Review of Possible Applications of Nanofi brous Mats for Wound Dressings

Skin is an important part of the human body. Its function is to control the body’s homeostasis mechanism. If a skin injury occurs, it is of utmost importance to heal the skin as soon as possible. The currently available medical treatment system, however, has limited eﬀ ectiveness on the regeneration of the structure and function of the injured skin, potentially causing wound infections and dehydration. The corresponding impact on the healing process may in the worst case also be fatal. To overcome these problems in wound dressing materials, nanoﬁ brous mats are excellent candidates for wound treatment and management. Such wound dressings can be found in biomedical applications not only in drug delivery, but also as antibacterial and antimicrobial materials, and as materials for the regeneration and repair of tissue or organs. The large sur-face-area-to-volume ratio is one of the unique properties of nanoﬁ brous mats. This paper gives a brief overview of possible materials and applications of nanoﬁ brous mats for wound dressing.


Introduction
Th e normal time for the wound healing process is about 2-3 days to some months, depending on the depth of the wound and the chronic condition. Th e healing of chronic wounds can take from a few months to several years. Th e classic wound dressing oft en has a poor fi t; it is stiff and relatively hard, whereas wound dressings from nanofi brous mats are extremely thin and fl exible. Th is type of nanofi brous mats has a breathable and water-absorbing eff ect, and can perfectly adapt to the wound geometry due to its high fl exibility and soft surface wound dressing. Th e process of modern drug delivery faces challenges, e.g. low solubility, bioavailability or targeted delivery of drugs with limited duration. Electrospun nanofi brous mats can overcome these problems [1,2]. Th eir high surface-to-volume ratio enables improved interactions with the environment, making them promising for wound care, drug delivery and biotechnology applications. Nanofi bres can thus be used for biomedical applications such as tissue engineering, wound healing processes and targeted drug delivery systems [3][4][5][6][7][8][9]. According to the results of several research groups, nanofi brous mats have the ability to absorb large concentrations of wound exudates without causing infections, and release anti-microbial and anti-infl ammatory agents. Nanofi brous mats have been shown to be ideal candidates for modern and efficient wound treatment, and wound care. Being produced eff ectively and inexpensively in an electrospinning process, they off er a multi-promising strategy for modern wound treatment [10][11][12][13]. Nanofi bres can be electrospun from natural or synthetic polymers such as polysaccharides, collagen, keratin, silk, tubulin, actin, cellulose, polyacrylonitrile (PAN), poly(lactic acid) (PLA), poly(L-lactic acid) (PLLA), acrylonitrile butadiene styrene (ABS), poly(lactic-co-glycolic acid) (PLGA), polyurethane (PU), polyvinyl alcohol (PVA), polycaprolactone (PCL), polymethyl methacraylate (PMMA), chitosan, fi brin, poly(ethylene glycol) (PEG), gelatine, casein and alginate. Th ese and many other polymers are known in tissue engineering and are applicable in wound dressing [14-25].

