severe skin damage and loss of the protective layer exposes underlying tissue to secondary infections [ 1 , 2 ] .   in the united states , treatment of fire and burn wound infections amount to more than 7.5 billion us dollars per annum .   from one million patients , an estimated 10 000 die from secondary microbial infections [ 2 , 49 ] .   if wounds are not treated effectively , pathogens form biofilms , rendering them resistant to antibiotics [ 1013 ] .   in severe cases , staphylococcus aureus , including methicillin resistant strains ( mrsa ) , are the most prevalent in skin infections .   pseudomonas aeruginosa , escherichia coli , acinetobacter spp . , and coagulase - negative staphylococci have also been isolated from skin lesions [ 1519 ] . more than 95% of s. aureus strains are resistant to penicillin and 6070% are resistant to methicillin [ 2022 ] . methicillin resistance is attributed to the mec a gene encoding penicillin binding proteins [ 20 , 23 ] . these proteins occur in the cell wall and play a role in the synthesis of peptidoglycan and are usually inactivated by beta - lactam antibiotics .   however , in mrsa the mec a gene encodes a low - antibiotic affinity penicillin binding protein , known as pbp2a , conferring methicillin resistance to the cells . some mrsa strains are also resistant to tetracyclines , sulphonamides , trimethoprim , macrolides , aminoglycosides , mupirocin , mafenide acetate , silver sulphadiazine , bacitracin , ciprofloxacin , and vancomycin [ 2429 ] .   vancomycin - resistant enterococci and p. aeruginosa strains resistant to several antibiotics have also been reported . this review focuses on the treatment of skin infections and open wounds and the biomedical application of electrospun nanofibers , with specific emphasis on antimicrobial delivery systems . silver sulfadiazine , a combination of silver nitrate and sodium sulfadiazine , has been used to treat invasive burn wound sepsis [ 6 , 14 , 32 , 33 ] .   with prolonged use , silver ions may be toxic , as it binds to dna and prevents replication [ 34 , 35 ] . mafenide acetate and chlorexidine digluconate creams have been used to treat burn wound infections [ 14 , 39 ] . the disadvantage of these topical creams is that they have to be applied twice daily . if incorporated in wound dressings , the bandages have to be changed daily , which may expose the wound to further infection .   as in the case of many other antimicrobials , pathogens with resistance to mafenide acetate nanotechnology offers the latest alternatives to wound dressings , of which acticoat a.b , silverlon , and silvasorb with nanoparticles are good examples . supporters of this technology claim that the nanocrystalline silver particles are released in a controlled manner , inhibiting the growth of a broad spectrum of pathogens [ 4345 ] . entrance of the nanoparticles into cells and their mode of action is summarized in figure 1 . endosomes , filled with silver nanoparticles , lysosomes , and silver nanoparticles in the nucleus of treated cells , have been observed . some concerns exist regarding the medical use of silver particles , as they form reactive oxygen species ( ros ) , reduce atp , and damage mitochondria and dna [ 31 , 46 ] . silver nanoparticles are , however , less toxic compared to gold nanoparticles , as observed in experiments with j774 a1 murine macrophages . nanofibers are produced from polymers treated in a specific manner to form threads of a few micrometers to nanometers in diameter . the large surface to volume ratio , and manipulation of surface properties , renders nanofibers the ideal matrix to develop super fine structures [ 4951 ] . the possibility to immobilize antibiotics , enzymes , antimicrobial peptides , and growth hormones to nanofibers , or encapsulation into fiber matrixes , opens a new field in biomedical engineering [ 5260 ] . several methods are used to produce ultra fine fibers , for example , self assembly of polymers , template synthesis , phase separation , and electrospinning [ 49 , 6266 ] . electrospinning , schematically presented in figure 2 , is the most cost effective and easiest way to produce large volumes of nanofibers . one electrode is placed in a polymer solution and the other electrode is linked to a collector , which is usually a stationary or rotating metal screen , plate , or wheel . the electrically charged polymer forms a taylor cone at the tip of the needle and is ejected at a specific charge .   