Electrospun fibers for the treatment of skin diseases

Skin diseases are among the most common diseases in the global population and with the growth of the aging population, they represent an increasing burden to healthcare systems worldwide. Even though they are rarely life-threatening, the suffering for those affected is high due to the visibility and physical discomfort related to these diseases. Typical symptoms of skin diseases include an inflamed, swollen or itchy skin, and therefore, there is a high demand for effective therapy options. In recent years, electrospinning has attracted considerable interest in the field of drug delivery. The technique allows producing multifunctional drug-loaded fibrous patches from various natural and synthetic polymers with fiber diameters in the nano-and micrometer range, suitable for the treatment of a wide variety of skin diseases. The great potential of electrospun fiber patches not only lies in their tunable drug release properties and the possibility to entrap a variety of therapeutic compounds, but they also provide physical and mechanical protection to the impaired skin area, exhibit a high surface area, allow gas exchange, absorb exudate due to their porous structure and are cytocompatible and biodegradable. In the case of wound healing, cell adhesion is promoted due to the resemblance of the electrospun fibers to the structure of the native extracellular matrix. This review gives an overview of the potential applications of electrospun fibers in skin therapy. In addition to the treatment of bacterial, diabetic and burn wounds, focus is placed on inflammatory diseases such as atopic dermatitis and psoriasis, and therapeutic options for the treatment of skin cancer, acne vulgaris and herpes labialis are discussed. While we aim to emphasize the great potential of electrospun fiber patches for the treatment of skin diseases with this review paper, we also highlight challenges and limitations of current research in the field.


Introduction
Skin diseases are a major health problem worldwide, often underestimated due to the large number of different skin conditions and their diverse appearance.They are the fourth most common group of human diseases, affecting about one third of the global population, and are ranked fourth among all non-fatal diseases in terms of years lost due to disability [1,2].A few of these diseases are life-threatening, such as skin cancer.Life-threatening or not, these diseases cause a high level of suffering for patients, as they are directly visible, accompanied by an unpleasant, painful, itchy skin sensation and have considerable psychosocial effects.An epidemiological population-based study of 44,000 people from 27 European countries found that skin infections, atopic dermatitis, psoriasis, acne and non-melanoma skin cancer are among the most common skin diseases [3].Studies like these underline the importance of recognizing skin diseases as a public health problem.Consequently, effective therapeutic options remain the subject of pharmaceutical research.
Electrospun fibers that can be applied directly to the skin as a patch represent an important alternative and interesting area of research.By far the most electrospinning studies in the field of pharmaceutical sciences are currently conducted on the subject of wound healing, encompassing antibacterial wound treatment, the treatment of burn wounds and the treatment of diabetic ulcers.The use of electrospun fibers is advantageous for wound healing, as the fibers' porosity and netlike structure enable oxygen exchange and promote the attachment of new cells [6].By choosing a suitable polymer as the base material for the fibers, properties such as absorption of wound fluid, stretchability and flexibility of the patch during application, as well as the wearing sensation can be influenced.Beyond this, many studies discuss the use of electrospun fibers for specific skin conditions such as atopic dermatitis, psoriasis, acne vulgaris and herpes labialis [7][8][9][10].Since active ingredients can be individually incorporated into the fibers and the release of the drugs can be controlled via the manufacturing process (uniaxial, coaxial, layer-by-layer or in combination with other systems), the fibers represent a viable alternative to conventional semi-solid formulations, potentially promoting patient compliance due to their usually lower application frequency [11,12].Another application for electrospun fibers is the treatment of skin cancer, providing an opportunity to treat skin cancer in the patient's own home away from the hospital setting, avoiding standard chemotherapy and radiation therapy [13].
This review gives a comprehensive overview on the topical treatment of skin diseases using electrospun fibers.More specifically, focus is placed on the treatment of wounds, atopic dermatitis, psoriasis, skin cancer, acne vulgaris and herpes labialis using electrospun fiber systems (Fig. 1).The aim is to highlight the potential of these systems as an alternative treatment option to common semi-solid formulations such as ointments and creams.On the other hand, this review critically discusses limitations of previous studies, which are often rather proof-of-concept than application-related studies and emphasizes the need for further research on these systems that goes beyond the proof-of-concept, e.g., through comparison with products available on the market and in vivo testing.

Electrospinning process
Electrospinning is used to produce continuous fibers in diameters ranging from a few nanometers to several micrometers.The history of this technology goes back to the early 20th century.Due to the previous lack of characterization possibilities in the submicrometer range, interest in this technique increased with the introduction of electron microscopy [11].The application of electrospun fibers is diverse, ranging from their use in filter systems, textiles, packaging systems and cosmetics to biomedical scaffolds [14].In recent years, the interest in the technique has continued to grow in particular in the biomedical field in the areas of tissue engineering and drug delivery [15].There are detailed reviews available on the electrospinning process, which give a comprehensive overview on the mode of action of this technique [11,[16][17][18][19].The following section is, therefore, kept short and should be understood as a thematic introduction.
The concept of electrospinning is based on the application of a positive high voltage to a drop of polymer solution (Fig. 2).An electrical potential is built up by an either grounded or negatively charged collector [18].The polymer solution is continuously delivered to the tip of the electrospinning needle through a syringe system.A pendant droplet is formed, which, as soon as the surface tension is exceeded by the electric field, deforms into a cone and subsequently into a jet.Due to the electric field, the jet stretches and thins out, the solvent of the polymer solution evaporates and thin, continuous fibers are formed and deposited on the collector [11].
The formation of electrospun fibers is highly complex.In addition to the solution parameters such as polymer type and concentration, surface tension, conductivity and rheological properties and process parameters have a significant influence on the fiber formation [15].Such process parameters include the voltage applied to the injector and collector, the flow rate of the polymer solution, the type of electrospinning needle and, above all, the distance between needle tip and collector.This distance influences the evaporation of the solvent, the stretching of the fibers and, thus, the fiber diameter.Finally, the environmental conditions such as temperature and humidity are also relevant, as these have an impact on the viscosity of the polymer solution and the evaporation of the solvent [15,19].

