Wound dressings based on chitosans and hyaluronic acid for the release of chlorhexidine diacetate in skin ulcer therapy

In the present work wound dressings, based on chitosan hydrochloride (HCS), 5-methyl-pyrrolidinone chitosan (MPC), and their mixtures with an anionic polymer, hyaluronic acid (HA), were prepared by freeze-drying. Chlorhexidine diacetate (CX) was used as an antimicrobic drug. The mechanical properties of the wound dressings were investigated. In particular, the wound dressings were subjected to dynamic hydration measurements to evaluate their capability to absorb wound exudate and to rheological analysis to investigate their resistance to mechanical stresses on hydration. The wound dressings were also characterized for drug release properties. The antioxidant and antimicrobial activities of medicated and non-medicated wound dressings were also investigated. All the wound dressings are characterized by mechanical resistance suitable for skin application. The addition of hyaluronic acid to chitosans leads to a reduction in wound dressing hydration properties and a modulation of drug release. The wound dressing based on MPC is characterized by the highest elastic properties and by the best scavenger activity. Antimicrobial activity against bacteria and C. albicans is shown by the dressing based on chitosan also in absence of chlorhexidine.     

Development of sponge-like dressings for mucosal/transmucosal drug delivery into vaginal cavity

The aim of the present work was the development of vaginal sponge-like dressings based on chitosan ascorbate (CS) and on hyaluronic acid sodium salt/lysine acetate (HAS) combination. Sponge-like dressings were prepared by freeze-drying and characterized for mechanical resistance and mucoadhesion. CS dressings show higher mechanical and mucoadhesion properties in comparison with HAS dressing. The enzymatic inhibition properties of the dressings were evaluated in vitro against carboxipeptidase A in view of their employment for vaginal delivery of peptidic drugs. All the dressings were able to inhibit carboxipeptidase activity; CS dressings, independently of polymer MW, completely inhibited enzyme activity. Release and penetration enhancement properties of the dressings loaded with a high molecular weight hydrophilic molecule, fluorescein isothiocyanate dextran (FD4), were assessed. CS dressings were able to prolong FD4 release. All the dressings showed penetration enhancement properties into pig vaginal mucosa although to a different extent: greater for dressings based on CS than for that containing HAS. Moreover, CS dressings demonstrated intrinsic antimicrobial properties. The suitability of sponge-like systems for the treatment of vaginal infections was assessed by loading the CS dressing characterized by the best mechanical and antimicrobial properties with an antibiotic drug (clyndamicin-2-phosphate) and by checking drug release.     

Novel chitosan and bacterial cellulose biocomposites tailored with polymeric nanoparticles for modern wound dressing development

Dressing biomaterials play a key role in wound management keeping a moisture medium and protecting against external factors. Natural and synthetic materials could be used as dressings where chitosan and bacterial cellulose is one of the most important solutions. These biopolymers have been used for wound dressing based on their non-toxic, biodegradable, and biocompatible features. In this study, biocomposites based on bacterial cellulose and chitosan membranes tailored with antimicrobial loaded poly(N-isopropylacrylamide)/polyvinyl alcohol nanoparticles were prepared. Core-shell polymeric nanoparticles, bacterial cellulose/chitosan membranes, and biocomposites were independently loaded with silver sulfadiazine, a well-known sulfonamide antibacterial agent used in the therapy of mild-to-moderate infections for sensitive organisms. The chemistry, structure, morphology, and size distribution were investigated by Fourier transformed infrared spectroscopy (FTIR-ATR), RAMAN spectroscopy, Scanning electron (SEM) and Transmission electron microscopy (TEM), and Dynamic light scattering (DLS). In vitro release behaviors of silver sulfadiazine from polymeric nanoparticles and biocomposites were investigated. The biological investigations revealed good biocompatibility of both the nanoparticles and the biocomposites in terms of human dermal fibroblasts viability and proliferation potential. Finally, the drug-loaded polymeric biomaterials showed promising characteristics, proving their high potential as an alternative support to develop a biocompatible and antibacterial wound dressing.     

