European Journal of Pharmaceutical Sciences 107 (2017) 148–167

Contents lists available at ScienceDirect

European Journal of Pharmaceutical Sciences

journal homepage: www.elsevier.com/locate/ejps

Review

Electrospun polymeric nanofibers: New horizons in drug delivery MARK

⁎
Shreya Thakkar, Manju Misra
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gujarat 380054, India

A R T I C L E I N F O A B S T R A C T

Keywords: Nanofibers obtained using electrospinning technique are being used since ages especially in fields of textile
Electrospinning industry, sensors, filters, protective clothing and tissue engineering. Their use as drug delivery system is an
Nanofibers emerging platform in the field of pharmaceuticals and now-a-days formulation scientists are paying great at-
Release profile tention to the technology due to several advantages prime being easy modulation of drug release profile de-
CPPs and CMAs
pending upon the properties of polymer/polymeric blends/other materials used. Although there are several
reports citing the use of antibiotics-loaded nanofibers as wound dressing materials and as antimicrobial therapy
in periodontics; still there is a good scope of expanding the horizon for its application in newer ailments. This
article reviews various aspects related to loading and release of drug as such or in nano-particulate form to
polymeric nanofibers by taking critical process parameters (CPPs) for electrospinning and critical material at-
tributes (CMAs) into account. Commercially available products and electrospinning technologies are described
in brief along with some of the patents related to their use as drug delivery systems. The main focus of this
review is applicability of drug/drug nanoparticle loaded nanofibers in the management of diseases/disorders
related to the brain, eye, ear, cardiovascular system, lungs and oral cavity. Use in diseases with higher mortality
rates like diabetes, Acquired immunodeficiency syndrome (AIDS) and cancer is also described in brief.

1. Introduction (Mahalingam and Edirisinghe, 2013) have been explored by researchers

Electrospinning is a process of conversion of polymeric solution/
melt (with or without additives/incorporable) into solid nanofibers by
application of electrical force. Amongst numerous conventional
methods reported for nanofiber formation such as drawing, template
synthesis, self-assembly, phase separation, and electrospinning; elec-
trospinning is more popular due to its advantages like easy control over
fiber diameter, morphology, surface characteristics, porosity and ease
of getting fiber diameter in nano range (Kowalewski et al., 2005; Nayak
et al., 2011).
Apart from electrospinning numerous other non-electro nanofiber
spinning techniques such as solution blowing (Polat et al., 2016),
centrifugal spinning (Taghavi and Larson, 2014), template synthesis
(Ikegame et al., 2003), phase inversion freeze drying (Kaiser et al.,
2014), spinneret based tunable engineered parameters technique
(STEP) (Stojanovska et al., 2016) and pressurized gyration process
for nanofiber spinning. These techniques provide new advances in the
field of nanofiber formation and are strong competitors of electro-
spinning technique offering several advantages and limitations. A
comprehensive comparison of all these techniques is summarized in
Table 1.
Nanofibers are solid fibers of materials having diameters below micron
range with a porous structure and very high surface area. These can be
easily fabricated by electrospinning process as this process provides con-
trol over properties as well as the alignment of fibers on collector used
(static or rotating cylinder). Specific alignment of nanofibers can result in
specific structures such as nanotubes and nanowires. Nanofiber of the only
conventional polymer will result in no specific function and can be used as
scaffolds only. To form functional nanofibers polymers of specific nature,
soluble/insoluble drug particles and nanoparticles of drugs/functional
material can be added to electrospinning solution (Frenot and Chronakis,
2003; Zhang and Yu, 2014).

Abbreviations: AIDS, acquired immunodeficiency syndrome; CMAs, critical material attributes; CPPs, critical process parameters; DMA, dimethylacetamide; DMF, dimethylformamide;
DMSO, dimethyl sulfoxide; EHDA, electrohydrodynamic atomization; FA, formic acid; FGF, fibroblast growth factor; HFIP, 1,1,1,3,3,3-hexafluoro-2-propanol; HIV, human im-
munodeficiency virus; HPβCD, hydroxypropyl-β-cyclodextrin; LCST, lower critical solution temperature; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant
Staphylococcus aureus; NEU, nanofibers electrospinning unit; NIR, near infrared; NMMO, N-methyl morpholine oxide; ODT, orally disintegrating tablets; PCL, polycaprolactone; PEG,
polyethylene glycol; PEO, polyethylene oxide; PLA, poly(L-Lactic acid); PLGA, poly(lactic-co-glycolic acid); PLLA, poly(L-Lactide acid); PMMA, polymethyl methacrylate; PVA, polyvinyl
chloride; PVP, polyvinyl pyrrolidone; SRP, scaling and root planing; STEP, spinneret based tunable engineered parameters; TFA, trifluoroacetic acid; THF, tetrahydrofuran; VEGF,
vascular endothelial growth factor; XRD, X-ray diffraction
⁎
Corresponding author.
E-mail address: manju@niperahm.ac.in (M. Misra).

http://dx.doi.org/10.1016/j.ejps.2017.07.001
Received 9 May 2017; Received in revised form 23 June 2017; Accepted 2 July 2017
Available online 08 July 2017
0928-0987/ © 2017 Elsevier B.V. All rights reserved.
 S. Thakkar, M. Misra

Table 1
Comparison of numerous nanofiber production techniques.

Method Governing forces Working principle Parameters affecting fiber properties Productivity Nanofiber Scalability on commercial level References
diameter
obtained

Electrospinning Electromechanical and Single jet splaying due to very high Applied voltage, tip-to-collector 5 μL/min 40 nm-2 μm Possible (Stojanovska et al.,
hydrodynamic forces voltage supply, electro- distance, temperature, humidity, 2016)
hydrodynamic atomization solution viscosity, flow rate and
electrical conductivity
Solution blowing Forces from high speed compressed Partition of single jet is commenced Gas pressure, nozzle geometry, Flow 20 μL/min 40 nm-several μm Possible (Polat et al., 2016;
air by virtue of compressed air (in high rate and solution viscosity Stojanovska et al.,
speed) 2016)
Centrifugal spinning Centrifugal force Partitioning of single jet leaving Orifice diameter, rotational speed, 1 ml/min 25 nm-several μm Possible (Stojanovska et al.,
orifice due to centrifugal force guides flow rate, solution surface tension and 2016; Taghavi and
the production of nanofibers viscosity Larson, 2014)

149
Pressurized gyration Forces of pressurized gyration Technique provides a combination of Polymer concentration, rotational 0.1 kg/min 60–1000 nm Possible (Mahalingam and
process centrifugal spinning and solution speed, working pressure of processing Edirisinghe, 2013)
blowing system
a
Template synthesis Vacuum pressure or capillary action Molding process, matrices with nano- Template shape, pore size and driving 40 to some Not amenable to scale up due (Ikegame et al., 2003;
of the polymer (electrostatic forces scale pores, made up of force hundred nm to production of fibers with Stojanovska et al.,
can also be used) polycarbonate and alumina are used shorter length 2016)
as templates
a
Phase inversion Reduced pressure of freezing and Freezing of very dilute polymeric Freezing rate and polymer 50 nm-1 μm Not amenable to scale up due (Kaiser et al., 2014;
freeze drying sublimation solutions and subsequent removal of concentration to various challenges Stojanovska et al.,
solvent by sublimation associated with maintaining 2016)
proper conditions
STEP techniques Forces from rotational and Micropipette spinneret from droplet Substrate speed, properties of 15–100 μL/min 50 nm to several Not possible (Stojanovska et al.,
translational motions by rotational and translational polymer solution (concentration and μm 2016; Wang and Nain,
forces, a movable substrate extends it molecular weight) 2014)
to filament