Electrospinning types
The conventional method of electrospinning is uniaxial blend electrospinning (Fig. 2).Different polymers are combined in a solution based on their properties, and electrospinning occurs through one spinneret system [20].In addition, active pharmaceutical ingredients are either dissolved or dispersed in the polymer solution and are homogeneously distributed in the fibers [21].The advantages are that no complex electrospinning apparatus is required, the process takes place in one step and different polymer properties can be combined as required in a hybrid scaffold [20].A disadvantage may be that such fibers often show a burst release of the incorporated drug [22].For this reason, coaxial or even triaxial electrospinning are suitable to introduce one or two additional sheaths around the loaded core of the fibers as a diffusion barrier [14] (Fig. 2).Two or three solutions are electrospun in parallel through a two-or three-nozzle electrospinning needle.The advantages of these electrospinning types are the possibility for modification of the release behavior of incorporated drugs and the separate processing of incompatible or sensitive drugs [23][24][25].Disadvantages are that a more complex electrospinning spinneret system is required and the jet formation may be more unstable.Even mixing of the different solutions may occur during solvent evaporation [26].In addition to commonly used uni-, co-or triaxial electrospinning, fiber mats can also be produced by layer-by-layer electrospinning or side-by-side electrospinning.Layerby-layer electrospinning is the production of sandwich-like systems by uniaxial electrospinning using several consecutive steps [6,27,28].In contrast, side-by-side electrospinning is a process, in which two or more polymer solutions are electrospun in parallel and mixing of the fibers takes place at the collector.An introduction of stabilizing fibers in addition to less stable, drug-loaded fibers may improve the mechanical properties of the fiber mat [29].After the electrospinning process, the surface of the fibers can be modified, for example by cultivating cells on the fibers in vitro and then applying them to a wound, or by absorbing active agents such as vascular endothelial growth factor onto the fibers [30,31] (Fig. 2).

Polymers used in electrospinning
Polymers provide the basis for electrospun fibers and determine their properties, such as elongation behavior, wettability, cell adhesion and release of incorporated active ingredients, to a large extent [21].Polymers can be divided into synthetic and natural polymers and are used alone or in combination.Synthetic polymers such as poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polyethylene oxide (PEO) and polyvinyl alcohol (PVA) are usually easy to electrospin, however, require organic solvents to dissolve them.Consequently, it is important to ensure that there is no residual solvent present in the fibers after electrospinning.Alternatively, so-called "generally recognized as safe" (GRAS) solvents are used, which allow easier commercialization of the fiber systems at a later stage [32].GRAS solvents include solvents that are safe to handle, harmless to health and environmentally friendly.Solvents that pose little to no risk to human health are for example water, acetone, ethanol (EtOH) and dimethyl sulfoxide (DMSO), whereas chloroform, dimethylformamide (DMF) or trifluoroethanol (TFE) are toxic and difficult to handle [33].Natural polymers such as gelatin, chitosan, collagen, elastin and alginates require less harsh solvents, but are more difficult to electrospin and can sometimes only be electrospun using synthetic co-polymers [15].In addition, in the case of chitosan, for example, crosslinking agents are needed to obtain stable fibers.The reader is referred to other excellent reviews that provide detailed summaries of the polymer properties, making it easy to select them for the electrospinning process and achieve the desired fiber properties [34][35][36].

Wound healing of infected wounds, burn wounds and diabetic ulcers
The treatment of wounds is a relevant topic that has been the subject of continuous research in recent years.Chronic wounds, for example, are characterized by a duration of more than 3 weeks and occur frequently with a prevalence of 2.21 per 1000 people [37].The reasons for this high prevalence are manifold and are linked to the increased incidence of diabetes, obesity and, above all, an aging population [38].Electrospun wound dressings are particularly promising in terms of facilitating wound healing, as they are breathable fiber scaffolds that mimic the extracellular matrix and promote cell adhesion, thereby allowing new Layer electrospinning is the consecutive electrospinning of several polymer solutions in different layers.In the case of sensitive drugs, functionalization of the fiber mat after electrospinning with the drug as a surface modification is an option.tissue to form.Fiber dressings further provide a moist wound environment and prevent or reduce bacterial infection, in particular when antimicrobial components are incorporated.Through the choice of the manufacturing process (uniaxial or coaxial electrospinning) and the choice of the polymer as the basic component of electrospun dressings, the type of release of the incorporated drugs can be controlled and adapted as required.Due to the high relevance of this topic, there are several review articles that go into great detail on the topic of wound healing [39][40][41][42].There are approved products on the market.In the US, many wound dressings are approved as medical devices via the 510(k) clearance.Examples of such market products are the Phoenix Wound Matrix RenovoDerm® (FDA approval 2018), Poly FIT™ (FDA approval 2012) or Acera Restrata® (FDA approval 2022) [43].
Due to the vast literature focusing on electrospinning and wound healing, the most recent studies covering the last year are included in this review to highlight the relevance of electrospun fibers in wound healing (Table 1).By far the most studies focus on the incorporation of antibacterial compounds into fibers, alone or in combination with antiinflammatory agents [44][45][46][47].Drug release studies are typically performed from several hours to several days, and in vivo experiments are often carried out through topical application of such fibers to infected wounds in either mice or rat wound models to assess their effectiveness in stimulating wound healing.For instance, Yoosefi et al. found in their in vivo study with rats that co-delivery of ibuprofen and vancomycin promoted wound healing and accelerated the healing process compared to the control group (drug-free fibers).Other studies deal with the incorporation of inorganic nanomaterials such as zinc oxide, graphene oxide, titanium dioxide, and iron oxide into the fibers [48][49][50][51].For example, Wang et al. showed in a full-thickness skin incision model in rats that their sodium alginate fibers loaded with zinc oxide lead to a