Skin is typically composed of a heterogeneous membrane but the outermost layer, the stratum corneum with thicknesses of about 20 and 25 µm, plays a major role in absorption and act as a barrier for foreign materials .
Nevertheless, skin appendages such as hair follicle could be used as alternative routes for the entrance of drugs across skin due to the presence of blood vessels and dendritic cells surrounding hair follicle . Cosmetics and skin medications use permeability property to enter into the circulatory system. Therefore, this area has great attention for drug delivery and provides the desired media for absorption of medications and entrance into the vascular system .
Conventional transdermal drug delivery systems (TDDS) and transdermal patches, release the medications in this manner. The patch is designed to deliver therapeutic agent across the skin and can be considered as the desired alternative to oral drug delivery . Drug controlled release from TDDS with reduction of the dose fluctuations in the body can lead to the improvement of efficacy of medications, stabilization of drug diffusion profile and greater bioavailability . Besides, this method can have patients consent because of the non-invasive nature and the ease  but it should be considered that a few number of medications could effectively penetrate into the depth of the skin since the skin only allows to hydrophobic elements (several hundred Dalton) with low concentration (Millionths of grams per day) to influx, so entrance of large hydrophilic drugs through the skin is an unresolved issue yet [4, 5].
A wide range of polymers is used in transdermal drug diffusion vehicles as gelatinization factors in gel systems and stabilizer in emulsions and creams . They could form patches matrix and wound dressings  and act as skin adhesives in transdermal systems and provide enhanced permeability for the improvement of treatment efficiency .
Application of polymeric micro and nanofibers in biomedicine has recently attracted great attentions. Nanofibers are prepared in different methods such as Phase separation, Template synthesis, Self-assembly and Electrospinning. Among them, electrospinning technique is preferred for fabrication of polymer micro and nanofibers due to simplicity and cost [9, 10].
Nanofiber mats produced by this technique have considerable properties, including high surface area, nanoscale pores, unique physical and mechanical properties beside surface capability for physical and chemical activation[11-13].
The other advantages can be pointed to simple usage, inexpensive cost, adjustability, and industrialization possibility . Due to these properties, electrospun nanofibers have good potential for biomedical applications, such as drug delivery, gene delivery, adhesion prevention after surgery, receptors, wound dressing and tissue engineering[4,14]. Drug release from electrospun nanofibers in comparison with polymeric films prepared with other methods makes them as proper tools for drug delivery purposes. These differences in drug release are because of their porous structures with a lot of nanofibers which provides appropriate drug molecules release from the polymer matrix . Furthermore, topical drug distribution through electrospun nanofibers dramatically reduces systemic absorption of the drug, resulting in the reduction in consumed dosage .
Pharmaceutical ingredients which are commonly delivered using electrospun scaffolds include antibiotics, antitumor drugs, Anti-inflammatory drugs, proteins and nucleic acids .
However, most studies have been focused on implantable scaffolds or wound dressing, whereas transdermal patch for application in the the healthy skin has attracted less attention in researchers. But these few studies are very impressive and promising for the practical applications in future .
Generally, active pharmaceutical agents delivered by polymeric nanofibers have been reported in papers in two categories.
First, nanofibers preparation and charac- terization with loaded medications, and second investigation of therapeutic applications in outer surfaces of the human body such as transdermal drug delivery and wound dressing [4, 16]. This paper reviews the electrospun polymeric scaffolds to apply in healthy skins TDDS.
Nanofiber fabrication via electrospinning
Nanofibers production using electrostatic force process has been known as electrospinning which is a simple method to make fibers from some microns to few ten nanometers . Various polymers including synthetics, natural, and synthetic-natural combination can are electrospun (Table 1) .
Properties such as high surface to volume ratio, flexible surface functional groups, adjustable surface properties and excellent mechanical performan- ceintroducenanofibers as an appropriate option for different applications .
Basic electrospinning systems are composed of three main components: a high voltage power source, a pipette like a spinneret, and plate or cylinder rotating (collector) covered with aluminum foil. Pumping polymer solution and the appearance of a drop at the tip of the syringe to lead Taylor cone when the electrostatic force is enough to overcome the surface tension of the solution.