a
Values are not reported in reference cited.
European Journal of Pharmaceutical Sciences 107 (2017) 148–167
S. Thakkar, M. Misra
Fig. 1. Use of nanofibers in daily needs.
Polymeric nanofibers are attaining great interest in recent years due
to its wide applications (with incorporation of some functional mate-
rials and remodeling) in numerous fields including electronics, fabric
formation (as protective clothing), separation industries (as filter
media/aids) medical field (tissue engineering, wound dressing material,
artificial organs, tissue grafts), photonics, biosensors, chemistry (as
catalyst), enzyme immobilization, as nano-composites and many others
(Haider et al., 2015) as shown in Fig. 1.
Nanofibers are different from other fibrous structures with a dia-
meter in the range of nanometers while the length in the range of
meters, and are thus referred to as link between nanotechnology and
micron size world (Begum et al., 2012; Bhardwaj and Kundu, 2010;
Demir et al., 2004; Frenot and Chronakis, 2003; Rujitanaroj et al., 2008;
Zhao et al., 2006). A number of synthetic, semisynthetic and biological
polymers have been used to form nanofibers using electrospinning
process as summarized in Table 2. However, not all the polymers are
capable of forming nanofibers, alginates are reported to have the
property of gelation at very low concentrations while at higher con-
centration, its solution becomes too viscous, to be injected. Often to
improve this behavior of alginates cosolvent/surfactant are added to
electrospinning solution to aid the process of nanofibre formation
(Bhattarai and Zhang, 2007). It is reported that, polymer solutions
depending upon the molecular weights and concentration used, exhibit
electrospinnability only when polymer concentration and viscosity is
optimum. Usually solutions with lower polymer concentration results in
electrospraying instead of spinning. Electrospinnability of low mole-
cular weight polymers can be enhanced, utilizing supramolecular ap-
proaches which allow cross-linking via hydrogen bonding or co-ordi-
nation interactions in solution using small molecules (Wang et al.,
2016). One should be cautious in selection of concentration and visc-
osity ranges of working solutions to get desired electrospinnability of
polymer used.
A sensible number of nanofibers based products produced by elec-
trospinning are already available commercially like NanoAligned™ and
NanoECM™ which are electrospun fiber multiwell plates useful for high
throughput cell culture, cancer research and regenerative medicine.
Similarly, AVflo™ commercialized by Nicast; is a certified polyurethane
vascular access graft used in hemodialysis. Fig. 2 provides a brief
glimpse of several nanofibers based products obtained from electro-
spinning specifically used in drug discovery or for therapeutic appli-
cations ([19-09-2016], n.d; [18-09-2016], n.d).
Electrospinning is a well-established technique for nanofiber for-
mation, more so in the area of textile industry, separation industry in-
cluding biomedical applications; however the use of this technique in
pharmaceuticals for drug delivery is still largely unexplored, as evident
150
European Journal of Pharmaceutical Sciences 107 (2017) 148–167
by very few reports, found in the literature. Nanotechnology has pro-
vided the pharmaceutical industry with new means of targeted drug
delivery and it would be interesting to see how electrospinning com-
bined with nanotechnology, could be the harbinger of a new era in drug
delivery. In the present review, we have discussed the various ther-
apeutic areas where electrospinning is used for drug delivery their
advantages and disadvantages. Emphasis is also laid on critical pro-
cessing parameters (CPP) and critical manufacturing attributes (CMA)
that may affect electrospinning process. An attempt is also made to
elaborate on the effect of these CPP and CMA on nanofiber morphology
especially upon nanoparticulate drug loading with specific applications
in drug delivery and tissue engineering.
2. Drug/drug nanoparticle fabrication in nanofibers
2.1. Electrospinning, the basic principle
Electrohydrodynamic atomization (EHDA) is a process well con-
trolled and driven by two regulatory forces working in combination as
electromechanical and hydrodynamic forces. Since decades, this pro-
cess has been utilized for skillful and precise production of particles or
fibers in a definite size range and morphology (Parhizkar et al., 2016b;
Xie et al., 2015). Basically EHDA process is divided into two main op-
erative techniques as electrospinning and electrospraying depending
upon the processing conditions and properties of polymeric solution
(Husain et al., 2016; Pina et al., 2017). One should pay considerable
attention to parameters involved in turning one process to other, as
these are critical to final product and the properties desired, more so if
the drug is potent. Polymer concentration is crucial factor affecting
product output from particle to fiber. Recently Husain et al. have in-
vestigated the effect of polymer concentration, flow rate, tip-to-col-
lector distance and applied voltage on the transition threshold for
particle to fiber. Findings of the study on PLGA suggested polymer
concentration to be the key factor involved. From investigated con-
centration range of 2–25% three different zones were differentiated as
1–10%, 10–20% and 20–30% concentration zones which resulted in
particles, particles with beads on strings and beaded/bead-less fibers
respectively. A complete transition from particle to fiber state was re-
ported at a concentration of 20% while other investigated parameters
had a minute or no impact on the transition of aforementioned opera-
tional techniques (Husain et al., 2016). In general it could be concluded
that very low polymer concentrations results in electro spraying with
final product yield in particulate product. Interestingly, change in
concentration of polymer, was also associated with different values of
surface tension, electrical conductivity and viscosity of final product
 Table 2
Polymers used in electrospinning process and their applications.

Polymer Solvent used Monomer Applications Reference

Biopolymers in electrospinning
S. Thakkar, M. Misra

Polysaccharides and Cellulose N-methyl morpholine oxide β(1 → 4) linked D-glucose In textile, paper, plastic industries as food (Kang et al., 2002)
derivatives (NMMO) additives, and as the propellant
Cellulose acetate Acetone β(1 → 4) linked D-glucose with two acetyl In textile, paper, plastic industries as food (Jaeger et al., 1998;
group per molecule additives, and as a propellant Konwarh et al., 2013)
Ethyl cellulose Tetrahydro furan (THF)/dimethyl β(1 → 4) linked D-glucose with some of the As a carrier for loading of functional material (Park et al., 2015; Wu et al.,
acetamide (DMA) hydroxyl groups converted to ethyl ether 2005)
Propionyl cellulose Acetone β(1 → 4) linked D-glucose with propionyl As a carrier for loading of functional material (Jaeger et al., 1998)
groups bound to some of the hydroxyl groups
Methyl cellulose Water/ethanol β(1 → 4) linked D-glucose with methyl groups As a carrier for loading of functional material (Frenot et al., 2007)
bound to some of the hydroxyl groups
Hydroxypropyl cellulose Anhydrous ethanol β(1 → 4) linked D-glucose with hydroxypropyl As a carrier for loading of functional material (Gencturk et al., 2016;
groups bound to some of the hydroxyl groups and in ceramic industry Shukla et al., 2005)
Hydroxypropyl methyl cellulose Water/ethanol β(1 → 4) linked D-glucose with hydroxypropyl As a carrier for loading of functional material (Frenot et al., 2007; Paaver
methyl groups bound to some of the hydroxyl et al., 2015)
groups
Carboxymethylcellulose Methanol/water β(1 → 4) linked D-glucose with carboxymethyl As a carrier for loading of functional material (Kessick et al., 2004)
groups bound to some of the hydroxyl groups
Chitin 1,1,1,3,3,3-hexafluoro-2-propanol N-acetyl glucosamine Tissue scaffolding and wound dressing with (Min et al., 2004; Noh et al.,
(HFIP) functional materials 2006)
Practical grade chitin HFIP N-acetyl glucosamine Tissue scaffolding and wound dressing with (Schiffman et al., 2009)
functional materials
Chitin/poly (glycolic acid) HFIP N-acetyl glucosamine Tissue scaffolding and wound dressing with (Park et al., 2006a)
functional materials
Chitin/silk fibroin HFIP N-acetyl glucosamine Clothing (Park et al., 2006b)