Alginate based bilayer hydrocolloid films as potential slow-release modern wound dressing

The aims of this research were to develop a novel bilayer hydrocolloid film based on alginate and to investigate its potential as slow-release wound healing vehicle. The bilayer is composed of an upper layer impregnated with model drug (ibuprofen) and a drug-free lower layer, which acted as a rate-controlling membrane. The thickness uniformity, solvent loss, moisture vapour transmission rate (MVTR), hydration rate, morphology, rheology, mechanical properties, in vitro drug release and in vivo wound healing profiles were investigated. A smooth bilayer film with two homogenous distinct layers was produced. The characterisation results showed that bilayer has superior mechanical and rheological properties than the single layer films. The bilayers also showed low MVTR, slower hydration rate and lower drug flux in vitro compared to single layer inferring that bilayer may be useful for treating low suppurating wounds and suitable for slow release application on wound surfaces. The bilayers also provided a significant higher healing rate in vivo, with well-formed epidermis with faster granulation tissue formation when compared to the controls. In conclusions, a novel alginate-based bilayer hydrocolloid film was developed and results suggested that they can be exploited as slow-release wound dressings.     

鱼皮胶原蛋白-壳聚糖复合海藻酸盐水凝胶敷料对烧烫伤创面的促愈合作用

本文以海藻酸钠为原料,复配壳聚糖、鱼皮胶原蛋白,通过Ca2+离子交联制备成海藻酸盐水凝胶敷料。测试了该敷料的物理机械性能及其对大白兔浅Ⅱ度烧烫伤创面的促愈合作用。结果表明：鱼皮胶原蛋白-壳聚糖复合海藻酸盐水凝胶的含水量≥80%,具有良好的吸湿保湿和机械性能,是一种理想的伤口创面敷料;对浅Ⅱ度烧烫伤的愈合周期远远少于医用纱布、市售聚氨酯水凝胶敷料,且能消除伤口炎症,抑制瘢痕的生成,在伤口护理方面有着良好的前景和应用方向。     

Delivery of Therapeutics from Layer-by-Layer Electrospun Nanofiber Matrix for Wound Healing: An Update

Increasing incidences of chronic wounds urge the development of effective therapeutic wound treatment. As the conventional wound dressings are found not to comply with all the requirements of an ideal wound dressing, the development of alternative and effective dressings is demanded. Over the past few years, electrospun nanofiber has been recognized as a better system for wound dressing and hence has been studied extensively. Most of the electrospun nanofiber dressings were fabricated as single-layer structure mats. However, this design is less favorable for the effective healing of wounds mainly due to its burst release effect. To address this problem and to simulate the organized skin layer's structure and function, a multilayer structure of wound dressing had been proposed. This design enables a sustained release of the therapeutic agent(s), and more resembles the natural skin extracellular matrix. Multilayer structure is also referred to layer-by-layer (LbL), which has been established as an innovative method of drug incorporation and delivery, combines a high surface area of electrospun nanofibers with the multilayer structure mat. This review focuses on LbL multilayer electrospun nanofiber as a superior strategy in designing an optimal wound dressing.     

Wound healing dressings and drug delivery systems: a review

The variety of wound types has resulted in a wide range of wound dressings with new products frequently introduced to target different aspects of the wound healing process. The ideal dressing should achieve rapid healing at reasonable cost with minimal inconvenience to the patient. This article offers a review of the common wound management dressings and emerging technologies for achieving improved wound healing. It also reviews many of the dressings and novel polymers used for the delivery of drugs to acute, chronic and other types of wound. These include hydrocolloids, alginates, hydrogels, polyurethane, collagen, chitosan, pectin and hyaluronic acid. There is also a brief section on the use of biological polymers as tissue engineered scaffolds and skin grafts. Pharmacological agents such as antibiotics, vitamins, minerals, growth factors and other wound healing accelerators that take active part in the healing process are discussed. Direct delivery of these agents to the wound site is desirable, particularly when systemic delivery could cause organ damage due to toxicological concerns associated with the preferred agents. This review concerns the requirement for formulations with improved properties for effective and accurate delivery of the required therapeutic agents. General formulation approaches towards achieving optimum physical properties and controlled delivery characteristics for an active wound healing dosage form are also considered briefly.     