as the polymer solution accelerates , the solvent evaporates and nanofibers are formed . fibers are aligned by using a rotating collector , an auxiliary electrical field , or a rotating collector with a sharp edge and a rapidly oscillating frame [ 6771 ] . coaxial electrospinning ( figure 3(a ) ) is used to produce nanofibers with a core - shell structure ( figure 4(a ) ) , which is ideal for encapsulating hydrophilic molecules . emulsion electrospinning is also used to produce core - shell - structured nanofibers ( figures 3(b ) and 4(b ) ) . an emulsion is prepared by emulsifying an aqueous phase , which contains a hydrophilic polymer or molecule to be encapsulated , into an organic phase containing a polymer that forms the shell [ 42 , 61 ] . the emulsion is then electrospun into core - shell - structured nanofibers ( figure 4(b ) ) . the quality and characteristics of the final product are determined by the temperature , viscosity , elasticity , conductivity , and surface tension of the solution , strength of the electric field , distance between the needle tip and collector , and humidity [ 49 , 73 , 74 ] .   larger fibers ( bigger diameter ) polyvinylpyrrolidone ( pvp ) at 4% ( w / w ) in a 50  :  50 ( w / w ) dimethylformamide  :  ethanol solution is used to produces fibers of 20  nm in diameter .   however , pvp at 8% ( w / w ) in the same solution produces fibers of 50  nm in diameter , and pvp at 10% ( w / w ) produce fibers of 300  nm in diameter . electrospinning different concentrations of poly l - lactic acid ( plla ) in a chloroform solution produce nanofibers with different morphologies ( figure 5 ) . plla of 1% ( w / w ) produces a  bead on a string  structure whereas 3% ( w / w ) plla forms nanofibers with a smooth structure . solvents influence the surface tension and viscosity of the solution and affect the morphology of fibers [ 75 , 76 ] . pvp ( 4% , w / w ) dissolved in dichloromethane ( mc ) forms fibers with spindle - like beads and hollow or solid structures whereas the same concentration pvp in n , n - dimethylformamide ( dmf ) forms sphere - like beads with solid structures . pvp dissolved in ethanol yields smooth fibers with a diameter ranging from 100 to 625  nm . the pvp / dmf and pvp / mc solutions have a high surface tension ( 47.1 and 38.7 centipoise , resp . ) and low viscosity ( 9.8 and 13.0 centipoise , resp . ) . a pvp / ethanol solution , on the other hand , has a low surface tension ( 29.3 centipoise ) and high viscosity ( 17.3 centipoise ) . changes in current may also affect the morphology of fibers , as observed with polyethylene oxide ( peo ) . an increase from 5.5  kv to 9.0  kv changed the morphology of the peo fibers from smooth to a the importance of processing variables that influence fiber morphology during electrospinning is reviewed by deitzel et al . . natural and synthetic polymers have been spun into nanofibers for potential use in biomedical engineering [ 53 , 54 , 61 , 7679 ] . chitin , a structural polysaccharide from arthropods , yielded fibers ranging from 40 to 600  nm in diameter . a combination of water - soluble carboxyethyl chitosan and poly - vinyl alcohol ( pva ) was electrospun to produce a wound dressing . the nanofibers revealed no toxicity when tested with a mouse fibroblast l929 cell line , and promoted cell attachment and proliferation . chitosan acetate bandages proved effective as an antimicrobial dressing when tested on balb / c mice with burn wounds that have been infected with p. aeruginosa and proteus mirabilis . backbone  and degrades over a long period whereas the more hydrophilic polymer degrades or dissolves faster . the choice of polymer or polymer blends play an important role in devices aimed at controlled release . examples of using hydrophilic and/or hydrophobic polymers for the controlled release of molecules , for example , antibiotics , plasmids , growth factors , proteins , silver particles , bacteria and viruses will be discussed in more detail [ 54 , 61 , 82 , 83 , 89 , 93 ] . rifampin , encapsulated in plla during electrospinning , and incubated in a 0.05  m tris - hcl buffer , was only released when proteinase k was added to the solution . this suggests that the release of rifampin was initiated by the degradation of plla and not by normal diffusion .   