151
Chitosan Trifluoroacetic acid (TFA) Random distribution of β(1 → 4) linked D- Removals of metals from solutions for (Mengistu Lemma et al.,
Ethanol/water glucosamine (deacetylated) and N-acetyl- environmental use and wound dressing with 2016; Ohkawa et al., 2004)
glucosamine functional materials
Chitosan/polyvinyl alcohol (PVA) Aqueous acetic acid Random distribution of β(1 → 4) linked D- Wound dressing with functional materials and (Ohkawa et al., 2004)
glucosamine (deacetylated) and N-acetyl- as carrier material
glucosamine
Hexanoyl chitosan Chloroform Hexanoyl units connected to some of the Wound dressing with functional materials and (Neamnark et al., 2006)
hydroxyl groups of chitosan monomer as carrier material
Dextran Dimethyl sulfoxide (DMSO)/water α-1,6-linked-D-glucose For incorporation of some functional material (Jiang et al., 2004)
Proteins Collagen and gelatin/polyethylene HFIP Irreversibly hydrolyzed collagen As tissue scaffolds and wound healing (Boland et al., 2004;
oxide (PEO) Matthews et al., 2002)
Silk/PEO Formic acid (FA) Fibroin protein Fabric industry (Park et al., 2004)
Human and bovine fibrinogen fraction HFIP/Earle's medium Fibrin protein Blood clotting and other protein reactions (Wnek et al., 2003)
I
Casein/poly ethylene oxide (PEO) THF Calcium, phosphorous and serine residues Food supplement (Xie and Hsieh, 2003)
Zein/hyaluronic acid/PVA Ethanol/water – Material for medical and packaging (Yao et al., 2007)
applications
Nucleic acid DNA Ethanol/water Nucleosides Delivery of genetic material (Fang and Reneker, 1997)

Synthetic and semisynthetic polymers

Polyurethanes DMF Organic units joined by carbamate Protective clothing (Schreuder-Gibson et al., 2002)
links
Polycarbonate Dichloromethane Organic units joined by carbonate Sensor and filter (Bognitzki et al., 2001b)
links
Polyacrylonitrile DMF Acrylonitrile Carbon nanotubes (Dzenis and Wen, 2001)
Polystyrene THF Styrene As catalyst (Torres, 2001)
Poly vinyl phenol THF Phenol moieties connected with Antimicrobial agent (Kenawy and Abdel-Fattah, 2002)
vinyl group
Polylactic acid Dichloromethane Lactic acid and lactide Drug delivery system (Caruso et al., 2001)
(continued on next page)
European Journal of Pharmaceutical Sciences 107 (2017) 148–167
S. Thakkar, M. Misra European Journal of Pharmaceutical Sciences 107 (2017) 148–167

obtained. In proceeding sections our main emphasis will be on elec-

trospinning process.
The electrospinning process utilizes high electrostatic forces for
nanofiber generation; generally from a polymeric solution or melt. The
main assembly of electrospinning unit comprises of electrical supply
Reference

(for generation of high electrical voltage), a syringe (contains solution/

melt/suspension to be electrospun), metallic needle (as a capillary) and
a grounded conductive collector (rotatable drum or static plate type) all
enclosed within a chamber (Schiffman and Schauer, 2008). The process
involves an application of the high electric field to the tip of the needle
which contains the solution fluid held in the form of a droplet, by
means of surface tension. The flow rate of solution/melt is controlled by
a syringe pump. As the electric field is increased the hemispherical
shape of solution droplet at the tip starts to elongate and forms a conical
shape known as Taylor cone. Further increase in electric field reaches a
(Bognitzki et al., 2001a)

point where repulsive forces overcome surface tension and a charged jet
is ejected from the apex of a conical meniscus. This charged jet after
(Li et al., 2002)

ejection from the tip is associated with elongation and various fluid
Applications

instability processes, simultaneously solvent start evaporating; finally,

fibers in the form of a solid non-woven mat are obtained on grounded
collector (Huang et al., 2003). Fluid instability also termed as ‘splaying’
is considered the process of splitting of the single jet into multiple fi-
laments due to repulsive forces generated by charge (Shin et al.,
2001).Various CPPs known to affect nanofiber properties are; applied
voltage, the distance between tip and collector and temperature inside
the chamber. Besides these CPPs, some parameters related to material
Scaffold for tissue engineering

have their impact on nanofiber properties and are known as CMAs.

These CMAs include the concentration of polymer, the viscosity of the
solution, the surface tension of solution and volumetric charge density.
Table 3 gives a cursory glimpse of these mechanistic aspects of nano-
fiber processing and its effect as reported in the literature. Numerous
Sensor, filter

commercial machines are available for electrospinning of feed to na-

Monomer

nofibers from various organizations as Elmarco, Katotech and others

(Angammana and Jayaram, 2016). Mass productivity always remains a
major concern, when it comes to industrial scale production, as in-
dustries engaged in large-scale production of nanofibers, require op-
diones) of glycolic acid and lactic

timum productivity. Despite the fact that lab scale and pilot scale
cyclic dimers (1,4-dioxane-2,5-

production is easier for electrospinning machines; challenges in their

scale-up to industrial level cannot be ignored. Improved techniques
with large mass productivities are emerging these days with the com-
bined efforts of academia and industries. One can select commercially
N-vinyl carbazole

available set-ups with good yield without compromising their specifi-

Solvent used

cations. Elmarco, Finetex, Katotech and Xanofi are some organizations

providing instruments with high productivities of 0.171 kg h− 1,
6.5 kg h− 1, 1.8 km h− 1 and 5 kg h− 1 respectively (Luo et al., 2012;
acid

Teo et al., 2011). Table 4 provide detailed information of commercially

available electrospinning machines along with their working principle.

2.2. Fabrication: mechanistic approaches

There are two ways for incorporation of drug/drug nanoparticles

into the nanofibers namely direct method and indirect method. The
Dichloromethane

direct method utilizes the approach of directly dispersing drug/drug

nanoparticles in electrospun solution. For drug/drug nanoparticles
which are not getting easily and uniformly dispersed within the elec-
THF

trospun solution; indirect method of nanoparticle fabrication is used. A

brief description of both of the methods is given in proceeding sections.
Poly(lactic-co-glycolic acid)

2.2.1. Direct method

The direct method is the conventional and most widely used method
Polyvinylcarbazole
Table 2 (continued)

for incorporation of drug/drug nanoparticles into nanofibers. Drug/

drug nanoparticles can be easily incorporated in nanofibers by pre-
paring homogenous dispersion with the polymeric solution used for
Polymer

electrospinning. Properties of nanofibers made of nanoparticles can be

easily modified by changing the amount of nanoparticles added. In case
one solvent is not suitable for incorporation of both the drug/drug

152
S. Thakkar, M. Misra European Journal of Pharmaceutical Sciences 107 (2017) 148–167

Fig. 2. Few nanofibers based commercial products

produced by electrospinning process.