Electrospinning techniques
Electrospinning is a technology which can be used to produce continuous ultrathin nanoscale fi bres or fibre mats composed of fi bres with the diameters in nanometre range [26][27][28][29][30][31]. Ultrathin fi bres can be produced easily using this technology from multitude of materials, e.g. polymers, polymer composites, inorganic [32] or inorganic/organic [33] materials, or even ceramics [34]. Th ese types of nanofi bres are especially useful in the applications which necessitate large surface areas, such as promotion of cell growth in biomedical applications, catalysers, novel fi lter materials, medical wound dressings etc. [35][36][37]. Electrospinning processes can be performed in two slightly diff erent ways, i.e. using needle-based or needleless electrospinning techniques ( Figure 1). Electrospinning with a needle is a simple process which depends on a high voltage power supply with adjustable control, a polymer solution reservoir (e.g. a syringe with a small diameter needle) with or without a control pump and a metal collecting screen. Th e spinnable polymeric solution is put into a reservoir with a metal needle or tip and connected to a power supply, enabling the formation of a charged polymer jet. Th e conductive collecting screen the nanofi bres are deposited on can either be a stationary plate or a rotating platform or substrate. Th e plate can be used to manufacture non-woven nanofi brous mats, while the rotating platform can be used to prepare both randomly oriented and aligned fi bres. With a vertical and a horizontal orientation, two standard electrospinning setups are available. Th ree essential operating parameters play a decisive   non-toxic features, and are both widely applicable in the medical sector [56][57][58][59]. Moreover, chitosan/ polyaniline composite nanofi brous mats have shown anti-bacterial properties and were found to be capable of accelerating wound healing processes [60]. PEO blended with alginate was used to prepare scaffolds by electrospinning to support human dermal fi broblast cell attachment. Nanofi bre scaff olds were found to promote tissue cell adhesion and enable encapsulation of drugs [61,62]. Chronic wound care products were improved using chitosan (PEO)/silica [73] and polyvinyl alcohol (PVA) blended with chitosan. Similarly, PVA/chitosan nanofi bres, as well as collagen/PEO wound dressings were shown to have high moisture vapour transmission characteristics, good antimicrobial function and no cytotoxic eff ects [64][65][66]. Generally, nanofi brous mats can serve as a base for therapeutic agents or can accelerate chronic wound healing processes [67,68]. A new generation of wound dressing can also be produced by electrospinning materials with high moisture absorption and anti-bacterial eff ects, including elements like zinc or copper alginate. Th ese types of wound dressings contain bioactive elements, such as antimicrobial, anti-bacterial and anti-infl ammatory agents, which can be released to wounds to improve their healing process [69]. Alternatively, it is even possible to electrospin fi bres including commensal bacteria for medical purposes [70]. PVA/BS nanofi bres have shown large potential for drug delivery, tissue engineering and tissue repair substitute properties in wound dressing [71]. PU/ chitosan has been examined as well, showing promising features for wound dressing applications similar to many other biopolymer blends, e.g. blends with starch or silk [72][73][74][75].
One of the most suffi cient biodegradable substances in nature is cellulose, which is widely applicable in the electrospun nanofi brous mats production [76][77][78]. It can be produced from certain bacterial species by fermentation. However, it is traditionally extracted from plants. Bacterial cellulose (BC) is extracted mainly from microorganisms belonging to the genera Gluconacetobacter. BC is widely used in biomedical applications, e.g. in drug delivery and tissue engineering [79]. It can be used to decrease pain and accelerate granulation, supporting a perfect wound healing process. It is also useful in the creation of a moist environment at the wound area and absorption of exudates. Furthermore, it can prevent microbial infections [80]. Bacterial cellulose-alginate nanocomposites were successfully produced by nanotechnology and they showed excellent antibacterial activity [81,82]. Th e synthesis of BC/chitosan or chitosan/gelatine composites with high mechanical reliability and antibacterial activity was investigated by diff erent research groups [83][84][85][86][87]. Similarly, chitosan blended with metallic nanoparticles has an eff ect on the microbial activity and wound healing [98]. Th e reductions of infl ammatory cells and mostly closed capillary lumens have been investigated by diverse research groups, using silver nanoparticles in diverse polymer matrices [89][90][91][92][93][94][95][96][97].
Another investigation showed strong antibacterial and anti-infl ammatory characteristics of silver nanoparticles [98]. Co-electrospinning of polyurethane and keratin which can be extracted, e.g. from human hair and fi xed with silver nanoparticles, results in PU/keratin/Ag composite mats of nanofi bres. Th ese nanofi brous mats showed very good cell viability and antibacterial properties, and were thus able to promote wound healing [99]. Similarly, PU or nylon nanofi bres with silver nanoparticles showed excellent antimicrobial properties [100]. Polyurethane-cellulose acetate-zein composite nanofi brous mats were found suitable for drug delivery and to have good antibacterial bio-active wound recovery characteristics [101]. Polylactic acid (PLA) nanofi bres with Fe 3 O 4 -COOH have strong antibacterial and drug delivery activities for wound dressings and other biomedical applications [102]. PLA/CNC/PEG composite nanofibres showed therapeutic drug release properties and allowed for controlling long-time drug delivery in wound dressings [103]. Spirulina extract-alginate PCL and PCL-gelatine nanofi bres were also found to show excellent wound care properties, especially for tissue regeneration [104][105][106].
Collagen is a widely used natural polymer substance for biomedical applications [107,108]. It has gained broad clinical and consumer adoption as a secure material. To architecturally imitate the skin structure, nonwoven nanofi brous mats from collagen can be applied in wound healing processes which are typically produced by electrospinning. As a major fibrous protein in the extracellular matrix (ECM), collagen plays an important role in maintaining the biological and structural integrity of ECM [109,110].

Review of Possible Applications of Nanofi brous Mats for Wound Dressings
For the cell attachment, proliferation and diff erentiation, nonwoven collagen nanofi brous mats are of utmost importance. Moreover, these collagen nanofibrous mats are designed to induce platelet adhesion and aggregation to increase the congealing, which is favourable in wound dressing applications for the improvement of cell adhesion and proliferation [111]. Carboxymethylcellulose (CMC)/dextran hydrogels were activated with a gallium bio-glass and can be applied to reduce cancer cell viability particularly for high Ga contents in the bio-glass. CMC hydro gels cross-linked with oxidized dextran or alginate/ CMC were found to signifi cantly support the wound healing and skin regeneration [112].

Conclusion
A remarkable improvement has been gained in the development of therapeutic approaches to be used in the treatment of chronic wounds. Among the developed types of wound dressings, electrospun nanofi bres are taken into consideration as one of the most eff ective wound dressing materials for the near future. Th ey show a high surface area to volume ratio as well as a porous structure that improves homeostasis, prevents infections, absorbs exudates, enables gas permeability and cell adhesion, migration, proliferation and properly targeted drug delivery. Several functionalization methods can be used to improve the surface properties of nanofi bres or to produce nanofi bres for carrier-based drug delivery, e.g. with blending electrospinnable polymers with diverse nanoparticles. Combining the intrinsic properties of diverse (bio)polymers with additional functions added in this way, electrospun nanofibrous mats belong to the most promising candidates for improved wound management.