Synthesis and characterization of a novel controlled release zinc oxide/gentamicin–chitosan composite with potential applications in wounds care

Freshly prepared ZnO nanoparticles were incorporated into a chitosan solution in weight ratios ranging from 1:1 to 12:1. Starting from the ratio of 3:1 the chitosan solution was transformed into a gel with a high consistency, which incorporates 15 mL water for only 0.1 g solid substance. The powders obtained after drying the gel were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM) and thermal analysis (TG-DSC). The electronic (UV–vis), infrared (FTIR) and photoluminescence (PL) spectra were also recorded. ZnO particles were coated with gentamicin and incorporated into the chitosan matrix, to yield a ZnO/gentamicin–chitosan gel. The release rate of gentamicin was monitored photometrically. This ZnO/gentamicin–chitosan gel proved great antimicrobial properties, inhibiting Staphylococcus aureus and Pseudomonas aeruginosa growth in both planktonic and surface-attached conditions. The results indicate that the obtained composite can be used in cutaneous healing for developing improved wound dressings, which combine the antibacterial activity of all three components with the controlled release of the antibiotic. This wound dressing maintains a moist environment at the wound interface, providing a cooling sensation and soothing effect, while slowly releasing the antibiotic. The system is fully scalable to any other soluble drug, as the entire solution remains trapped in the ZnO–chitosan gel.     

Antimicrobial PLGA ultrafine fibers: Interaction with wound bacteria

The structure and functions of polymer nanofibers as wound dressing materials have been well investigated over the last few years. However, during the healing process, nanofibrous mats are inevitably involved in dynamic interactions with the wound environment, an aspect not explored yet. Potential active participation of ultrafine fibers as wound dressing material in a dynamic interaction with wound bacteria has been examined using three wound bacterial strains and antimicrobial fusidic acid (FA)-loaded electrospun PLGA ultrafine fibers (UFs). These were developed and characterized for morphology and in-use pharmaceutical attributes. In vitro microbiological studies showed fast bacterial colonization of UFs and formation of a dense biofilm. Interestingly, bacterial stacks on UFs resulted in a remarkable enhancement of drug release, which was associated with detrimental changes in morphology of UFs in addition to a decrease in pH of their aqueous incubation medium. In turn, UFs by allowing progressively faster release of bioactive FA eradicated planktonic bacteria and considerably suppressed biofilm. Findings point out the risk of wound reinfection and microbial resistance upon using non-medicated or inadequately medicated bioresorbable fibrous wound dressings. Equally important, data strongly draw attention to the importance of characterizing drug delivery systems and establishing material-function relationships for biomedical applications under biorelevant conditions.     

Dual function of tributyrin emulsion: solubilization and enhancement of anticancer effect of celecoxib

The polysaccharide ulvan, composed of sulphated rhamnose, glucoronic and iduronic acids was used to produce polymeric membranes by solvent casting. As ulvan is soluble in water, a cross-linking step was necessary to render the membrane insoluble in water and stable at physiological conditions. Cross-linked ulvan membranes were characterized by FTIR, SEM, swelling behaviour was investigated and the mechanical performance assessed by quasi-static tensile testing. Furthermore, the ability and mechanism of sustained release of a model drug from ulvan membranes was investigated. Produced membranes revealed remarkable ability to uptake water (up to ～1800% of its initial dry weight) and increased mechanical performance (1.76 MPa) related with cross-linking. On the other hand, medicated ulvan dressings demonstrate the potential as drug delivery devices. Using a model drug we have observed an initial steady release of the drug - of nearly 49% - followed by slower and sustained release up to 14 days. The properties of ulvan membranes herein revealed suggest a great potential of this natural sulphated polysaccharide as a wound dressing.     

The preparation and characterisation of drug-loaded alginate and chitosan sponges

Sponges composed of sodium alginate and chitosan were prepared via a freeze drying process in order to assess the utility of mixed sponges as potential wound dressings or matrices for tissue engineering. Sponge preparation involved dissolving both polymers (either individually or mixed) in 1% acetic acid and freeze-drying the corresponding solutions. The mechanical properties of the sponges were assessed using texture analysis and the microstructure examined using scanning electron microscopy. The dissolution of a model drug (paracetamol) from the sponges was assessed as a function of polysaccharide composition. It was noted that the sponges had a flexible yet strong texture, as assessed macroscopically. Measurement of the resistance to compression ('hardness') indicated that the chitosan sponges were the 'hardest' while the alginate sponges showed the least resistance to compression, with all sponges showing a high degree of recovery. In contrast, the breaking force (tensile force) of the sponges were greatest for the single component systems, while the elongation prior to breaking was similar for each material. SEM studies indicated that the mixed systems had a less well-defined microstructure than the single component sponges. This was ascribed to the two polysaccharides interacting in aqueous solution via coulombic forces, leading to a more randomly ordered network being formed on freezing. Dissolution studies indicated that systems containing chitosan alone showed the slowest release profile, with the mixed systems showing a relatively rapid dissolution profile. The use of chitosan and alginates together, therefore, appears to allow the formulator to manipulate both the mechanical properties and the drug release properties of the sponges.     