nanoparticles and polymer to be electrospun; two miscible solvents can
be used to individually dissolve/disperse drug/drug nanoparticles and
subsequently can be mixed with each other. Occasionally Surfactants
can be added to modify the surface of drug/drug nanoparticles to make
them easily dispersed (Zhang and Yu, 2014). Several metal/metal oxide
nanoparticles, polymeric nanoparticles, and organic nano-chains have
been electrospun in different diameters and with different types of
polymers using this direct method of nanoparticle incorporation. Gold
nanoparticles have been electrospun by direct incorporation method for
their use as scaffolds in skeletal muscle tissue engineering (McKeon-
Fischer and Freeman, 2011). Due to photothermal properties of gold
nanoparticles; gold nanoparticle fabricated nanofibers can provide a
therapeutic strategy for cancer treatment (Abadeer and Murphy, 2016)
as well as can be utilized as a source of localized heat for melting of
polymers and alteration in their nanostructure (Maity et al., 2011).
Silver nanoparticles which are well known for their antimicrobial
property have been electrospun in different diameters of gelatin na-
nofiber mats (Rujitanaroj et al., 2008); as well as in PVA nanofibers
(Tan et al., 2016). These metallic nanoparticles have found to be
randomly distributed in polymeric nanofibers; silver nanoparticles have
reported forming the chain-like structure in electrospinning solution of
PVA polymer after mechanical shaking (He et al., 2009). Some nano-
particles are found to be specifically present on the surface and some
are concentrically arranged depending upon the diameter and proces-
sing conditions. If the diameter of a nanoparticle to be incorporated is
below the diameter of nanofibers; these are known to be randomly
arranged. Nanoparticles with a diameter of 260 nm and above are
aligned with the axis of nanofibers and form necklace type structure as
shown in Fig. 3 (Jin et al., 2009; Zhang and Yu, 2014). The size de-
pendent alignment of SiO2 could be attributed to two possibilities as
either smaller size of particles force them to aggregate for a reduction in
overall surface area or the diameter of nanofibers which is larger than
the size of nanoparticles wants them to pack inside in the form of
clusters. When a mixture of two or more solvent is used positioning of
nanoparticles depends upon vapor pressure. SiO2 nanoparticles were
reported to migrate to the surface from the middle of nanofibers when
the vapor pressure of solvent system used (THF/DMF) was decreased
(Hsu and Liu, 2010). Nanofibers of quantum dots (inorganic

Table 3
Effect of CPPs and CMAs on properties of nanofibers.

Parameter/attribute Effect Reference

Distance between tip and collector As distance is decreased nanofibers become more sticky and tend to stick to collector as (Huang et al., 2003)
well as to each other, diameter increases with decrease in distance
Viscosity of solution/melt As viscosity is increased nanofibers become thicker in diameter but are more continuous (Baumgarten, 1971; Doshi and Reneker,
in nature; while reduced viscosity is associated with finer and shorter nanofibers 1993; Huang et al., 2003)
Concentration of polymer Higher the concentration; higher will be the nanofiber diameter, also the chances of bead (Huang et al., 2003; Sill and von Recum,
formation are less in case of higher polymer concentration 2008)
Operating temperature Diameter of nanofiber obtained at higher temperature are generally more uniform (Huang et al., 2003; Zampetti et al., 2011)
Applied voltage Increase in voltage results in larger nanofiber diameter with less bead formation (Shao et al., 2015; Sill and von Recum,
(optimum value is required) 2008; Theron et al., 2004)
Surface tension Reduction of surface tension results in avoidance of bead formation, lower fiber diameters (Doshi and Reneker, 1993; Huan et al.,
are obtained 2015)
Volumetric charge density and solvent Increase in charge density and solvent conductivity results in finer nanofibers with fewer (Sill and von Recum, 2008)
conductivity chances of bead formation and finer diameter
Flow rate Increase in flow rate is generally associated with increased fiber diameter (Megelski et al., 2002; Sill and von Recum,
2008)
Solvent volatility Increased solvent volatility results in higher chances of pores formation and increased (Liu et al., 2015b; Megelski et al., 2002)
surface area
Temperature Increase in temperature is associated with decrease in nanofiber diameter (Chen et al., 2016)
Humidity Formation of circular pores takes place on nanofibers with increase humidity (Chen et al., 2016)
Concentration of drug and polymer In case of electro-spraying, reduction in concentration of polymer usually results in (Parhizkar et al., 2016b)
uniformly smooth particle with reduced size, and polydispersity index (PDI)

153
S. Thakkar, M. Misra European Journal of Pharmaceutical Sciences 107 (2017) 148–167

Table 4
Commercially available electrospinning instruments, their manufacturers, and principle of working.

Name of the provider Area Name of the instrument Working principle Pictorial view

Elmarco Czech Republic NS 1S500U Production Line Smallest nanofiber production equipment, working on the
principle of bath spinning using a rotatory cylinder

Katotech Japan Nanofiber electrospinning Capable of producing 50–800 nm fibers, working on the
unit (NEU) principle of nozzle spinning with 400 needles

Nadetech innovations Spain ND-ES lab electrospinning Nozzle spinning with precise control on all parameters
unit

IME technologies Netherland EC-DIG 4 integrated nozzle technology

Finetex technology South Korea – Nozzle spinning with block nozzles

Fig. 3. SEM and TEM images of electrospun PVA/SiO2 fibers with different SiO2 diameters: (A, B) SEM images of 143 nm, PVA: SiO2 = 500:500; (C, D) SEM images of 265 nm, PVA:
SiO2 = 800:200; (E, F) SEM images of 910 nm, PVA: SiO2 = 500:500; work distance 10 cm, voltage 10 kV, TEM images of (G) TEM images of 143 nm, PVA: SiO2 = 500:500, (H) TEM
images of 265 nm, PVA: SiO2 = 700:300, (I) 910 nm, PVA: SiO2 = 300:810 (after removing part of water in the solutions); work distance 10 cm, voltage 15 kV.
“Reprinted (adapted) with permission from (Jin et al. Fabrication of necklace-like structures via electrospinning. Langmuir 2009, 26, (2), 1186–1190.) Copyright (2010) American
Chemical Society.”