in another experiment , doxorubicin hydrochloride and paclitaxil doxorubicin hydrochloride was detected on the surface of the nanofibers but paclitaxil remained encapsulated . rifampin and paclitaxil were more soluble in the chloroform / acetone solvent compared to doxorubicin hydrochloride . the solubility of the molecule to be encapsulated in the polymer solvent plays an important role in its distribution throughout the nanofibers . tetracycline hydrochloride ( 5% , w / w ) encapsulated in poly - ethylene - co - vinyl acetate ( peva ) , or in a blend of peva and plla , has a relatively slow and consistent release rate . the peva and peva / plla blend containing 5% ( w / w ) tetracycline hydrochloride had a similar release rate to actisite , a commercial drug delivery system , following the initial high burst release . the antibiotic mefoxin ( cefoxitin sodium ) was encapsulated in poly - lactate - co - glycolide ( plga ) fibers and in fibers consisting of a poly - lactate - co - glycolide / polyethylene glycol - block - poly(l - lactide ) copolymer ( plga / peg - b - plla ) . mefoxin released from the fibers inhibited the growth of s. aureus in culture and on an agar surface . the feasibility of encapsulating plasmid dna in electrospun nanofibers and to use these nanofibers as gene delivery vehicles has also been shown . plga and a pla - peg block copolymer was electrospun with a 7164  bp plasmid ( pcmv ) , encoding -galactosidase . the bioactivity of pcmv was evaluated by conducting transfection experiments with preosteoblastic mc3t3 cells . the -galactosidase gene was successfully expressed by preosteoblastic mc3t3 cells that have taken up the plasmid . human -nerve growth factor ( ngf ) was encapsulated into fibers consisting of a copolymer of poly -caprolactone and ethyl ethylene phosphate ( pcleep ) through electrospinning . the bioactivity of ngf was evaluated by incubating rat pheochromocytoma ( pc 12 ) cells in the supernatant of nanofibers containing encapsulated ngf and searching for differentiation into neurons . human glialcell - derived neurotrophic factor ( gdnf ) , encapsulated into pcleep nanofibers , was released in active form for up to two months . a 15  mm nerve lesion was made in the left sciatic nerve of 3.5 month - old sprague  dawley rats . aligned fibers with no gdnf encapsulated within served as controls .   in rats that received encapsulated gdnf , a bridge formed across the lesion and the nerve was regenerated after three months .   however , the nerve system in only half the number of rats that received control fibers was regenerated . the stimulation of bone regeneration in nude mice that have been treated with bone morphogenetic protein-2 ( bmp-2 ) encapsulated in plga - hydroxyapatite ( hap ) nanofibers was also shown in . the highest release of lysozyme ( 87% over 12 days ) was recorded in a peo / pcl nanofiber with a 90/10 ratio . this was done by emulsifying an aqueous solution of cytochrome c in a chloroform solution containing plla . controlled release was obtained when plla was blended with poly(l - lysine ) ( pll ) and poly(ethylene imine ) ( pei ) , hydrophilic polymers .   a blend containing 50% pll released most of the protein ( 75% ) with a high initial burst release . escherichia coli ,   staphylococcus albus , and bacteriophages t7 , t4 , and  were encapsulated in pva nanofibers with water as solvent . the encapsulated cells and bacteriophages survived the electrospinning process and remained viable for three months at 20 and 55c . the fibers were dissolved in a tris - buffered saline solution ( ph 7.5 ) . micrococcus luteus and e. coli were encapsulated into peo nanofibers with water as solvent . up to 74% of the m. luteus cells , but only 0.1% of the e. coli cells , survived the electrospinning process . we recently reported on the encapsulation of a probiotic lactic acid bacterium in electrospun peo nanofibers . however , the cells that survived were still able to produce the antimicrobial peptide ( bacteriocin ) and inhibited the growth of e. faecium hklhs that served as target strain . silver nanoparticles were incorporated in cellulose acetate nanofibers by electrospinning cellulose acetate with 0.5  wt% agno3   . silver particles were generated on the surface of the nanofibers after irradiation at 245  nm . almost all viable cells ( 99.9% ) of gram - positive bacteria , e. coli ,   klebsiella pneumoniae , and p. aeruginosa were