Novel multifunctional platforms for potential treatment of cutaneous wounds: Development and in vitro characterization

An original formulative/manufacturing approach for the development of a multi-composite wound dressing able to control the release of a water soluble API (lidocaine HCl) for several days was evaluated. The prepared multi-composite wound dressing is a microstructured spongy matrix, which embeds solid lipid microparticles (SLMs). The matrices were obtained by freeze drying of polyelectrolyte complexes made up two biopolymers: three different chitosan to alginate weight ratios (1:1, 3:1 and 1:3) were studied. The drug-loaded matrices were investigated as regards water uptake ability, swelling, drug loading, morphology and release profiles. SLMs were prepared at two different drug loadings (5% and 25%, w/w) by the spray congealing technology and were then incorporated in the spongy matrices. The characterization of the SLMs evidenced their spherical shape, mean dimensions lower than 20 μm, controlled release and the modification of the drug crystalline state. Comparing the release profiles of the SLMs-loaded sponges, the matrices with 1:3 chitosan/alginate ratio displayed a sustained release profile with the lower burst effect. Then hyaluronan and cysteine were embedded into the matrix to enhance the wound healing properties of the dressing. The final multi-composite platform was able to promote the growth of fibroblasts maintaining its prolonged release characteristic.     

Preparation, Characterization, and Release of Amoxicillin from Electrospun Fibrous Wound Dressing Patches

Purpose

To produce electrospun polymeric fibrous wound dressing patches that can release the antibiotic drug amoxicillin in a controlled manner.

Methods

Poly(D,L-lactide-co-glycolide) acid (PLGA) fibrous dressings with entrapped amoxicillin were produced by electrospinning. The morphology and successful entrapment of amoxicillin in the PLGA fibrous dressings were validated by scanning electron microscopy (SEM) and Fourier Transform Infrared (FTIR) spectroscopy. The rate of drug release from the dressing patches was measured in various media for a period of 21 days using UV spectroscopy.

Results

PLGA fibres entrapping amoxicillin were collected for 300 s and then cut to form square patches with an average weight of 55 mg. Each dressing patch contained ~2 mg of amoxicillin. The mean fibre diameter was 2.2?±?0.4 μm. The drug release from the PLGA dressings was found to be different for each medium during the 21-day release period with the highest and lowest concentration of drug released observed when the dressings were immersed in simulated body fluid (SBF) and phosphate buffered saline (PBS), respectively.

Conclusions

The release profiles obtained in this study and the well-established biocompatibility of PLGA indicate that the fibre-based patches with entrapped amoxicillin fabricated in this work are very well suited for applications in wound healing and infection control.     

PVA-PEG physically cross-linked hydrogel film as a wound dressing: experimental design and optimization

The development of hydrogel films as wound healing dressings is of a great interest owing to their biological tissue-like nature. Polyvinyl alcohol/polyethylene glycol (PVA/PEG) hydrogels loaded with asiaticoside, a standardized rich fraction of Centella asiatica, were successfully developed using the freeze–thaw method. Response surface methodology with Box–Behnken experimental design was employed to optimize the hydrogels. The hydrogels were characterized and optimized by gel fraction, swelling behavior, water vapor transmission rate and mechanical strength. The formulation with 8% PVA, 5% PEG 400 and five consecutive freeze–thaw cycles was selected as the optimized formulation and was further characterized by its drug release, rheological study, morphology, cytotoxicity and microbial studies. The optimized formulation showed more than 90% drug release at 12?hours. The rheological properties exhibited that the formulation has viscoelastic behavior and remains stable upon storage. Cell culture studies confirmed the biocompatible nature of the optimized hydrogel formulation. In the microbial limit tests, the optimized hydrogel showed no microbial growth. The developed optimized PVA/PEG hydrogel using freeze–thaw method was swellable, elastic, safe, and it can be considered as a promising new wound dressing formulation.     