154
S. Thakkar, M. Misra
nanocrystals) have shown to have luminescent property. A Photo-
luminescence spectrum of CdTe quantum dots in nanofiber form was
found to be blue shifted due to different quantum confinement effect in
different media (Cho et al., 2010). Nanoparticles have already been
established as a platform for delivery of gene, proteins, and drugs to the
biological system. The simplest way of delivery of aforementioned xe-
nobiotic to the body is encapsulation into polymeric nanoparticles;
which can be mechanically strengthened by means of electrospinning in
nanofiber. Innumerable polymeric nanoparticles have been successfully
electrospun in nanofiber sheets; such as poly(Ɛ-caprolactone), poly
(styrene-block-isoprene), polyacrylamide, poly(lactide-co-glycolide),
polyurethane, poly(methyl methacrylate) and poly(hexamethyleneadi-
pate)-PEO block copolymers (Zhang and Yu, 2014). Coaxial electro-
spinning and blending represent a part of direct incorporation methods.
A unique approach for the direct method of incorporation is elec-
trospinning of cyclodextrin inclusion complex drug delivery systems. A
small number of researchers have reported polymer free electrospin-
ning of various drug candidates with incorporation into cyclodextrin
inclusion complexes. Celebioglu et al. have reported the formation of
polymer free nanofibers with electrospinning of highly concentrated
(160% w/v) aqueous solutions of hydroxypropyl-β-cyclodextrin
(HPβCD) as such, along with urea and its inclusion complexes with
triclosan as depicted in Fig. 4 (Celebioglu and Uyar, 2011). Urea is used
as it is well known for breaking hydrogen bonds of cyclodextrins and
prevents the aggregation of these during the formation of nanofibers at
an optimum concentration.
2.2.2. Indirect method
As described in preceding sections for some drugs/drug nano-
particles which are not homogeneously dispersed in electrospinning
solution even after the use of dispersing agents; surface treatment be-
comes a necessary step for incorporation into nanofiber mats. Based on
different methods for surface treatment nanoparticles can be formed on
the surface or within the nanofiber. Surface treatment of electrospun
nanofibers is very easy way to get nanoparticles attached on the
Fig. 4. SEM image of (A) HPβCD nanofibers obtained from a 160% (w/v) HPβCD solution and (B) HPβCD nanofibers with 5% (w/w) urea (C) HPβCD nanofibers with 10% (w/w) urea
and (D) bead structures obtained from 160% (w/v) HPβCD containing 20% (w/w) urea.
“Reprinted (adapted) with permission from (Celebioglu et al. Electrospinning of polymer-free nanofibers from cyclodextrin inclusion complexes. Langmuir 2011, 27, (10), 6218–6226.)
Copyright (2011) American Chemical Society.”
155
European Journal of Pharmaceutical Sciences 107 (2017) 148–167
surface; In general, for surface loading of nanoparticles, nanofibers are
dipped in colloidal dispersions of nanoparticles, to allow surface ad-
sorption of these nanoparticles by means of various types of interac-
tions. Electrostatic forces, hydrogen bonding and interactions between
various functional groups are some of the interactions responsible for
this type of adsorption. Mahanta et al. have shown the enhanced effi-
cacy of PVA nanofibers to adsorb gold and silver nanoparticles after
surface modification of hydroxyl group with thiol and amine group.
They have shown 90% increase in the propensity of nanofibres to in-
teract with silver and gold nanoparticles, upon surface modification
(Mahanta and Valiyaveettil, 2011). In- situ reduction (Chen et al., 2008;
Li et al., 2004), hydrothermal assisted process (Hedenquist and
Lowenstern, 1994; Shi et al., 2013), ultra-sonication and sputtering
etching (Hsu et al., 2013; Hsu et al., 2012; Wu et al., 2013) are some of
the indirect methods used for surface fabrication of nanoparticles to
nanofibers (Zhang and Yu, 2014).
The other way of drug/drug nanoparticle incorporation into nano-
fibers is the formation of nanoparticles within electrospun nanofibers.
In this technique, metallic or ceramic precursors are first electrospun in
the form of nanofibers and then other treatments like calcination, gas-
solid reaction, and laser ablation are done to form nanoparticles within
nanofibers (Zhang and Yu, 2014).
There are certain limitations of the indirect method as many of these
are more suitable for incorporation of metallic nanoparticles. Indirect
fabrication requires polymeric nanofiber to be stable and not to get
dissolved in the colloidal solution used for pretreatment. In-situ reduc-
tion method is associated with limitation of re-oxidation, further
treatments like vacuum drying at room temperature and use of organic
stabilizers can help to prevent these problems but at the same time
increases the cost of all over processing (Li et al., 2004). Hydrothermal
assisted process is a well-known method for nanoparticle fabrication;
different morphologies (sphere, plate, and rod) of various nanoparticles
can be easily synthesized on electrospun nanofiber surfaces. Both the
direct and indirect methods have their own advantages and limitations;
depending upon the requirements of the user, limitations can be
S. Thakkar, M. Misra
overcome by subsequent treatment strategies.
Apart from electrospinning; electro-spraying can be utilized for di-
rect production of nanoparticles (desired size and morphology) by
controlling properties of polymeric solution along with processing
conditions as described in preceding sections. In line to this Eltayeb
et al. have reported production of core-shell lipid nanoparticles using
ethyl-vanillin as active ingredient and stearic acid as model shell for
controlled release of actives. After optimization of process parameters,
nanoparticles were shown to have size in range of 60–70 nm with en-
capsulation efficiency of 70% (Eltayeb et al., 2016). In the same year
Parhizkar et al. have reported production of cisplatin loaded PLGA
nanoparticles for controlled drug delivery. Applied voltage, flow rate
and the concentration of cisplatin and polymer were found to be key
parameters affecting particle size. Prepared nanoparticles with 70%
entrapment efficiency demonstrated sustained release of drug
(Parhizkar et al., 2016a). Same group have reported production of core
shell nanoparticles of same drug by electrohydrodynamic atomization
process (Reardon et al., 2017). Studies show the potential of electro-
spraying technique for production of various nanoparticles with effec-
tive control over size. Electrospinning technique is almost fully ex-
plored in terms of drug delivery but there is room for electro-spraying
which can further be explored in various drug delivery processes.
3. Control of drug release from nanofibers
Nanofibers can be used as release rate controlling devices based on
the choice of inactive used for fiber formation. Drug release from na-
nofibers could be due to desorption of drug from the surface, diffusion
from pores and/or matrix degradation. These all processes of drug re-
lease are likely to get affected by choice of inactive (polymer or other
material), porosity, morphology, and geometry of nanofibers (Goonoo
et al., 2014). Generally smaller the diameter of nanofiber faster the
release rate is considered from it based on the fact that smaller diameter
fiber has higher surface area and dissolution rate. Later findings sug-
gested that drug release cannot be solely governed by diameter and at
the same time effect of porosity is to be considered. It is often shown
that thicker nanofibers with very high porosity release drug faster as
compared to thinner fibers with low porosity. Nanofiber alignment is
another parameter known to affect drug release and in general rando-
mized pattern is associated with faster drug release because of in-
creased tendency of water uptake (Cui et al., 2006).
3.1. Polymer parameters affecting drug release
Various polymers related parameters are known to affect drug re-
lease from nanofibers including polymer composition, crystallinity and
molecular weight of the polymer. The polymer composition is a key
parameter leading to drug loading and release from nanofibers; reports
says that use of hydrophilic and amphiphilic copolymers results in in-
creased drug loading and decreased chances of burst release of the drug
(Chou and Woodrow, 2017). Polymers with very high crystalline re-
gions are known to have slower release rates as compared to amorphous
regions due to very low water uptake in highly ordered three-dimen-
sional arrays of crystals (Chou et al., 2015). Chou et al. examined the
effect of the mechanical property of drug-eluting nanofiber on drug
release by taking tenofovir as a model drug (Chou and Woodrow,
2017). Authors have conducted release studies in 15% (wt%) nanofi-
bers with varying concentrations of PCL and PLGA after mechanical
deformation to show the effect of mechanical properties of polymeric
nanofibers on drug release as shown in Fig. 5. It was found that the drug
release was sustained in nature when no mechanical stretching was
applied. In contrast all the fibers when stretched to the levels of failure
there was a shift in drug release from sustained to faster drug release as
PCL/PLGA (20:80) showed around 70% of drug release in 96 h after
stretching as compared to the almost same drug release in 240 h for un-
stretched sample (Chou and Woodrow, 2017). This faster release
156
European Journal of Pharmaceutical Sciences 107 (2017) 148–167
achieved could be due to one of the two reasons. First being a reduction
in fiber diameter owing to stretching could help in the faster release as
fiber diameter is known to affect drug release. The second reason could
be smaller diameter which can lead to decreased distance to diffuse for
drug particles situated in the core of nanofibers. In addition to this
PLGA rich nanofibers have shown surface imperfections due to the re-
lease of drug as shown in Fig. 5.
3.2. Drug-related parameters affecting drug release
Drug-related parameters affecting its release form nanofibers are
drug loading, molecular weight, the physical state of drug, solubility,
and drug-polymer interactions (Hrib et al., 2015). In general, higher
drug loading is associated with the faster release. The crystalline form
of the drug gets deposited on nanofiber surface and provides burst re-
lease; while amorphous form gets deposited deeper inside and get re-
leased in a sustained manner. Low molecular weight drugs are known
for their fast release rate (Natu et al., 2010). Fig. 6 provides glimpse of
drug related parameters affecting drug release.
3.3. Stimuli-responsive drug delivery systems
Research in the field of polymer sciences has given new opportunity to
formulation scientist by the discovery of stimuli-responsive polymers.
Stimuli-responsive systems are dependent upon the rate by which stimuli
get transferred to the corresponding responsive material. As nanofibers are
the concerns; their high surface area to volume ratio makes them the
suitable candidate for faster response as compared to other materials
(Frenot and Chronakis, 2003; Zhang and Yu, 2014). Various electrospun
nanofibers are reported for stimuli-responsive delivery upon exposure to
external stimuli as pH, temperature, light and others. Demirci et al. have
reported pH sensitive nanofibers of polymer poly(4-vinylbenzoic acid-co-
(ar-vinylbenzyl)trimethylammonium chloride) [poly(VBA-co-VBTAC)] for
stimuli controlled the release of drug ciprofloxacin. The release profile of
drug was checked in acidic, neutral and basic medium to check the pH-
responsive behavior of drug-loaded nanofibers (Demirci et al., 2014) as
depicted in Fig. 7. The study has shown the homogeneous dispersion of the
crystalline drug in an amorphous form supported by the absence of any
diffraction peak of drug crystals in XRD analysis. In this study authors have
examined release profile for 720 min (12 h) which doesn't seem to be
enough for determination of mechanism of release (whether diffusion/
permeation controlled or via degradation of the polymeric matrix). Drug
ciprofloxacin used here as the model drug is known to be showing pH
dependent solubility of its own; increase in drug release examination time
could have shown the clearer view of release mechanism involved as both
the drug as well as the polymer is reported to have pH dependent beha-
vior. In another study conducted by Toncheva et al. the same drug ci-
profloxacin was incorporated in nanofibers of poly(L-lactide-co-D,L-lactide)
in crystalline form. Results of release study conducted in buffer pH 7.4
have shown initial burst release of 50% in initial 400 min; further ex-
amination for drug release up to 24 h does not lead to any significant
increase in the amount. This clearly showed the release of drug which was
diffusion controlled. Authors in this study have reported the increase in %
drug release by the addition of hydrophilic polymer PEG which could be
due to easier permeation of release media upon addition of hydrophilic
polymer (Toncheva et al., 2012).
In line with this Li et al. have reported the formation of hybrid
nanofibers which can be reversibly controlled to deliver cells and drug
both by virtue of near infra-red (NIR) light. Hybrid nanofibers were
composed of poly (N-isopropyl acrylamide), silica-coated gold nanorods
and polyhedral oligomeric silsesquioxanes. Co-electrospun nanofibers
of these showed very large volume change of about 83% on exposure to
NIR light; interestingly this change is reported to be reversible with
proper retention of nanofiber structures (Li et al., 2016). Doxorubicin
was used as a model drug and the nanofibers were reported to reduce
cell viability up to 97% in human cervical cancer HeLa cells lines.
S. Thakkar, M. Misra European Journal of Pharmaceutical Sciences 107 (2017) 148–167