significantly stronger healing effect after 14 days in comparison to the control group (treated with a sterile adhesive patch), due to the antibacterial and anti-inflammatory fiber properties of zinc oxide [49] (Fig. 3).Inorganic nanomaterials such as zinc oxide show a photocatalytic activity or can interact with the bacterial cell wall, restricting the transport of nutrients and triggering oxidative cell stress through the formation of reactive oxygen species.These reactive oxygen species can further act as signaling molecules and promote cell division and, hence, wound healing by stimulating growth factors [48].Wu et al. and Yu et al. emphasized that a large amount of reactive oxygen species in the wound bed can interfere with wound healing.For this reason, the authors produced antioxidant fibers by incorporating iridium nanozymes or N-acetyl cysteine [52,53].In other studies, natural substances such as Calendula officinalis extract, propolis, tannic acid or rosmarinic acid are used for their antibacterial, anti-inflammatory, and wound healing properties [54][55][56][57][58].
In addition to these symptomatic, antibacterial wound dressings, live cells can be electrospun, e.g., using hand-held devices, directly initiating new tissue formation [62].Hsieh et al. developed electrospun fibers as a carrier for hyaluronic acid together with adipose-derived stem cells to promote wound healing in an in vivo rat model [30].Another interesting application of electrospun fibers is their use as theranostic systems (=combination of therapeutics and diagnostics) e.g., for wound monitoring.For example, infection can be indicated by a skin pH shift from slightly acidic, physiological pH of 5-6 to a slightly alkaline, infected environment with a pH of >7.Brooker et al. used the dye bromothymol blue for this purpose, which indicated the wound pH after only 1 min contact time with the wound fluid [85].The therapeutic agent in this system is considered to be the fiber base collagen, which has wound healing properties.Li et al. introduced electrospun fibers as "e-skin" to assess the wound status via the implementation of strain and moisture sensors and subsequent transmission of the data to a smartphone [64].The authors describe their system with a high porosity of 55% and a high absorption capacity of wound fluid with 180% to be a well-suited wound therapeutic agent that promotes cellular growth and tissue regeneration.Therefore, these fibers are another example of a smart combination of different types of applications in one theranostic system.
Electrospun fibers have also been evaluated for their application in burn wounds (Table 2).A risk factor of these wounds is bacterial infection, which can significantly delay wound healing.Therefore, treatment focus is on supplying the wound with important nutrients, inhibiting bacterial infection through antibacterial components and a proper wound exudate management.Shadman et al. produced a PCL/ PEO-based dressing with egg yolk oil, which is suitable for this application due to the essential nutrients it contains in addition to fats, vitamins, phospholipids, and cholesterol [103].In the in vivo model with rats suffering from 3rd degree burn wounds, a significantly faster reduction of the wound surface as well as a rapid angiogenesis and collagen synthesis were observed compared to the control group.Further, Bryan et al. performed a study on chitosan-elastin fibers loaded with the wound-healing component magnesium phosphate [104].The authors emphasized that the fibers mimic the extracellular matrix and promote the settlement of new cells due to elastin acting as a ligand for adhesion receptors of the cells.For the settlement of fibroblasts, both the fiber size and the porosity of the fiber mat are crucial.The product Acera Restrata® has a fiber size between 500 nm and 1500 nm and represents a highly porous matrix with 60% to 90% [105].The pore size is 90 μm to 130 μm, allowing rapid fibroblast migration.The fiber size is also a similar to that of collagen fibers, which are important components of the extracellular matrix.Based on these properties, the Acera Restrata® membrane is intended for the treatment of partial and full-thickness wounds, ulcers, burns and draining wounds [105].Sun et al. found a similar highly porous structure (85% and 92%) for their silk protein/ PVP systems, which is ideal for adequate air-fluid exchange on the wound surface [65].High porosity facilitates adequate nutrient exchange and wound fluid absorption.Mishra et al. determined a porosity of 91% and 96% for their fibers, showing equivalent properties to the market product Acera Restrata® [97].In addition to fulfilling certain requirements with respect to the fiber size distribution and porosity, a fiber patch should be stretchable and flexible, while providing sufficient mechanical support for fibroblast adhesion.For example, the market product is 0.5 mm thick and has a tensile modulus of 40 MPa to 80 MPa [105].This value is significantly higher than that reported by Sun et al.The authors compared their fibers with the tensile strength of 2.5 MPa to 16 MPa in human skin [65].Similarly low values were found by Yoosefi et al. and Wang et al. (both authors report values below 20 MPa) [44,49].The ability to absorb wound fluid is another important property of wound dressings and has been tested in many studies [29,83,93].Bao et al. found that their fibers can absorb moisture rapidly and continuously, thus providing a dry wound environment [55].The product Acera Restrata® has a high longevity and application time of 30 days [105].It is capable of continuously absorbing wound fluid, which means that no reapplication is necessary.Degradation of the fibers occurs during this period, which is desirable since the degradation products have an antimicrobial effect.Lv et al. prepared PCL/gelatin fibers that showed more than 500% uptake capacity within 30 min of contact time with moisture [67].After dehydration, the fibers showed a water retention capacity of 50% and remained structurally intact.Furthermore, the stability of fibers in the wound environment is crucial, as this determines when the wound dressing needs to be replaced.For example, Mancipe et al. found that their crosslinked collagen fibers were stable for up to 28 days (in saline solution) [83].In contrast, monolithic, non-crosslinked fibers completely disintegrated within 24 h.In another study, Brooker et al. demonstrated the integrity of their fibers in simulated wound fluid at pH 5 and pH 8 for more than 96 h [85].
Diabetic ulcers are another potential application of electrospun fibers (Table 3).Walther et al. processed the growth hormone insulin into PCL/PEO fibers and demonstrated that insulin was released from the fibers into the wound bed and its degradation was delayed [112].In a human in vitro wound model, the authors demonstrated the wound healing-promoting properties of their fibers through the rapid migration of fibroblasts and keratinocytes into the wound bed.Zhang et al. showed