The potential difference between the needle and the collector creates a thin jet from polymer solution to collector plate . The solvent evaporation and cooling the molten polymer create a nonwoven fibrous mat on the collector surface . Fig. 1 schematically illustrates the components of an electrospinning set.
Nowadays, electrospun nanofibers loaded with drug are used in the treatment of various diseases. Electrospun membranes are applied to local drug delivery systems or implants, cancer treatment, DNA and or siRNA distribution, and growth factor delivery .
Here, we have an overview of drug incorporation methods into electrospun nanofibers for the transdermal drug delivery systems for healthy skin, and drugs which have been studied for this purpose.
Drug loading procedures in Electrospun nanofibers
In order to construct the electrospun micro and nanofibers using in drug delivery, a variety of methods have been used. They can be divided into several categories :
In this mode, the drug is dissolved or dispersed in a polymer solution to be encapsulated by fibers. This method is simpler than the other techniques, but to achieve desired results needs some supplies. For example, drug release profile is strongly affected by the distribution of drug molecules and morphology of nanofibers. In addition, it is also important for drug and polymer to be hydrophilic and or hydrophobic. For this reason, in order to achieve an anoptimal mode of drug encapsulation in the fiber, lipophilic drugs such as Rifampicin and Paclitaxel should be electrospun with hydrophobic polymers, and hydrophilic drugs such as Doxorubicin Hydrochloride, electrospinning process should be done in blend with hydrophilic polymers .
Core-shell electrospinning (Coaxial)
This method is a modified technique for the production of Core-Shell electrospun fibers. The solution containing a drug or biological molecule formed by the inner jet and Polymer solution would be Electrospun from the outer jet which is concentric with inner jet simultaneously [7,37,38].
Shell polymer not only causes a slow and delayed release of the drug but also plays a vital role in the protection of the drug from the surrounding environment . This technique is used in Transdermal drug delivery (e.g. Antibiotics) and Tissue Engineering [38-40].
In this technique, a hydrophilic drug with polymer solution (As the oil phase) makes an emulsion. After electrospinning process, a drug with low molecular weight is distributed into nanofibers prevent their accumulation on the nanofibers surface .
If macromolecules with high weights are applied, fibers are shaped into the core-shell structure and the drug placed in the the aqueous phase of thecore[42,43]. However, there is a risk of damage or destruction in some macromolecules such as DNA, which can be due to shear or tension force between the aqueous phase and the organic emulsion. This problem resolves with modifications such as DNA condensing [42, 43].
Another form for loading a drug in electrospun nanofibers is their chemical or physical surface modification. In this technique, drug agent is immobilized chemically on the nanofibers surface, resulting in drug release reduction and its stability on Electrospun nanofibers surface due to strong bonding. This method is appropriate for delivery of genes, growth factors, and enzymes.
Other drug delivery approaches via electrospinning
One of the recent advances in effective drug delivery systems is complex treatment, such as multidrug delivery with the same or different therapeutic effects. The most important factor in multidrug distribution systems is the autonomous drug controlled release, which is effective in the prevention of multidrug resistance, cancer and or other complex diseases. It is not a simple process for researchers to access the independently controlled release of drugs in a carrier, and it is obtained with drug release profile pre-regulation in all pharmaceutical compounds. It can be an approach to electrospun polymer solutions containing drug consecutively for this type of drug delivery. Fiber size and layer thickness are effective variables in rate and release time can be controlled this way .
Nanoparticles containing various drugs could be electrospun with the desired polymer solution. For example, Wang and coworkers dissolved chitosan nanoparticles containingNaproxen, (a nonsteroidal anti-inflammatory drug; NSAID) and Rhodamin B (a chemical dye) in polycaprolactone (PCL) solution and they produced a chain of nanoparticles in nanofibers core with electrospinning technique [44, 45]. In a similar study with Xu research team, it was observed as the same result.