Fig. 5. Cumulative release curves of PCL/PLGA blend fibers loaded with 15% TFV (a) prior to mechanical stretching (b) after mechanical stretching to failure. (Open circles) 100PCL,
(open squares) 80PCL/20PLGA, (open triangles) 60PCL/40PLGA, (filled circles) 40PCL/60PLGA, (filled squares) 20PCL/80PLGA, and (filled triangles) 100PLGA. (c) SEM images of PCL/
PLGA blend fibers mechanically stretched followed by a 10-day in vitro release study, scale bar = 2 μm.
“Reprinted (adapted) with permission from (Chou et al. Relationships between mechanical properties and drug release from electrospun fibers of PCL and PLGA blends. J. Mech. Behav.
Biomed. Mater. 2017, 65, 724–733.) Copyright (2016).”

Fig. 6. Effect of nanofiber diameter, porosity, nano-

fiber alignment, polymer crystallinity and molecular
weight on drug release.

Studies on similar lines have shown the potential of nanofibers in en-
capsulating and delivering NIH3T3 fibroblast cells in their functional
form. In this study photothermal property of gold nanostructures were
used to alter the swelling behavior of poly (N-isopropyl acrylamide)
which in turn was responsible for the release of drug/cells. The increase
in NIR laser density and time is reported to be associated with the in-
crease in temperature. Precaution is required in the selection of NIR
exposure intensity and time which could lead to cell death at higher
temperatures when the objective of the study is cell delivery in the
functional state. The further study reported an in-vitro therapeutic effect
of released doxorubicin alone; whereas hyperthermia is well-known
therapy for cancer treatment. Study of combination effect of
hyperthermia along with drug could have resulted in better therapeutic
effects as well as a reduction in required dose of the drug. Liu et al. have
reported the formation of nanofibers with thermo-sensitive copolymer
poly(N-vinyl caprolactam-co-methacrylic acid) (PNVCL-co-MAA);
choosing captopril and ketoprofen as model drug candidates. The de-
veloped nanofibers exhibited slow release lasting several hours at 40 °C
while burst release of few seconds was observed at 20 °C; following
Korsmeyer–Peppas model as a major drug release mechanism (Liu et al.,
2016). Authors have clearly mentioned mechanism of release as below
lower critical solution temperature (LCST) polymer fiber is hydrophilic
and drug release is diffusion controlled. In contrast above LCST polymer
fiber behaves as hydrophilic one and drug release becomes slower with

