickly within 10 min, adhere to and gather platelets, and achieve hemostasis. It has good antibacterial and biocompatibility. Therefore, PDMS-Ag NW-CB has great potential in application to emergency treatment.     

Smart Bandage for Monitoring and Treatment of Chronic Wounds

Chronic wounds are a major health concern and they affect the lives of more than 25 million people in the United States. They are susceptible to infection and are the leading cause of nontraumatic limb amputations worldwide. The wound environment is dynamic, but their healing rate can be enhanced by administration of therapies at the right time. This approach requires real‐time monitoring of the wound environment with on‐demand drug delivery in a closed‐loop manner. In this paper, a smart and automated flexible wound dressing with temperature and pH sensors integrated onto flexible bandages that monitor wound status in real‐time to address this unmet medical need is presented. Moreover, a stimuli‐responsive drug releasing system comprising of a hydrogel loaded with thermo‐responsive drug carriers and an electronically controlled flexible heater is also integrated into the wound dressing to release the drugs on‐demand. The dressing is equipped with a microcontroller to process the data measured by the sensors and to program the drug release protocol for individualized treatment. This flexible smart wound dressing has the potential to significantly impact the treatment of chronic wounds.     

Amniotic membrane extract-loaded double-layered wound dressing: evaluation of gel properties and wound healing

The conservative single-layered wound dressing system is decomposed when mixed in polyvinyl alcohol (PVA) solution, which means it cannot be used with a temperature-sensitive drug. The goal of this investigation was to make an amniotic membrane extract (AME)-loaded double-layered wound dressing with an improved healing result compared to the conservative single-layered wound dressing systems. The double-layered wound dressing was developed with PVA/sodium alginate using a freeze–melting technique; one layer was PVA layer and the other was the drug-loaded sodium alginate layer. Its gel properties were assessed compared to single-layered wound dressings. Moreover, in vivo wound-healing effects and histopathology were calculated compared to commercial products. The double-layered wound dressing gave a similar gel fraction and Young’s module as single-layered wound bandages developed with only PVA, and a similar inflammation ability and WVTR as single-layered wound dressings developed with PVA and sodium alginate. Our data indicate that these double-layered wound bandages were just as swellable, but more elastic and stronger than single-layered wound dressings comprised of the same polymers and quantities, possibly giving an acceptable level of moisture and accumulation of exudates in the wound zone. Compared to the commercial product, the double-layered wound dressing comprising 6.7% PVA, 0.5% sodium alginate and 0.01% AME significantly enhanced the wound-healing effect in the wound-healing test. Histological investigations showed that superior full-thickness wound-healing effects compared to the commercial product. Therefore, the double-layered wound dressing would be an outstanding wound-dressing system with improved wound healing and good gel property.     

Hyaluronic acid and silver sulfadiazine-impregnated polyurethane foams for wound dressing application

Five different kinds of PU foam wound dressings were prepared to investigate their wound healing capability. They include (i) PU+silver sulfadiazine (AgSD), (ii) PU+alginate (Al), (iii) PU+Al+AgSD, (iv) PU+hyaluronic acid (HA), and (v) PU+HA+AgSD. Physical properties and in vitro behaviors of AgSD release and fibroblast adhesion on those dressings were evaluated. From the drug release and fibroblast adhesion studies, it was observed that PU foam impregnated with both HA and AgSD shows good drug release behavior and low adhesion of the cells. Furthermore, the HA and AgSD-containing PU foam showed excellent wound healing effect without any inflammation or yellow cluster. The wound size decreased around 77% after 1 week application of that foam dressing onto a rat skin defect.     

On-Demand Removable Self-Healing and pH-Responsive Europium-Releasing Adhesive Dressing Enables Inflammatory Microenvironment Modulation and Angiogenesis for Diabetic Wound Healing

Current diabetic wound treatments remain unsatisfactory due to the lack of a comprehensive strategy that can integrate strong applicability (tissue adhesiveness, shape adaptability, fast self-healability, and facile dressing change) with the initiation and smooth connection of the cascade wound healing processes. Herein, benefiting from the multifaceted bonding ability of tannic acid to metal ions and various polymers, a family of tannin–europium coordination complex crosslinked citrate-based mussel-inspired bioadhesives (TE-CMBAs) are specially developed for diabetic wound healing. TE-CMBAs can gel instantly (< 60 s), possess favorable shape-adaptability, considerable mechanical strengths, high elasticity, considerable wet tissue adhesiveness (≈40 kPa), favorable photothermal antimicrobial activity, excellent anti-oxidant activity, biocompatibility, and angiogenetic property. The reversible hydrogen bond crosslinking and sensitive metal–phenolic coordination also confers TE-CMBAs with self-healability, pH-responsive europium ion and TA releasing properties and on-demand removability upon mixing with borax solution, enabling convenient painless dressing change and the smooth connection of inflammatory microenvironment modulation, angiogenesis promotion, and effective extracellular matrix production leveraging the acidic pH condition of diabetic wounds. This adhesive dressing provides a comprehensive regenerative strategy for diabetic wound management and can be extended to other complicated tissue healing scenarios.     