Table 1
Electrospun fibers for the topical treatment of bacterial wounds.that the application of their chitosan/PVA fibers loaded with the antiinflammatory compound anemoside B4 in a diabetic mouse in vivo model significantly shortened the inflammatory phase [113].In summary, these studies show that electrospun wound dressings are highly promising and tunable systems for healing different types of wounds, such as infected wounds, burn wounds and diabetic ulcers, including those which are extremely oozing with exudate or colonized by bacteria [45,55,108].Many studies have proven the efficacy of electrospun fiber systems in in vivo studies and skin models, highlighting the great potential of such systems [31,52,112,114].

Dermatitis and eczema (atopic dermatitis)
Atopic dermatitis (AD) is a chronic, inflammatory skin disease that occurs with a prevalence of 15% to 20% in children and can persist into adulthood [132][133][134].The symptoms are manifested by an eczema that appears all over the body and is mainly concentrated on the head, face, cheeks, arms, and legs primarily by scaly and pruritic lesions.AD shows a fluctuating course and consequently patients are dependent on lifelong medical care.In addition to the external appearance and the associated stigmatization, itching, skin lesions and bacterial superinfections cause severe psychological suffering.Regardless of how severe the form of AD is, patients are required to apply emollients to the skin daily.During flare-ups and depending on the severity of the disease, steroids and/or calcineurin inhibitors such as tacrolimus must be applied twice daily as topical formulations [132,135].In addition, the topical therapy has now been augmented with the Janus kinase (JAK) inhibitor ruxolitinib for the treatment of mild to moderate AD in adult patients [134].On a weekly basis, additional relief can be achieved by bathing with bleach and using wet textile wrap treatments [133].
Various studies have shown that electrospun fibers have the potential to be used in the topical therapy of AD, expanding the application of textile-based therapy (Table 4).Textile based therapy is the application of moist compresses to reduce the itching caused by the disease and to improve skin hydration and is well established in AD treatment [134].Recent studies can basically be differentiated into two approaches: (I) where the fibers either contain active ingredients, which suppress inflammatory reactions, or (II) where they contain oils or moisturizing agents, which help restore the physiological skin hydration.Obaidat et al. incorporated the anti-inflammatory substance pioglitazone into PVP fibers and compared the release behavior with a conventional film [136].Due to the high fiber porosity, the release from the fibers was significantly faster.By increasing the polymer concentration, the authors obtained fibers with a larger diameter, which proved to be an advantage in tuning the drug release time.Shams et al. showed that the highly lipophilic anti-inflammatory agent tacrolimus can be incorporated into nanofibers [7].To ensure that the active ingredient would diffuse into the hydrophobic stratum corneum upon skin contact, the authors chose a mixture of PVA and chitosan as the hydrophilic material for the base of the fibers.To circumvent solubility problems of the very lipophilic tacrolimus, the authors incorporated the drug into a selfmicroemulsifying drug delivery system (SMEDDS), which was electrospun together with the polymer solution.The in vivo study in an AD mouse model showed that the fibers caused a thinning of the cornified skin layer of the epidermis (Fig. 4).Even though the fibers were only applied every two days, they still had the same effect as a standard tacrolimus ointment applied once a day.Another advantage of this system is that, unlike standard ointment, it is not greasy and can be worn comfortably under clothes.
AD patients have impaired skin barrier function due to a loss-offunction mutation of the filaggrin gene, which leads to a lack of the natural moisturizing factor and skin lipids.As a result, the skin loses moisture quickly, becomes dry and provides an easy entry point for microbial pathogens [132].Dry skin areas cause an unpleasant skin sensation and promote itching.For this reason, it is important to ensure physiological hydration of the skin, which is currently done using traditional creams and ointments.Nanofibers provide advantages over semi-solid formulations.They can, for example, act as a drug delivery system for nourishing oils, and they can be cut to size and comfortably applied to the affected areas without leaving an unpleasant feeling on the skin.Oils used for this purpose in previous studies are primarily natural oils from evening primrose, black cumin seed, borage, hemp seed, or black currant seed [137][138][139][140][141][142].These natural oils are rich in linoleic and gamma-linoleic acids, which are often deficient in eczematous skin.Nanofibers have the advantage of acting as a reservoir for these oils due to their porous structure and can thus be worn overnight to increase skin moisturization [139].When choosing polymers, however, it is important to ensure that the material is not too hydrophobic so that the oil can be released.Krysiak et al. found that much more oil was released from hydrophilic nylon patches than from the more hydrophobic polystyrene patches, which nevertheless showed high oil loading capacity [138].The size of the fibers also seems to have an influence on the oil spread-ability and on the release of the oils.Krysiak et al. found in the production of poly(vinyl butyral-co-vinyl alcohol-co-vinyl acetate) (PVB) patches that nano-sized fibers were much more wettable than microfibers of the same material due to their porous structure (92% and 97% porosity) and larger surface area [137].Furthermore, the authors found that both fiber systems were very robust (maximum tensile A.-L. Gürtler et al. strength 0.66 MPa for nanofibers and 0.48 MPa for microfibers).In another study with PVB fibers, the same authors found that a small fiber diameter is associated with a small pore size (0.83 μm for nanofibers and 2.67 μm for microfibers) and concluded that a small pore size results in a higher capillary pressure, which allowed for oil being both rapidly absorbed and released to the skin [139].The incorporation of natural oils into electrospun fibers is an interesting addition to the established AD therapy.In addition to moisturizing the skin, oils have antiinflammatory and antibacterial effects and thus prevent bacterial superinfections.Besides natural oils, it has been shown that moisturizing agents such as urea or active chlorine can also be incorporated into fibers [143,144].Krysiak et al. produced urea-containing PVB fibers by blend electrospinning [143].Since process instabilities were found when incorporating 10% urea, a second formulation was prepared by simultaneous electrospinning of PVB and electrospraying of urea.This demonstrates the importance of process stability during electrospinning, which is influenced not only by the choice of polymer and solvent, but also by the drug and its concentration.A.-L. Gürtler et al.
In summary, electrospun fibers show great potential for the treatment of AD.They complement current treatment options with advantages such as ease of use, comfortable wearing and low application frequency.This can significantly increase patient compliance and well-being.However, there are still some challenges that need to be addressed before such fiber patches can be used in clinical AD treatment.Such challenges include process instabilities during electrospinning and limitations in terms of the drug concentrations that can be incorporated  -a4) shows acanthosis, pointed with white star (a1), thick cornified layer (black star), with visible remnants of the nucleus (black arrow) referred to as parakeratosis (a2), Presence of inflammatory cells in the collagen bundles (black arrows), dilation of blood vessels and hyperemia (a3).Hyperemia, hemorrhage (white arrows) and intercellular edema (black star) in the dermis and acanthosis (white star) in the epidermis are also visible (a4).Positive-control group mouse skin pathology (b1& b2) shows decreased epidermal thickness and the keratin layers on the epidermis compared with negative-control group.There are also no inflammatory cells in the dermis.Drug-free 90:10 membrane group mouse skin pathology (c1& c2) shows increased number of inflammatory cells in the dermis (red star) (c1).Thickened layers of keratin (black star) on the epidermis are observable (c1, c2).90:10 membrane group mouse skin pathology (d1& d2) shows decreased thickness of the epidermis and the cornified layer on the epidermis compared to negative-control group.Also, in the dermis there are no inflammatory cell visible; into the fibers.Moreover, the polymer needs to be chosen with care, as too strong interactions between the polymer and the drug can affect the drug release behavior negatively.Further clinical studies are needed to address and improve these drawbacks to implement nanofibers as a significant platform in the treatment of AD.

Papulosquamous disorders (psoriasis)
Psoriasis is a chronic, inflammatory, immune-modulated skin disease that currently affects approximately 125 million people worldwide.Plaque psoriasis is the most common form, accounting for 80% of the cases, and is mainly characterized by erythematous, sharply demarcated, scaly plaques that can appear on the trunk, gluteal fold, extensor surfaces as well as internal surfaces of the hands and soles of the feet [146,147].Often, the plaques cause an unpleasant itch.Scratching can cause scales to detach from the plaque and lead to skin lesions.The disease has an oscillating course and is characterized by flare-ups, which can be triggered by various factors.For this reason, patients are dependent on lifelong anti-inflammatory therapy.Regardless of the severity of psoriasis, topical treatment is always applied and systemic therapy is used as a supportive measure in more severe cases [148].As the psoriasis plaques are sharply demarcated from the surrounding tissue, a drug-loaded patch that can be cut to size is ideal for daily treatment.It is advantageous if the drug is released over a period of 24 h, so that the patch only needs to be changed once a day.Such a patch can be produced by electrospinning polymer solutions (Table 5).Brooker et al., for example, incorporated antioxidant and anti-inflammatory poly (propylene sulfide) nanoparticles in PEO fibers, creating a platform for the treatment of inflammatory skin diseases such as psoriasis [149].Martínez-Ortega et al. have used poly(methylvinyl ether-alt-maleic ethyl monoester) nanofibers as a vehicle for salicylic acid, methyl salicylate and capsaicin, providing a platform for the prevention of psoriasis lesions [150].The authors demonstrate the possibility of combining several active ingredients together in one drug delivery system, but also emphasize the importance of drug release and storage stability testing.For example, after 15 days of storage, significant loss of methyl salicylate was observed due to its high volatility at room temperature [150].
The controlled release of active ingredients from a drug delivery system is an important quality feature.Electrospun fibers typically either show a burst release or the release is delayed over a long period of time so that the active ingredient is not fully released.Andrýsková et al. developed electrospun fibers containing magnetic nanoparticles.This system was exposed to an alternating magnetic field, resulting in local hyperthermia, which then caused the controlled release of the contained active ingredient tazarotene [8].In contrast to commonly produced electrospun fibers, the authors emphasize the possibility of applying the fibers directly to the psoriasis plaque using a hand-held electrospinning device.
If the nanofiber patch is electrospun prior to application, it is important to provide sufficient mechanical stability of the patch against wear and tear.Moreover, the production must be cost-effective.Azandaryani et al. produced a cost-effective nano bandage made from polyacrylonitrile (PAN) loaded with hydrocortisone for topical psoriasis treatment [151].Upon FTIR spectroscopic analysis, the active ingredient showed no interaction with the polymer and was released in a controlled manner, making the nano bandage a promising drug delivery system for psoriasis therapy.Furthermore, tensile strengths between 1 MPa and 15 MPa were determined for the different formulations, which are comparable to other studies from the field of wound healing and demonstrate the robustness of the fibers.
In summary, a few studies have been conducted on electrospun fibers for psoriasis therapy.The focus lay on the incorporation of antiinflammatory agents into the electrospun fibers, such as tazarotene or antioxidant nanoparticles.Andrýsková et al. have also demonstrated a way to electrospin fibers directly onto the skin using a handheld device [8].In addition, several active ingredients can be incorporated into a fiber mat at the same time, but it is important to investigate the stability of the drug delivery systems as well as possible drug interactions [150].However, further proof-of-concept studies are needed to evaluate the full potential of fibers in topical psoriasis therapy.In particular, in vivo studies are needed to investigate the applicability and efficacy of the fibers to promote their use in clinical psoriasis therapy.