壳聚糖-左氧氟沙星长效缓释敷料的体外细胞毒性和抗菌效果研究

【摘要】目的 研究壳聚糖-左氧氟沙星长效缓释敷料的体外细胞毒性、抗菌效果以及肿瘤坏死因子（TNF）-α作为评价抗菌效果指标的可行性。方法 参照ISO 10993-5:2009评价该敷料的细胞毒性;制作染菌创伤白兔模型15只并分为3组,空白对照组用凡士林油纱包扎,阳性对照组用纳米银创伤贴包扎,实验样品组用壳聚糖-左氧氟沙星长效缓释敷料包扎,于6 h、1 d、4 d、7 d,采用活组织培养法检测3组的菌落数,用双抗体夹心法检测TNF-α含量,与菌落数实验结果进行比较。结果 该敷料体外细胞毒性反应为0级;实验样品组4个时点的菌落数均低于空白对照组,在6 h、1 d、4 d时,实验样品组均低于阳性对照组（P < 0.05）;实验样品组的TNF-α含量在6 h、1 d、4 d、7 d时低于空白对照组,在6 h、1 d时显著低于阳性对照组（P < 0.05）。结论 壳聚糖-左氧氟沙星长效缓释敷料无细胞毒性,具有长效抗菌能力,TNF-α不能作为评价抗菌效果的指标。     

An innovative bi-layered wound dressing made of silk and gelatin for accelerated wound healing

In this study, the novel silk fibroin-based bi-layered wound dressing was developed. Wax-coated silk fibroin woven fabric was introduced as a non-adhesive layer while the sponge made of sericin and glutaraldehyde-crosslinked silk fibroin/gelatin was fabricated as a bioactive layer. Wax-coated silk fibroin fabrics showed improved mechanical properties compared with the non-coated fabrics, but less adhesive than the commercial wound dressing mesh. This confirmed by results of peel test on both the partial- and full-thickness wounds. The sericin-silk fibroin/gelatin spongy bioactive layers showed homogeneous porous structure and controllable biodegradation depending on the degree of crosslinking. The bi-layered wound dressings supported the attachment and proliferation of L929 mouse fibroblasts, particularly for the silk fibroin/gelatin ratio of 20/80 and 0.02% GA crosslinked. Furthermore, we proved that the bi-layered wound dressings promoted wound healing in full-thickness wounds, comparing with the clinically used wound dressing. The wounds treated with the bi-layered wound dressings showed the greater extent of wound size reduction, epithelialization, and collagen formation. The superior properties of the silk fibroin-based bi-layered wound dressings compared with those of the clinically used wound dressings were less adhesive and had improved biological functions to promote cell activities and wound healing. This novel bi-layered wound dressing should be a good candidate for the healing of full-thickness wounds.     

Development and characterization of transdermal drug delivery systems for diltiazem hydrochloride

Transdermal drug delivery system of diltiazem hydrochloride was developed to obtain a prolonged controlled drug delivery. Both the matrix diffusion controlled (MDC) and membrane permeation controlled (MPC) systems were developed. The matrix diffusion controlled systems used various combinations of hydrophilic and lipophillic polymers, whereas membrane permeation controlled systems were developed using the natural polymer chitosan. The MDC systems were prepared using the cast film method and the MPC systems by an adhesive sealing technique. Both the systems were characterized for in vitro and in vivo performance. The MDC systems were characterized for physicochemical properties such as tensile strength, moisture content, and water vapor transmission. The in vitro release studies showed that the release from the matrix diffusion controlled transdermal drug delivery systems follows a nonfickian pattern and that from the membrane permeation controlled transdermal drug delivery systems follow zero-order kinetics. The release from the matrix systems increased on increasing the hydrophilic polymer concentration, but the release from the membrane systems decrease on cross-linking of the rate controlling membrane and also on addition of citric acid to the chitosan drug reservoir gel. The in vivo studies of the selected systems showed that both systems are capable of achieving the effective plasma concentration for a prolonged period of time. The MPC system achieved effective plasma concentration a little more slowly than the MDC system, but it exhibited a more steady state plasma level for 24 hr.     