157
S. Thakkar, M. Misra
Fig. 7. Stimuli-responsive drug release from various nanofibers.
more dependence on polymer degradation. Huang and coworkers effi-
ciently worked on the preparation of thermal and pH sensitive nano-
fiber scaffolds of poly(NIPAAm-Co-N-methylo acrylamide) (PNN) and
chitosan. They have reported thermal and pH sensitive release of drug
doxycycline hyclate from PNN/chitosan nanofibers (Huang et al.,
2014). Most of the researchers have failed to report release mechanism
of drug which could be an important parameter governing the overall
performance of stimuli-responsive polymeric nanofibers. Based on
aforementioned studies one can conclude that nanofibers can be ef-
fectively used as good candidates for stimuli-responsive drug delivery.
4. Applications in drug delivery
Electrospinning being very versatile technique has been recognized
useful in the formation of nanofibers for drug delivery applications.
Recently nanofibers have gained huge attention as new drug delivery
platforms based on the principles of increase in dissolution rates of the
drug due to a tremendous increase in surface area. Besides this nano-
fibres are also amenable to easy modifications to alter release rate
controlling properties owing to stimuli-sensitive nature of some poly-
mers used in electrospinning, which can be suitably tweaked. Selection
of inactive material (polymers) for fiber formation can be based on the
release properties desired like either only diffusion controlled or dif-
fusion controlled along with nanofiber degradation as described above.
Similarly, various incorporation techniques (direct or indirect) can be
used to load drug onto nanofibers as previously described in preceding
section. Proceeding sections will deal with the use of nanofibers as drug
delivery systems for various disease/disorders of the body.
158
European Journal of Pharmaceutical Sciences 107 (2017) 148–167
4.1. Nanofibers for management of diseases/disorders related to brain
Dementia associated with Alzheimer's disease is a major neurode-
generative disease in elderly patients. Various drugs used for treatment
are donepezil, rivastigmine, galantamine and others. Gencturk et al.
have reported preparation of polyurethane/HPC nanofibers of drug
donepezil hydrochloride for effective management of dementia asso-
ciated with Alzheimer's disease. The transdermal polymeric mat of the
drug showed effective diffusion controlled delivery of drug following
Korsmeyer–Peppas release kinetics. In-vitro cytotoxicity studies by MTT
assay has shown nanofiber mat to be well tolerated and non-irritant for
skin (Gencturk et al., 2016). Aricept, marketed product of drug done-
pezil hydrochloride is present in the form of orally disintegrating tablets
(ODT) having 5 and 10 mg of the drug. Incorporation of the drug in
nanofiber mat could provide easy control over dose as well as can result
in better patient compliance in dementia. Traumatic and/or surgical
brain injury is associated with various pathological changes; giving rise
to severe parenchymal damage in the brain. Sulejczak et al. have re-
ported delayed/reduces neuro-destructive phenomena after dressing
with L-lactide-caprolactone copolymer nanofiber net; whereas un-
dressed rat model of surgical brain injury was having massive neuro-
degeneration and scar formation (Sulejczak et al., 2014). Experimental
results proved the ability of biodegradable polymer-based nanofiber
mats in reducing scar formation associated with various brain injuries
which otherwise could hamper the proper functioning of the brain.
Xie et al. have reported formulation of Paclitaxel-loaded PLGA na-
nofibers for the treatment of brain tumor as alternative drug delivery
device. The encapsulation efficiency of the drug in nanofibers was
found to be more than 90%. DSC analysis was carried out in the study to
see the solid state property of drug, and it was found to be present in a
S. Thakkar, M. Misra
solid solution state. Sustained release of paclitaxel was reported along
with IC50 value which was comparable to the commercial product in
the cytotoxicity assay (Sulejczak et al., 2014). The main limitation of
the aforementioned study is a requirement of preliminary surgery for
positioning of drug liberating biodegradable implant in the part having
a cancerous growth. Proper studies mentioning any possible dose
dumping should be conducted when working with anticancer drug-
loaded nanofibers which would otherwise be associated with severe
toxicities. In most of the studies reported till date, issues related to the
homogeneity of drug distribution is not addressed. This becomes even
more pertinent, if drug under consideration is extremely potent (like
anticancer drugs) and not completely soluble in the prepared polymer
solution, resulting in non-homogenous distribution. Therapeutic agents
showing an effect at very low concentration must be properly examined
for their homogeneity in the sample, particularly when the drug is to be
incorporated in suspended form or in crystalline form. It is advisable
under such circumstances to collect samples of uniform size (of drug
incorporated nanofiber sheet) from different parts of collector plate and
analyze for the amount of drug to rule out any drug uniformity related
issues. Fig. 8 displays role of nanofibers in the management of brain
disorders. Except few, most of the studies have not reported the form of
drug (crystalline or amorphous) as well as % loading, which could be an
important parameter for drug release properties from nanofibers as
described in preceding sections. The form of a drug not only gives the
idea about release profile but is also essential to find out the site where
probable deposition of the drug will occur (on the surface or deeper
inside the nanofiber), making it an important parameter for formulation
development scientist.
4.2. Nanofibers in the management of diseases/disorders related to eye
Researchers have reported the efficient use of nanofibers with the
drug for treatment of various diseases and disorders related to eye.
Cejkova et al. have shown treatment of alkali-injured cornea with
Fig. 8. Electrospun nanofiber mediated drug therapy for brain diseases/disorders.
159
European Journal of Pharmaceutical Sciences 107 (2017) 148–167
cyclosporine A nanofibers as an alternative mode of therapy. poly(L-
lactic acid) (PLA) was used as a polymer for nanofiber formation with
modified needleless Nanospider™ technology. Authors have checked
the extent of inflammatory reaction and corneal healing by macro-
scopic, immunohistochemical and biochemical examinations. As com-
pared to blank nanofibers and eye drops of drug cyclosporine A; na-
nofibers of the drug were found to be more effective in suppression of
inflammatory response and neovascularization. The proposed reason
for eye drops of the same drug to be less effective was lesser contact
time with an injured eye (Cejkova et al., 2016). Authors have reported
representative photographs of alkali-injured eye after 12 days of injury
along with eyes after treatment in various groups. It was shown that
immediately after the alkali injury, the cornea became opalescent. On
day 12 after the injury, the untreated injured corneas were showing
very high vascularization, and corneal transparency was nearly lost
while in the case of eye drop/blank nanofiber treated eyes were shown
to have partial restoration of corneal transparency. In compared to all
these drug-loaded nanofibers treated eyes corneal neovascularization
was strongly suppressed and corneal transparency was restored along
with restoration of physiological levels of central corneal thickness as
shown in Fig. 9. These findings suggested the effective use of drug
nanofibers for the treatment of various eye diseases/disorders over-
coming the major hurdle associated with conventional ocular drug
delivery. Preclinical studies in rabbit eye have depicted more effica-
cious delivery of drug and recovery as compared to conventional eye
drops however applicability of dosage form is still a cause for concern.
In this study authors have sutured drug containing nanofiber sheet to
conjunctiva of eye, requiring a skilled personnel, a process which might
be cumbersome, if extrapolated in humans. Gagandeep et al. have re-
ported treatment of another disorder related to eye, glaucoma with
nanofibers of drug timolol maleate and dorzolamide hydrochloride.
They have reported preparation of polycaprolactone (PCL) and PVA
nanofibers of these drug candidates and evaluated for the in-vivo effect
of nanofiber formulation by inserting it in a cul-de-sac of the glaucoma
S. Thakkar, M. Misra
Fig. 9. The appearance of injured and treated corneas. Representative photographs of healthy corneas (A), corneas immediately after the injury with 0.25 N NaOH (B), injured corneas
with nanofibers sutured to conjunctiva (C), injured untreated corneas on day twelve after the injury (D), injured corneas treated with CsA drops on day twelve after the injury (E) or
injured corneas treated with nanofibers drug-free (day twelve after the injury) (F) or injured corneas treated with CsA-loaded nanofibers (day twelve after the injury) (G).
“Reprinted (adapted) with permission from (Cejkova et al. Treatment of alkali-injured cornea by cyclosporine A-loaded electrospun nanofibers–An alternative mode of therapy. Exp. eye
Res. 2016, 147, 128–137.) Copyright (2016) Elsevier.”
induced rabbit. Results have shown the potential of formulation for
effective use in glaucoma; as intraocular pressure was found to be
significantly reduced when compared with commercial eye drop for-
mulation (Garg et al., 2014). Hsu et al. have reported ophthalmic de-
livery of drug dexamethasone for various disorders of eye. Many dis-
eases related to eye require instillation of dexamethasone eye drops 4–6
times a day and long term administration of disease is associated with a
number of local and systemic side effects. Authors have shown for-
mulation of PCL nanofibers and microbeads for extended release of the
drug. This benefit of extended release for achieving efficacy with re-
duced side effects was proposed due to increased crystallinity (Hsu
et al., 2016). Fig. 10 have shown diagrammatic presentation of the
strategies.
4.3. Nanofibers in the management of diseases/disorders related to ear
Chances of ear infection with Methicillin-resistant Staphylococcus
aureus (MRSA) are getting increased these days in patients with middle
ear surgery. The major problem associated with the treatment of peri-
prosthetic infections is to treat an established biofilm. These biofilms
are often known to be formed on implanted medical device like ossi-
culoplasty prostheses and implantable hearing devices. Once formed