Skin cancer (melanoma)
Skin cancer is one of the most diagnosed cancers worldwide and is particularly prevalent in the fair-skinned population.Its incidence is increasing every year, however, its seriousness is obscured by the significantly lower number of deaths per year [153].Skin cancer is divided into malignant melanoma and non-malignant melanoma, which includes basal cell carcinoma and squamous cell carcinoma as the most common subtypes [154].Malignant melanoma is the less common form but is more often associated with a high risk to metastasize and, thus, an increased skin cancer-related mortality.Current treatment modalities are primarily surgical removal of tumor tissue or radiation therapy if the former is not possible [155].The disadvantage is that cosmetic defects appear, the tissue cannot always be completely removed or wound infections occur.Therefore, further technologies have been implemented, focusing on local (e.g., radiation and surgical removal of tumor tissue) or molecularly targeted treatment (depending on the gene mutation that determines the melanoma disease) as well as on-site activation of the drug [155].Drug delivery systems such as liposomes, nanoparticles or electrospun fibers offer the possibility of targeting cancer cells.A potential application after surgical tumor removal is, for example, in the form of an implant [156].
Nanotechnology is a relevant and promising field of research in cancer therapy: nanoparticles loaded with active ingredients as a drug delivery system positively influence the biodistribution of drugs compared to free, systemically applied drugs [157,158].However, nanoparticle therapeutics may require targeted delivery through another drug delivery system to maximize their efficiency [159].Nanofibers are beneficial in this context, as they have large loading capabilities, can be selectively applied to the affected tissue, and particles can be incorporated and exert their effects through direct skin contact without being released from the fibers and causing toxic side effects (Table 6).In such cases, fiber scaffolds can be handled as a bulk material and utilized as a patch, while maintaining the characteristics of nanoparticle therapeutics [160].
Janani et al. prepared molybdenum oxide-PCL nanofiber composites that can be applied topically, resulting in mitigated side effects.

Table 5
Electrospun fibers for the topical treatment of psoriasis.A.-L. Gürtler et al.
Exposure to a magnetic field can induce local hyperthermia, which causes the death of cancer cells.Cell studies showed the potential of the fibers to specifically target cancer cells (epidermoid carcinoma cell line (A431), fibrosarcoma cell line (HT1080), melanoma cell line (G361); cell viability <50%) with only a minor effect on normal skin cells (keratinocyte cell line (HaCaT), fibroblast cell line (Swiss 3 T6); cell viability >80%).In vivo studies in zebrafish showed a reduction of skin cancer cells by more than 30% after a treatment period of 14 days [159].Similar to molybdenum oxide, iron oxide nanoparticles can be used to induce local hyperthermia by exposure to a magnetic field [154,161,162].Suneet et al. fabricated a PCL-Fe 3 O 4 fiber bandage that induced local hyperthermia (> 45 • C) after externally applying an alternating magnetic field.An in vivo study with BALB/c mice showed complete recovery within two weeks of a chemically induced skin tumor after five hyperthermia doses of 15 min.An in vitro study with HeLa cells showed 85% cell death after application of the Dox-loaded hyperthermia fiber bandage.In contrast, treatment with a Dox-loaded fiber bandage without hyperthermia development did not result in significant cell death.The study demonstrates a potential method for killing skin cancer cells by targeting them with localized heat.The fiber mat allowed heat generation needed to kill the cancer cells without skin uptake of embedded toxic Fe 3 O 4 nanoparticles [154].Samadzadeh et al. fabricated nanofibers that contained metformin-loaded mesoporous silica nanoparticles and pure metformin in addition to the magnetic iron oxide nanoparticles [162].The result was a synergistic inhibition of cancer cells due to chemotherapy (both rapid and delayed release) and hyperthermia treatment.This synergistic inhibition has also been exploited by Wei et al., who developed nanofibers consisting of a thermosensitive copolymer loaded with curcumin and magnetic iron oxide nanoparticles [163].In addition to reversible heating capacity and drug release, the toxicity test with B16F10 melanoma cancer cells resulted in cell death of more than 80% after three days of treatment with the fiber composites.
In contrast to heat generation by magnetic fields, near-infrared (NIR) radiation can be exploited to cause local hyperthermia by photothermal activity of bismuth selenide nanoplates or copper sulfide nanoparticles embedded in nanofibers [164,165].Shao et al. demonstrated controlled heat generation of bismuth selenide-loaded fibers in an in vivo experiment with mice.After NIR irradiation of the fibers, they recorded continuous shrinkage of the tumor until complete removal after 14 days (Fig. 5).A major advantage is the applicability of the fibers in areas that are difficult to access surgically.In addition, unlike injected particles, the tumor can be selectively targeted and the heat development is more controlled.In topical cancer therapy, nanofibers can also be used as an alternative to radiation therapy.Several studies showed the potential of using holmium-165 (nonradioactive) that can be activated to the radioactive form holmium-166 in skin patches [166][167][168].Osipitan et al. fabricated a nylon-laminated holmium-166-containing bandage that significantly reduced the size of non-melanoma skin cancer in an in vivo study with mice [13].The fibers showed potential for use in the clinic, where patients most likely will be prescribed to wear the radiotherapeutic bandage one to several times per month.The short half-life of holmium allows easy storage and discarding.
Nanofibers are also suitable for directly incorporating chemotherapeutic agents.For example, 5-fluorouracil (5-FU) is a chemotherapeutic agent used topically for melanoma treatment, which, however, also can A.-L. Gürtler et al.
damage normal skin cells as a side effect.Zhu et al. produced coaxially electrospun nanofibers containing 5-FU in the core, which was rapidly released and significantly inhibited the development of melanoma cells (62.2% early apoptosis B16F10 cells after 24 h treatment) [169].To minimize cytotoxic effects on healthy cells during treatment, chitosan was used as a shell component and showed a significant increase in vital L929 cells.This study shows that synergistic therapeutic effects can be achieved through appropriate polymer selection.In addition, the authors found that the addition of 5-FU led to a slight decrease in mechanical stability of their fibers although overall robust fibers (maximum tensile strength between 4 MPa and 33 MPa) were obtained.Yuan et al. also showed how decisive the choice of polymers for the fibers is for their drug release characteristics.In a study with coaxially electrospun PLGA/ polyvinylpyrrolidone (PVP) fibers, the authors were able to achieve a delayed release of 5-FU depending on the PLGA composition [170].Other chemotherapeutic agents such as gold complexes or silver nanoparticles were successfully incorporated into fibers [171].Guadagno et al. found significant cytotoxic effects of goldcomplexes to the malignant melanoma cell line MeWo [172].
Another potential application for nanofibers in topical cancer therapy is their use as a protective and healing dressing after radiotherapy.Patients often develop radiodermatitis, which can appear as erythema or ulceration 15 days to three months after the start of radiotherapy.Kyritsi et al. produced electrospun nanofibers loaded with an anti-inflammatory Pinus halepensis bark extract [173].In their study of 12 patients receiving radiotherapy over 4 weeks, treatment with the electrospun patches resulted in significantly improved transepidermal water loss (TEWL) values, reduced erythema, pain experience, itching and skin texture compared to treatment with a commercially available reference cream.Unlike the cream, which had to be applied twice a day, the patch was changed once a day and left on the affected areas for 24 h.The promising results of the study underline the potential of the use of nanofiber patches in promoting patient compliance due to the simplicity of application.Overall, the examples highlight that nanofibers provide multiple applications in skin cancer therapy.Active agents such as 5-FU incorporated into coaxial fibers showed substantial cytotoxicity against melanoma cells [169].The cytotoxicity of gold complexes incorporated into fibers was also demonstrated [172].Another approach is the incorporation of toxic nanoparticles such as molybdenum oxide or Fe 3 O 4 , which cause local hyperthermia when excited by a magnetic field and showed therapeutic effects in in vivo studies [154,159].Finally, electrospun fibers also offer the possibility of delivering antiinflammatory substances such as Pinus halepensis extract to the site of action as protective care after radiation therapy [173].Such systems exhibit a great potential, making the current therapy options more comfortable for patients not only through synergistic drug effects, but also by reducing the application frequency compared to standard therapeutics [169,173].