killed after 18 hours of exposure to the encapsulated silver particles . growth inhibition of up to 99.27% of s. aureus and up to 98.44% of e. coli was recorded when the strains were cultured in the presence of these nanofibers . human dermal fibroblasts that attached to the nanofibers continued to proliferate , suggesting that the fibers may be used as wound dressings . however , some authors have reported that silver may elicit toxic side effects on human cells as discussed elsewhere in this paper . table 1 summarizes various molecules that have been encapsulated into synthetic and natural polymers , or blends thereof , by electrospinning to facilitate their release . lactic acid bacteria ( lab ) are a diverse group of organisms with gras ( generally regarded as safe ) status and have been consumed over decades . most species produce bacteriocins , that is , ribosomally synthesized proteins or protein complexes with bacteriostatic or bactericidal activity against closely related species [ 97 , 98 ] . the peptides have a net positive charge ( cationic ) and are amphiphilic or rather more hydrophobic . they intercalate into the cell membrane of sensitive cells , form pores and disrupt the proton motive force ( pmf ) [ 99101 ] . class i contains the lantibiotics that are small peptides that undergo posttranslational modifications and have lanthionine or -methyllanthionine residues , for example , nisin , merscadin [ 102 , 103 ] . class ii contains the nonlanthionine - containing bacteriocins that are small ( < 10  kda ) heat - stable peptides that do not undergo extensive post - translational modifications . examples include pediocin pa-1/ach , plantaricin s , enterocin as-48 , and lactococcin a [ 104107 ] . some bacteriocins , such as mersacidin , have shown activity towards mrsa that have been associated with various hospital acquired infections . nisin f was also investigated as treatment for subcutaneous skin infections caused by s. aureus . bacteriocins are thus attractive natural alternatives to antibiotics , which can be used in the treatment of bacterial infections . a localized delivery system is , however , required to control the level and rate of bacteriocins delivered to the wound .   a novel approach would be to encapsulate bacteriocins into electrospun nanofibers and use this as wound dressings for burned victims . the bacteriocin plantaricin 423 retained activity after electrospinning and inhibited the growth of e. faecium hklhs and lactobacillus sakei dsm 20017 that served as target strains . nisin , a bacteriocin produced by lactococcus lactis , was successfully loaded in plla nanoparticles by using semicontinuous compressed co2 antisolvent precipitation . nisin was released in the active form and exerted its antibacterial activity up to 45 days , when incubated with a culture of lactobacillus delbrueckeii . electrospinning is a versatile and relatively easy technique to produce large amounts of nanofibers with diverse molecules encapsulated within . the large surface to volume ratio of nanofibers allows the encapsulation of high concentrations of bacteriocins and direct delivery to sites of skin infection .   the use of bacteriocins to control infections may help to prevent further increase in antibiotic resistance amongst bacteria and may prevent negative side effects some current medication has on patients . release of bacteriocins from nanofibers can be controlled by selecting polymers of specific composition . furthermore , specific nanofiber scaffolds can be designed that are oxygen permeable and structurally similar to the extracellular matrix ( em ) in skin . ideally , nanofiber wound dressings should not only contain antimicrobial agents , but a combination of compounds that would accelerate the healing process and alleviate discomfort . although anti - inflammatory drugs have been encapsulated into nanofibers , no reports have been published on the encapsulation of combined compounds . future research has to focus on developing nanofber wound dressings containing a combination of antimicrobial compounds , anti - inflammatory drugs , and painkillers . furthermore , the nanofiber scaffold has to be designed to allow controlled released of the drugs over an extended period to avoid frequent changes of wound dressings . the toxicity of nanofibers needs to be researched , that is , much more in vivo studies need to be performed .