Furthermore, multilayer coated nanofibers are the other construction method of electrospun nanofibrous drug delivery systems [47, 48]. Using hydrogel polymers, such as polyvinyl alcohol (PVA) and cellulose acetate can be produced electrospun nanofibers containing vitamins, Anti-inflammatory agents and antioxidants . PVA nanofibers in comparison with PVA film show protuberances reduced weight and an increase in the amount of drug release. Transdermal distribution experiment on pigs skin showed that molecular weight of the pharmaceutical agents plays a much better role than the properties of water absorption in drug release .A drug delivery system model is composed of a formulation and or a mechanism, which improves efficacy and safety of drug concurrent with the drug release into the body. This system supports transmission and storage of the appropriate amount of drug in a determined period. In addition, it is expected that drug delivery system prevents the destruction of non-released drugs from fibers. During recent decades, drug delivery systems based on micro and nano polymeric structures have attracted great attention. Drug delivery using polymeric micro and nanostructures is based on the principle that increasing levels of drug carrier surface leads Tomo redissolution rate .
The shape, size, morphology and combination of micro and nanostructures can be changed by variable parameters of electrospinning and material choice, resulting in optimization of drug release profile.
Drug Release from ElectrospunNanofibers
A wide range of polymers has been used to fabricate Electrospun scaffolds. Natural polymers are collagen, chitosan, gelatin, hyaluronic acid, and famous synthetic polymers like polylactic acid (PLA), polycaprolactone (PCL), polyethylene oxide (PEO) and other similar copolymers[3,50].
For Drug delivery purposes using electrospun nanofibers, it is more demanded to use biodegradable polymers.
This category of a polymer containing drugs releases their cargo with one of two methods which are erosion and diffusion (Fig. 3).
However, in relation to the speed ratio of each of two methods, drug release from these polymers can be controlled by a combination of both of them in vivo. Most of the biodegradable polymers in drug delivery are degradable by hydrolysis process and some polymers are mediated by enzymatic catalytic activity. It should be noted that drug release occurs simultaneously with the degradation of biodegradable polymers and this may cause the toxicity resulting from a sudden increase in drug concentration into the body.
Thus, in the selection of materials for drug delivery and polymer fibers, the drug release rate and degradation rate of the polymer both should be optimized simultaneously. Both hydrophilic drugs (such as tetracycline hydrochloride and doxorubicin hydrochloride) and hydrophobic ones (such as Rifampin and Paclitaxel), and biomacromolecules (such as proteins and DNAs) can be encapsulated in electrospun nanofibers. For drug delivery using electrospun nanofibers .
The pharmaceutical agent should be taken on the patch in amorphous or non-ionic form to optimize drug into the skin. The restrictions on drug release reduce due to high surface to volume ratio and three-dimensional porous structure of nanofibers .
On the other hand, localized drug delivery via electrospun nanofibers can lead to a reduction of the minimum required dose of a drug which provides decreased systemic absorption and unwanted side effects of drugs.In comparison with other forms of drug carriers such as liposomes, hydrogels, and micro-nano structures produced by common methods, electrospun nanofibers have superior efficiency in encapsulating drugs and decreasing burst effect in the body. Furthermore, electrospun dressings over films prepared by casting methods lead to facilitation of the distribution of drug molecules to the surrounding environment [36,53].
Fig. 3. Schematic drug release manners from electrospun nanofibers
Medications and or therapeutic agents loaded in electrospun nanofibers
As yet, transdermal patches have been used for the limited number of pharmaceutical agents’ delivery which are steroid hormones, nicotine, nitrogly- cerine, analgesics such as Fentanyl(Opioid Analgesic) and Buprenorphine(Opioid Anal- gesic)(Madhaiyan, Sridhar, Sundarrajan, & Ramakrishna, 2013).
Four major categories of drugs or biological agents with distinct pharmacological applications consist of antibiotics and antimicrobial agents, antioxidants and antitumors, Anti-inflammatory drugs and vitamins. In addition to proteins with medical applications (such as enzymes and hormones), material such as ions, metals, and oxides, and natural materials obtained from plants or animals have an effective therapeutic potential if loaded in the patches .
an overview of the pharmacological agents in the electrospinning of polymeric patches and their application particularly in transdermal patches is presented in this section.