Disorders of skin appendages (acne vulgaris)
Acne vulgaris is a chronic inflammatory skin disease, affecting more than 640 million people worldwide [186].Not only young adults are affected, but the entire population, with the incidence decreasing in adulthood.Acne symptoms can vary in severity and are classified on acne grading scales, differentiating between a mild form with inflamed or inflammation-free comedones appearing on the face and a severe form with widely distributed and inflamed lesions on the face, chest, and upper back.These lesions often remain for several weeks, leading to an erythematous skin appearance with later scarring [187].Consequently, acne should be treated early and professionally to avoid persistence and scarring into adulthood.
Depending on the severity of acne vulgaris infections, topical treatment is first-line therapy.In topical combination therapy, antiinflammatory retinoids and antibacterial agents, including benzoyl peroxide or antibiotics such as clindamycin or erythromycin, are administered together to comprehensively address acne pathogenesis [186,188].In more severe cases, oral antibiotics, hormone-based drugs, or the systemically acting retinoid isotretinoin are recommended in addition to topical therapy [189].
However, skin irritation during topical therapy is a common problem.Although this can be minimized by short contact times (1− 2h), a major drawback of some topical formulations remains their limited ability to penetrate the stratum corneum [187].For this reason, nanotechnology and the development of novel drug delivery systems such as nanofibers are becoming increasingly important.Depending on their base polymer, nanofibers offer the advantage of incorporating hydrophilic and lipophilic drugs as well as releasing the drug in a controlled manner.The release behavior determines the application frequency and is, thus, crucial for achieving good patient compliance [188].
Electrospun fibers are suitable for the use as acne cosmetics as well as for the direct incorporation of prescription drugs such as tretinoins (Table 7).Amer et al. produced electrospun composite nanofibers of PVA, quercetin and essential oils for acne relief [190].In a clinical study with twenty patients suffering from mild to moderate acne, these nanofibers significantly reduced inflammation (61.2% ± 10.2% reduction compared to 12.5% ± 15.2% reduction for Panthenol® cream) and reduced the total number of acne lesions (52.9% ± 9.9% compared to 15.3% ± 10.7% for Panthenol® cream).Incorporation of the antimicrobial agent quercetin into the nanofibers proved advantageous, as the high fiber porosity and surface-to-volume ratio allowed a high permeability and contact area with the bacteria, leading to stronger antibacterial effects (average zone of inhibition of 18 mm ± 0.01 mm compared to quercetin alone 8.25 mm ± 2.08 mm) [190].In another study, zinc oxide was used as an antibacterial agent and its toxicity could be reduced by preventing particles from being released to the skin layers through incorporation into fibers [191].
To be a suitable alternative to semi-solid formulations in acne therapy, the application of nanofibers must be convenient and simple.This can be achieved by a delayed release of the active ingredient which allows for a low application frequency of the nanofibers.The release behavior is largely controlled by the choice of polymer.For example, Ahmed et al. used a blend of the water-soluble polymers PVA and hydroxyethylcellulose and increased the fiber stability by crosslinking [192].Without crosslinking, 80% of the active ingredient was already released after 2 h, whereas crosslinking prolonged the release to over 24 h.Khoshbakht et al. prepared water-insoluble electrospun PCL nanofibers loaded with tretinoin, in which the drug was released over a period of four days, first with a burst release followed by a more continuous release [193].These fibers appear to be a desirable platform for acne therapeutics.However, some active ingredients potentially cause skin irritation when in prolonged contact with the skin [194].Therefore, an application of the fibers as in the study design by Amer et al. seems appropriate, where patients wore a 1 cm × 1 cm patch moistened with a drop of water eight hours a day for eight weeks [190].In contrast, Rahnama et al. found stronger antibacterial effects against P. acnes with increasing application time (up to 72 h) of chitosan/PEO/ melittin fibers [195].
Polymer properties can exert synergistic effects against bacterial growth.For example, Tang et al. showed substantial growth inhibition of P. acnes by applying herbal extract-loaded PVA/chitosan fibers, which was also confirmed by Rahnama et al. [195,196].Chitosan as the basis of the fibers has an antimicrobial effect [197] and thus enhances the effect of the incorporated antimicrobial agents.
In summary, nanofibers represent an interesting alternative in acne therapy.Not only do they represent a platform through which the release behavior of active ingredients can be adjusted as needed, but they also offer advantages over semi-solid formulations through synergistic effects between active ingredients and the selected polymer.To assess the potential and advantage of nanofibers over established products that are already found on the market, it is crucial that standard products, such as a 1% clindamycin gel, serve as a comparison for manufactured fibers [198].