Controlled Release of Chitosan and Sericin from the Microspheres-Embedded Wound Dressing for the Prolonged Anti-microbial and Wound Healing Efficacy

One approach in wound dressing development is to incorporate active molecules or drugs in the dressing. In order to reduce the frequency of dressing changes as well as to prolong wound healing efficacy, wound dressings that can sustain the release of the active molecules should be developed. In our previous work, we developed chitosan/sericin (CH/SS) microspheres that released sericin in a controlled rate. However, the difficulty of applying the microspheres that easily diffuse and quickly degrade onto the wound was its limitations. In this study, we aimed to develop wound dressing materials which are easier to apply and to provide extended release of sericin. Different amounts of CH/SS microspheres were embedded into various compositions of polyvinyl alcohol/gelatin (PVA/G) scaffolds and fabricated using freeze-drying and glutaraldehyde crosslinking techniques. The obtained CH/SS microspheres-embedded scaffolds with appropriate design and formulation were introduced as a wound dressing material. Sericin was released from the microspheres and the scaffolds in a sustained manner. Furthermore, an optimized formation of the microspheres-embedded scaffolds (2PVA2G+2CHSS) was shown to possess an effective antimicrobial activity against both gram-positive and gram-negative bacteria. These microspheres-embedded scaffolds were not toxic to L929 mouse fibroblast cells, and they did not irritate the tissue when applied to the wound. Finally, probably by the sustained release of sericin, these microspheres-embedded scaffolds could promote wound healing as well as or slightly better than a clinically used wound dressing (Allevyn®) in a mouse model. The antimicrobial CH/SS microspheres-embedded PVA/G scaffolds with sustained release of sericin would appear to be a promising candidate for wound dressing application.     

Pectin‐based microspheres for colon‐specific delivery of vancomycin

Objectives The aim of this study was to describe a colon‐specific delivery system based on pectin hydrogels formed by complexation with chitosan. Methods Hydrogels were prepared at different weight ratios (4: 1, 7: 1, 10: 1; pectin/chitosan), loaded with vancomycin hydrochloride (2: 1, 4: 1; polymer/drug weight ratio) and collected by spray‐drying. The microspheres obtained were characterized in terms of morphology, swelling behaviour, mucoadhesive properties and drug loading efficiency. The influence of different pectin/chitosan hydrogels on the release behaviour of microspheres at pH 2.0, 5.5 and 7.4 were evaluated in vitro with and without pectinolytic enzyme. Key findings The results showed that water uptake was increased by raising the environmental pH (from 2.0 to 7.4) and the pectin/chitosan weight ratio, while drug availability was increased by raising the environmental pH (from 2.0 to 7.4) and decreased by raising the pectin/chitosan weight ratio. In the presence of pectinase, the glycoside bonds of pectin were degraded and a considerable amount of drug was released in a short time. Conclusions This study suggested that pectin/chitosan microspheres were able to limit the release of vancomycin under acidic conditions and release it under simulated colonic conditions, confirming their potential for a colon‐specific drug delivery system.     

Hyaluronic acid and chitosan-based nanosystems: a new dressing generation for wound care

ABSTRACT

Introduction: The main goal in the management of chronic wounds is the development of multifunctional dressings able to promote a rapid recovery of skin structure and function, improving patient compliance.

Areas covered: This review discusses the use of nanosystems, based on hyaluronic acid and chitosan or their derivatives for the local treatment of chronic wounds. The bioactive properties of both polysaccharides will be described, as well as the results obtained in the last decade by the in vitro and in vivo evaluation of the wound healing properties of nanosystems based on such polymers.

Expert opinion: In the last decades, there has been a progressive change in the local treatments of chronic wounds: traditional inert dressings have been replaced by more effective bioactive ones, based on biopolymers taking part in wound healing and able to release the loaded active agents in a controlled way. With the advance of nanotechnologies, the scenario has further changed: nanosystems, characterized by a large area-to-volume ratio, show an improved interaction with the biological substrates, amplifying the activity of the constituent biopolymers. In the coming years, a deeper insight into wound healing mechanisms and the development of new techniques for nanosystem manufacturing will results in the design of new scaffolds with improved performance.