Table 2 shows an overview of medications loaded on/into electrospun nanofibers with the applications of transdermal drug delivery.
Antibiotics and antimicrobial agents
Among electrospun nanofibers containing antibiotics, Amoxicillin, Chlorhexidine, Ciprofloxacin HC1, Ornidazole, and Tetracycline Hydrochloride can be pointed out. In a study, core-shell patches, cellulose acetate (CA) and polyvinylpyrrolidone (PVP) were prepared by electrospinning method to investigate controlled the release of loaded Amoxicillin into the nanofibers for application on the gastrointestinal tract and transdermal patches .
In another work, by treatment with organic Titanate in the presence of water vapor, Chlorhexidine on electrospun cellulose acetate nanofibers was immobilized. Then the antibacterial activity of surface (by the inhibition region) against E.coli and S.epidermis bacteria with a simple diffusion model was observed .
The other study, electrospun cellulose acetate nanofiberscontainingN-halamine, an antimicrobial agent by (N-choloro-2, 2, 6, 6-tetramethyl-4-piperidinyl) sebacate (CI-BTMP), showed desired antibacterial performance over the films prepared by casting solution method. Furthermore, composite fibers showed an excellent bioavailability in mammalian cells . Besides, Kenya yet al reported the release of 5% tetracycline hydrochloride from electrospun poly(ethylene-co-vinyl acetate) ¡poly(lactic acid) fibers and their blends .
most drugs, consumed in the world, are non-steroidal anti-inflammatory drugs (NSAIDs). This class of the drug is a desirable candidate for preliminary studies on controlled release processes .
In a study, four groups of these drugs including Naproxen, Indomethacin, Ibuprofen, and Sulindac (with different solubilities in water) were electrospun with CA and nanofibers with the diameter of 263-297 nm were produced. Drug release profile in CA nanofibers and CA film containing drugs was evaluated.
The result showed that no accumulation of drug crystals in nanofibers surface occurred, and appropriate encapsulation of drug molecules in fibers formed against the CA film with drug accumulation on its surface and the drug release in electrospun nanofibers was better than CA polymericfilm .
Vitamins in therapeutic applications
Vitamins are important elements for human health , but a limited number of investigations have been done on loaded vitamin in electrospun polymeric fibers. Among them, most studies have been on vitamin A and E , because vitamin A and E display various biological activities and protective functions .
In a study, these two vitamins immobilized on CA nanofibers with the diameter of 247–265 nm produced by electrospinning process.
Vitamin A was used in Trans retinoic acid or vitamin An acid (Retin-A) form that is a derivative of vitamin A or retinol, and vitamin E was used in a-tocopherol (Vit-E) form. A steady and gradual increase in the vitamin release from nanofibers was observed in this research, whereas a burst release from CA cast films was seen [60, 63, 64].
Other therapeutic agents loaded in electrospun nanofibers
There are some enzymes, hormones, nucleic acids and chemicals investigated for loading in electrospun nanofibers , but there has not been any promising result indicating that their transdermal application possibility, yet.
Conclusion and future outlook
TDDS have attracted great attention due to the delivery of therapeutic agent across the skin and the absorption of medications and entrance into the vascular system [1-3].
Controlled Drug release from TDDS reducing the dose fluctuations in the body can lead to the improvement of efficacy of pharmaceutical agents, stabilization of drugs diffusion profile, and greater bioavailability.
As the passage of hydrophilic drugs is limited into the deeper layers of skin, incorporation of these drugs with electrospun nanofibers has been suggested due to the advantages such as reduction in consumed dosage and systemic absorption of the drug,  but using electrospun nanofibers in TDDS is still in its early stages and it requires more studies.
Authors are thankful to the School of advanced technologies in medicine, Tehran University of Medical Sciences, Tehran, Iran.
CONFLICT OF INTEREST
The authors confirm that this article content has not any conflicts of interest.
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