Other disorders of the skin and subcutaneous tissue (herpes labialis)
HSV-1 infections are among the most common viral infections in humans.Approximately 67% of all people under the age of 50 suffer from this recurring disease worldwide [201].The infection usually progresses in phases that last 7 to 10 days in total.At first, the patient feels a slight burning, pain or itching on the lip.Later, painful, oozing blisters and eventually crusts form [202].After the crust has fallen off, healing takes place without scarring.The course of the disease is very unpleasant for those affected.Relief can only be provided by topical treatment with antivirals, nourishing and moisturizing creams and concealing patches [201,203].
Nanofibers are characterized by their high drug loading capacity.Depending on the polymer base, they are a suitable drug delivery system for drugs such as acyclovir, which are otherwise difficult to formulate in hydrophilic semi-solid bases and show a low bioavailability (Table 8).In a study with 60 volunteers suffering from herpes labialis, Golestannejad et al. compared the effect of an acyclovir nanofiber patch with a commercially available acyclovir cream [204].The authors assessed the duration of crusting and healing time, however, found no significant differences between the two groups and the control group.They justify this result with the course of the disease.It is a recurring disease as the virus remains in the sensory nerve cells and multiplies in host cells in the presence of certain trigger factors such as stress, sun exposure or fever [201,204].Acyclovir is most effective during the replication phase of the virus, as it inhibits viral replication and thus the inflammatory cascade.If therapy is started too late, the formation of the characteristic and painful herpes blisters cannot be prevented and the healing time cannot be reduced [203].This result is consistent with Boes et al., who compared three commercially available herpes medications (filmforming patch Herpatch®, semi-occlusive hydrocolloid patch Compeed®, Zovirax cream®) in a study with 180 patients.Although no significant difference in the healing time of the herpes infection was found, a better therapy quality (exploited by the Clinician's Global Assessment of Therapy and the Subject's Global Assessment of Therapy, e.g., protection of lesion, relief of discomfort, aesthetics) was shown especially for the film-forming patch.Disadvantages of the cream were, for example, that it did not look aesthetically pleasing due to its white colour and was removed quickly after/while eating and thus had to be applied every 3 h to 5 h.The Compeed® patch also had to be replaced frequently as the edges of the patch came off easily due to eating, saliva and mouth movements.With each patch renewal, the already formed crust was torn off with the patch, which caused pain.
The requirements for nanofiber patches for herpes labialis treatment are permanent contact with the skin and stability against saliva and mouth movements [12].Furthermore, such patches should need to be applied as rarely as possible, which requires a controlled, slow release of the active ingredient.Moreover, they should be easy and simple to apply to maintain patient compliance.Costa et al. have designed a patch that can be applied to the lips in a size of 2 × 2 cm for 24 h, which is five times less often than a commercially available acyclovir cream [12].In addition to acyclovir, omega-3 fatty acids were included as a nourishing and wound-healing component.In permeation studies with pig skin, the authors found that acyclovir was released more quickly from the comparative product Zovirax® than from the nanofibers, but that the nanofibers achieved a higher drug permeation.In addition to the high porosity of the fibers (93% non-drug loaded fibers and 74% drug-loaded fibers), which allowed continuous drainage of wound fluid from the blisters and aeration with oxygen, the authors found a mild occlusion effect of 12% (measured by covering a glass container filled with water either with a microfiber cellulose filter, a cellulose filter coated with Zovirax® cream or a glass container covered with a fiber mat at 37 • C and weighed at regular intervals), which enhances drug permeation [12].Further studies confirmed how easily acyclovir can be incorporated into nanofibers [205][206][207][208]. Kazsoki et al. emphasized that their fibers are particularly advantageous for topical application as the fibers release the containing drug acyclovir much faster than a conventional standard cream (Zovirax®) due to their large specific surface area and high porosity as well as a small pore size [208].In addition to the choice of polymer, the release behavior also depends on the structure of the fibers (uniaxial/coaxial).Celebioglu et al. have tried to avoid organic solvents during electrospinning and have produced uniaxial nanofibers on a cyclodextrin-water basis.In addition to an improved incorporation of acyclovir (98%) in contrast to PVP fibers (66%), the authors found a rapid dissolution of their fibers using artificial saliva [205].Despite an increased application frequency, the authors claimed that the rapid drug release would be beneficial, as the lesions are rapidly supplied with active substance.This is in agreement with a similar study, in which cyclodextrins in combination with other hydrophilic polymers were used [208].In contrast, Azizi et al. placed emphasis on a delayed release of acyclovir and thus a low application frequency of the fiber patch [206].The authors achieved this by designing core/shell nanofibers, which resulted in sustained release of acyclovir compared with uniaxial fibers.The benefits of coaxial electrospinning were also verified in a study by Lv et al., where the coaxial design minimized the initial burst release of acyclovir and a well-controlled delayed drug release was obtained instead [207].Barani et al. found similar results in their study with thiosemicarbazone-loaded PVA core-shell fibers [209].However, the authors emphasize that the difference in the release of thiosemicarbazone to uniaxial fibers is marginal but present.They suggest that when PVA is replaced with a slightly more hydrophobic polymer, interactions with the hydrophobic agent may be present and a more delayed release may be achieved compared to the uniaxial fibers.
Taken together, the studies show that it is possible to successfully incorporate both viral drugs such as acyclovir and nourishing components such as omega-3 fatty acids into nanofibers.However, current studies are primarily of a proof-of-concept nature [12].Azizi et al. have shown that in contrast to uniaxial fibers, a delayed release of acyclovir can be achieved by a coaxial fiber structure [206].In addition to a comparison with standard products in in vitro experiments, it is essential in the future to investigate the performance of the formulations in in vivo A.-L. Gürtler et al.
studies [204].Even though a new drug delivery system such as nanofiber patches does not necessarily lead to a shortened course of the disease, a better quality of therapy can be achieved with nanofiber patches as shown by Golestannejad [204].In contrast to a cream, patches are not quickly removed from the lips and can release the active ingredient over a period of 24 h [12,203].