Silver-doped self-assembling di-phenylalanine hydrogels as wound dressing biomaterials

Chronic and acute wounds can be quickly contaminated and infected by microorganisms such as bacteria, multi-resistant organisms or fungi. The introduction of silver as anti-microbial agent into wound management has widely been demonstrated to be effective and contribute to wound healing. As a consequence, many approaches and different materials have been employed to synthesize antibacterial silver-hydrogels. In this work the introduction of silver particles into the fibrillar structure of self-assembling aromatic di-phenylalanine derivatives modified with aromatic groups such as 9-fluorenylmethoxycarbonyl is proposed to produce antibacterial wound dressings. Hydrogels doped with increasing amounts of silver were tested and adopted to modify flax textiles. The influence of silver on the structure of hydrogels was studied using light and confocal microscopy, while SEM–EDX allowed the characterization of the hydrogel coating on the surface of the textile substrates as well as the identification and distribution of silver nanoparticles. The antibacterial potential of the treated flax was demonstrated through microbiological tests on Staphylococcus aureus. The combination of the physico-chemical and anti-bacterial properties, together with the ease of preparation of these biomaterials, fulfils the requirement of clinically-effective wound dressings.     

Injectable melatonin-loaded carboxymethyl chitosan (CMCS)-based hydrogel accelerates wound healing by reducing inflammation and promoting angiogenesis and collagen deposition

Carboxymethyl chitosan(CMCS)-based hydrogels have antibacterial activity,and have shown the abilities of preventing wound infection,promoting cell proliferation,accelerating collagen deposition,and stimulating hyaluronic acid formation during wound healing.As a hormone produced by the pineal gland in humans and animals,melatonin promotes skin wound healing by regulating the release of inflammatory mediators and accelerating the proliferation and migration of cells,angiogenesis,and collagen deposition.However,the combined effects of CMCS and melatonin on wound healing remain unclear.Injectable CMCS-based hydrogels containing melatonin were prepared,and their healing effects were evaluated using a full-thickness cutaneous wound model in rats.Compared with the control and the hydrogel with no melatonin groups,the melatonin-loaded hydrogel significantly increased the percentage of wound closure,promoted the proliferation of granulation tissue and re-epithelialization,and accelerated collagen deposition.Additionally,the melatonin-loaded hydrogel promoted angiogenesis and vascular endothelial growth factor receptor protein expression and increased the expression of cyclooxygenase-2 and inducible nitric oxide synthase.The melatonin-loaded hydrogel also markedly increased the expression of collagen III,α-smooth muscle actin,and transforming growth factor-β1 proteins and reduced collagen I expression.These results suggest that the melatonin-loaded hydrogel promoted granulation tissue formation and accelerated wound healing by reducing inflammation and promoting angiogenesis and collagen deposition.     

新型胶原-腐植酸钠复合水凝胶的研制与分析

水凝胶具有弹性高、含水量高,冷效应、保湿性强、形状多变等优点,是医用敷料的主要材料之一。将具有优良生物相容性、促细胞增殖功能的胶原(COL)与具有止血、消炎等作用的腐植酸钠(NaHA)按不同比例(COL∶NaHA)共混并采用自组装方式制备了一种新型胶原-腐植酸钠复合水凝胶,并考察两者间的相互作用及复合水凝胶的结构与性能,以期应用于医用敷料行业。NaHA不改变胶原的三股螺旋结构且两者之间存在氢键与静电作用。当COL∶NaHA≥4∶6时,两者间的静电结合被NaCl所屏蔽,因此体系相容性较好;然而继续增加NaHA会引起聚沉现象。当COL∶NaHA=4∶6时,两者结合率最高,达到93.2%且相容性较好,复合水凝胶的纤维具有明显的D-周期且各方面性能最佳。NaHA的释放较缓慢,24 h后仍有约80%保留在水凝胶中;热稳定性较纯胶原提升了34.9℃;储能模量和损耗模量分别为31.89 Pa和3.99 Pa。此外,随着NaHA的加入,冻干复合水凝胶的孔径缩小、孔隙分布更加均匀;复合膜的亲水性明显提升。     

Biomedical evaluation of polyvinyl alcohol–gelatin esterified hydrogel for wound dressing

The wound is a biosynthetic environment in which numerous cellular processes are interlinked in the process of repair. Modern dressings are designed to facilitate wound healing rather than just to cover it. Hydrogel dressing can protect injured skin and keep it appropriately moist to speed the healing process by absorbing exudates while maintaining the products of tissue repair, including growth factor and lysosomes, in contact with the wound. The design and development of novel membrane of hydrogels prepared by esterification of polyvinyl alcohol with gelatin were attempted. Contact angle of goat blood was determined. The hydrogel was characterized by hemolysis test and water vapor transmission rate. Diffusion coefficient of salicylic acid (SA) and gatifloxacin, a fourth generation fluoroquinolone, through the membrane was determined. Both the drugs were used as model drug. Methyl tetrazolium dye assay of the membrane was done using L929 fibroblast cell line and mice splenocytes to establish the biocompatibility of the membrane. The equilibrium goat blood-in-air contact angles of measured ester films ranged from 56 to 60°. The hydrogel was found to be hemocompatible and moisture retentive indicating its possible use in moist wound care. The diffusion coefficient of SA and gatifloxacin through the membrane was found to be 1.49 × 10⁻⁵ and 3.97 × 10⁻⁶ cm²/s respectively. The membrane was found to be compatible with the L929 fibroblast cell line and mice splenocytes.