Conclusion
Electrospun fibers show many applications in the treatment of skin diseases due to their versatile and adjustable properties.They are breathable due to their porosity and mimic the extracellular matrix, making them beneficial for cell adhesion and formation of new tissue.It is possible to incorporate antibacterial components such as zinc oxide or graphene oxide, which on the one hand are photocatalytically active and on the other hand can interact with the bacterial cell wall and restrict the transport of nutrients.Furthermore, electrospun fibers can be used as theranostic systems for wound monitoring through the incorporation of pH indicators such as bromothymol blue.Electrospun fibers are suitable for various types of wounds (infected, burns, diabetic ulcers) that are either extremely oozing or colonized with bacteria.The possibility of incorporating photocatalytic agents is also useful for melanoma treatment.Through irradiation with an external magnetic field, local heat development can lead to the death of melanoma cells.In the treatment of AD, electrospun fibers expand the possibilities of textile-based therapy.For example, the fibers act as a drug delivery system for moisturizing oils such as evening primrose oil.Other topical diseases that are clearly demarcated from the surrounding tissue, such as herpes blisters or psoriasis plaques, represent further research topics.By incorporating active ingredients such as tazarotene, the fibers can even be electrospun directly onto the skin as needed using a handheld device.Electrospun fibers can not only enhance the effect of established active substances (e. g., synergistic effect of chitosan with antimicrobial components), but also make them more comfortable for the patient to use.Several studies already demonstrate these advantages in comparison with standard therapeutics and test their fibers not only in in vitro studies, but also in in vivo experiments.However, to further enhance the clinical use of electrospun patches and introduce them to the pharmaceutical market, in vivo studies are needed for all relevant electrospun systems to demonstrate their applicability and benefits over conventional treatment options.

Fig. 1 .
Fig. 1.Overview of potential applications of electrospun fibers for skin diseases.

Fig. 2 .
Fig. 2. Electrospinning process and methods.Commonly used types of electrospinning include uniaxial electrospinning with one polymer solution, coaxial electrospinning with two solutions, and triaxial electrospinning with three solutions.The active ingredient can be individually introduced into the polymer solution.Layer electrospinning is the consecutive electrospinning of several polymer solutions in different layers.In the case of sensitive drugs, functionalization of the fiber mat after electrospinning with the drug as a surface modification is an option.

Fig. 3 .
Fig. 3. Effect of composite fibers on wound healing.(A) Representative images showing wound healing at different time points up to day 14.(B) Wound closure of various groups.(C) Histological analysis of retrieved specimens by using hematoxylin and eosin (H&E).Masson's trichrome (MT) staining of retrieved tissues at day 3, 7, and 14 post-operatively (D).(n = 3, *p < 0.05).Scale bars are shown on each photograph.Scale bar, C-D.Upper panel, 400 μm and lower panel, 100 μm at day 3, 7, and 14.Reprinted from International Journal of Biological Macromolecules, Vol 232, Wang et al. [49], Synthesis of oxidized sodium alginate and its electrospun bio-hybrids with zinc oxide nanoparticles to promote wound healing, Page No. 9, Copyright (2023), with permission from Elsevier.

Fig. 4 .
Fig. 4. AD model induction on mouse and assessment of treatment.(A) Clinical representation of AD on mouse model (Negative-control group, day 4 DNCB application).Dry scaly lesions are apparent; (B) Skin histopathology (hematoxylin and eosin staining): Negative-control group mouse skin pathology (a1-a4) shows acanthosis, pointed with white star (a1), thick cornified layer (black star), with visible remnants of the nucleus (black arrow) referred to as parakeratosis (a2),Presence of inflammatory cells in the collagen bundles (black arrows), dilation of blood vessels and hyperemia (a3).Hyperemia, hemorrhage (white arrows) and intercellular edema (black star) in the dermis and acanthosis (white star) in the epidermis are also visible (a4).Positive-control group mouse skin pathology (b1& b2) shows decreased epidermal thickness and the keratin layers on the epidermis compared with negative-control group.There are also no inflammatory cells in the dermis.Drug-free 90:10 membrane group mouse skin pathology (c1& c2) shows increased number of inflammatory cells in the dermis (red star) (c1).Thickened layers of keratin (black star) on the epidermis are observable (c1, c2).90:10 membrane group mouse skin pathology (d1& d2) shows decreased thickness of the epidermis and the cornified layer on the epidermis compared to negative-control group.Also, in the dermis there are no inflammatory cell visible; (C) epidermal thickness of mouse skin in different groups as taken in day 19 (mean ± SEM, ****P value <0.0001, **P value <0.01, *P value <0.05, and ns refers to not significant).(For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)Reprinted from Journal of Drug Delivery Science and Technology, Vol 62, Shams et al. [7], Self-microemulsification-assisted incorporation of tacrolimus into hydrophilic nanofibers for facilitated treatment of 2,4-dinitrochlorobenzene induced atopic dermatitis like lesions, Page No. 6, Copyright (2023), with permission from Elsevier.(For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Fig. 4. AD model induction on mouse and assessment of treatment.(A) Clinical representation of AD on mouse model (Negative-control group, day 4 DNCB application).Dry scaly lesions are apparent; (B) Skin histopathology (hematoxylin and eosin staining): Negative-control group mouse skin pathology (a1-a4) shows acanthosis, pointed with white star (a1), thick cornified layer (black star), with visible remnants of the nucleus (black arrow) referred to as parakeratosis (a2),Presence of inflammatory cells in the collagen bundles (black arrows), dilation of blood vessels and hyperemia (a3).Hyperemia, hemorrhage (white arrows) and intercellular edema (black star) in the dermis and acanthosis (white star) in the epidermis are also visible (a4).Positive-control group mouse skin pathology (b1& b2) shows decreased epidermal thickness and the keratin layers on the epidermis compared with negative-control group.There are also no inflammatory cells in the dermis.Drug-free 90:10 membrane group mouse skin pathology (c1& c2) shows increased number of inflammatory cells in the dermis (red star) (c1).Thickened layers of keratin (black star) on the epidermis are observable (c1, c2).90:10 membrane group mouse skin pathology (d1& d2) shows decreased thickness of the epidermis and the cornified layer on the epidermis compared to negative-control group.Also, in the dermis there are no inflammatory cell visible; (C) epidermal thickness of mouse skin in different groups as taken in day 19 (mean ± SEM, ****P value <0.0001, **P value <0.01, *P value <0.05, and ns refers to not significant).(For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)Reprinted from Journal of Drug Delivery Science and Technology, Vol 62, Shams et al. [7], Self-microemulsification-assisted incorporation of tacrolimus into hydrophilic nanofibers for facilitated treatment of 2,4-dinitrochlorobenzene induced atopic dermatitis like lesions, Page No. 6, Copyright (2023), with permission from Elsevier.(For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 5 .
Fig. 5. (a) Infrared thermographic maps and (b) time-dependent temperature increase of the tumor-bearing nude mice irradiated by an 808 nm laser (0.5 W/cm 2 ); (c) typical photographs of the tumor-bearing mice before (day 0) and after (day 14) PTT treatment; and (d) corresponding growth curves of tumor in different groups of mice after NIR laser irradiation.Reprinted with permission from Shao et al. [164].Copyright (2023) American Chemical Society.

Table 2
Electrospun fibers for the topical treatment of burn wounds.

Table 3
Electrospun fibers for the topical treatment of diabetic ulcers.

Table 4
Electrospun fibers for the topical treatment of atopic dermatitis.

Table 6
Electrospun fibers for the topical treatment of skin cancer.

Table 7
Electrospun fibers for the topical treatment of acne vulgaris.

Table 8
Electrospun fibers for the topical treatment of herpes labialis.