these are hard to disrupt and are associated with endo-cochlear in-
flammation, persistent non-traceable infections along with patient dis-
comfort (Jang et al., 2015). Authors have reported the formation of
biocompatible and biodegradable PCL/PEO nanofibers for effective
delivery of vancomycin for prevention of MRSA biofilm on the ossicular
prostheses and otitis media. A triphasic release profile was followed by
a drug from drug-loaded nanofibers. In-vitro studies revealed the ab-
sence of biofilm on implanted medical devices. Otitis media was found
to be devoid of MSRA after treatment with drug-loaded nanofibers
(Jang et al., 2015). This seems to be an interesting and novel way of
avoiding infections in otitis media during implantation of medical de-
vices and can be explored further to deliver various classes of anti-
biotics. Diagrammatic representation is shown in Fig. 11.
4.4. Nanofibers in the management of cardiac and vascular diseases/
disorders
When heart receives lower volumes of oxygenated blood, it results
in Angina pectoris. Potassium channel openers are the class of
160
European Journal of Pharmaceutical Sciences 107 (2017) 148–167
compounds which are now-a-days frequently used for the conditions of
hypertension as well as angina pectoris. Singh et al. have reported
preparation of nanofiber formulation of such class of compounds and
shown its use for the treatment of conditions like angina as depicted in
Fig. 12. Nicorandil as drug candidate is associated with problems of low
bioavailability, slow onset of action and mucosal ulceration at the site
of action. Several carrier systems have been tried with drug and have
shown no improvement for complications of mucosal ulceration and
delayed onset of action. Author and coworkers have reported pre-
paration of polymeric nanofibers of vitamin B 12 and a blend of hya-
luronic acid and PVA loaded with nicorandil drug for its sublingual
delivery. Electrospun nanofibers were found to be uniform, non-beaded
with the diameters of 200–450 nm. In-vitro drug release has shown
sustained drug release over a long period of time. Histopathological
images revealed the absence of mucosal ulceration at the site of ap-
plication. This study shows the potential of nicorandil nanofibers in
overcoming hurdles related to its delivery (Singh et al., 2015). These
kinds of approach could be effectively used to deliver drugs having
solubility issues and require instant effect such as in the management of
pain. Besides, therapeutic actives having very high first pass metabo-
lism can be formulated as oral patches having nanofibers consisting of
immediate release polymers.
Intracranial aneurism is another disease related to a cerebrovascular
system which ultimately can lead to hemorrhagic stroke, brain damage
and death. Wang et al. have reported formulation of poly(L-lactide-co-
caprolactone) nanofibers loaded with a potent anticoagulant, heparin
and vascular endothelial growth factor (VEGF). Fibers were reported to
be covered on stent surface; for use in the treatment of intracranial
aneurism. Release profiles have shown the long-lasting release of both
the moieties for more than 30 days without any initial burst release
effect. This study has shown the potential of drug nanofiber coated stent
for treatment of aneurism and induction of endothelialization (Wang
et al., 2015b).
For many reasons vascular surgery is associated with prosthetic
graft infections. Drug delivery system which can deliver antibiotics
locally in a pattern of sustained release can provide an effective way of
treatment for these types of infections. Liu et al. have reported pre-
paration of biodegradable nanofiber loaded vascular prosthetic graft for
sustained release and local delivery of vancomycin in the treatment of
vascular infections. Eluting method has shown the higher release of
drug for more than 30 days. Finally in-vivo implantation of nanofiber
S. Thakkar, M. Misra
Fig. 10. Nanofibers for treatment of ocular ailments.
loaded grafts in subcutaneous pockets of rabbits has shown the poten-
tial of these systems for effective of prosthetic graft infections (Liu et al.,
2015a).
4.5. Nanofibers in the management of diabetes
Diabetes is one of major and life-threatening disease of the 21st
century. Several microvascular and macrovascular complications are
associated with diabetes as effect on retina, kidneys and risks of heart
diseases. These complications can generally be minimized with the
control of blood glucose level. Electrospinning technique has been
utilized in the formation of biosensors as well as in the treatment of
disease. Vellayappan et al. have shown an effective comparison of
conventional biosensors with advanced electrospun biosensors which
provide insight into the application of electrospinning for the
Fig. 11. Drug-loaded nanofiber therapy for ear infection.
161
European Journal of Pharmaceutical Sciences 107 (2017) 148–167
preparation of biosensors (Vellayappan et al., 2016). Injectable are able
to provide effective delivery of insulin/anti-diabetic drugs but is asso-
ciated with poor patient compliance. To develop oral means of ad-
ministration for diabetes treatment is a great challenge for pharma-
ceutical scientist till date. Xu et al. have reported preparation of
gelatin/insulin fibers by co-electrospinning for transbuccal delivery of
insulin. Extended release of insulin was found for 4 h. Released insulin
was checked for showing activity and was found to successfully trigger
intracellular AKT phosphorylation. Results concluded successful trans-
buccal delivery of insulin from gelatin/insulin fibers formulated by co-
electrospinning of gelatin and insulin (Xu et al., 2015). Another elec-
trospinning based nanofiber formulation for anti-diabetic effect is re-
ported by Modgill et al. in 2015. They have shown the formation of
linagliptin loaded PVA nanofibers to form a biodegradable polymeric
sheet as shown in Fig. 1. Prepared nanofibers were reported to have
S. Thakkar, M. Misra
encapsulation efficiency of 92%. When evaluated for mucoadhesive
strength drug-loaded nanofiber patches were found to have higher
mucoadhesion as compared to blank nanofibers; probably due to higher
surface area and water holding capacity. Results were found to be
comparable with commercial formulation upon evaluation of in-vivo
activity (Modgill et al., 2015). Choi et al. have reported nanofibers with
basic fibroblast growth factor (bFGF) and epidermal growth factor
(EGF) for the treatment of diabetic ulcers and reported an increase in
accumulation of both collagen and cemented matrix of keratin. These
findings show promising potential nanofibers mats in the treatment of
diabetic ulcers (Choi et al., 2011).
4.6. Nanofibers in the management of rheumatic diseases/inflammatory
autoimmune diseases
Inflammatory diseases are associated with pain/discomfort and may
require acute/chronic treatment with anti-inflammatory drugs. As de-
scribed in preceding sections, the composition of nanofibers can be
easily modified to have either instant release or controlled or sustained
release depending upon the properties required. On these basis nano-
fibers present promising drug delivery technique for the acute/chronic
therapy of inflammatory diseases. Meng et al. have reported prepara-
tion of fenbufen loaded PLGA/gelatin nanofibers for effective treatment
of rheumatoid arthritis and osteoarthritis. When investigated regarding
drug release, the release was found to increase with an increase in
gelatin content and randomness of nanofiber arrangement as shown in
Fig. 12. Thus effective control over drug release was reported with these
drug-loaded composite nanofibers (Meng et al., 2011). A possible
reason for the increase in drug release could be the addition of gelatin.
Addition of gelatin increases the charge density of the solution which
ultimately improves the stretching force and the self-repulsion of the jet
leading to decrease in the fiber diameter and subsequently increase in
drug release. Fig. 12 provides glimpse of various nanofiber mats formed
by PLGA alone and after addition of gelatin. In line with this Park et al.
have reported ketoprofen loaded PLA nanoparticles for controlled re-
lease of drug. When evaluated to check release pattern nanofibers
showed, increased release rates with an increase in drug content as well
as temperature (Park and Lee, 2011).
Saifaka et al. on similar lines reported preparation of teriflunomide
loaded nanofibers of PLA and poly(butylene adipate) (PBAd) blends.
Various techniques were used to check miscibility of polymeric blends
and state of drug been incorporated. The drug was reported to be in-
corporated in amorphous form (Siafaka et al., 2016). In-vitro drug re-
lease was found to be dependent upon the diameter of nanofibers. For
analgesic and anti-inflammatory drugs selection of polymer plays an
important role as in some chronic diseases sustained release of the anti-
inflammatory drug is required (Fig. 13).
4.7. Nanofibers in the management of lung diseases
Pneumonia is very common lung infection caused by Streptococcus
pneumoniae and is leading cause of deaths till date in developing as well
as developed countries (Shaddock, 2016). Adibkia et al. have reported
nanofiber formulation of drug azithromycin for enhanced antimicrobial
effect against Streptococcus pneumoniae and Staphylococcus aureus. Na-
nofibers made up with eudragit RS 100 was found to be showing en-
hanced efficacy against Streptococcus pneumoniae as compared to Sta-
phylococcus aureus which showed lower MIC (minimum inhibitory
concentration) values of 40 μg/ml and ˃120 μg/ml respectively. The
probable reason given was enhanced adsorption efficiency of nanofi-
bers on capsulated cell wall; which can provide an antibiotic depot on
the bacterial surface. Results made it clear that these antibiotic drug-
loaded nanofibers can be a potential candidate for the eradication of
Pneumonia (Adibkia et al., 2016).
Švachová et al. have reported formulation of novel gelatin/oxy-
cellulose nanofibers for suitable lung disease modeling and evaluated
162
European Journal of Pharmaceutical Sciences 107 (2017) 148–167
them for inhibitory effect against Escherichia coli. They have also re-
ported it to be effective for testing of anticancer drugs (Švachová et al.,
2016).
4.8. Nanofibers in the management of AIDS
AIDS is a syndrome due to infection from human immunodeficiency
virus (HIV) which adversely affects immunity of the patient making
him/her more vulnerable to other infections. It generally requires a
combination or multidrug therapy with antiretroviral agents. Blakney
et al. have reported preparation of drug-loaded PVA nanofibers for
combined therapy of tenofovir and levonorgestrel for prevention of HIV
acquisition. Results show preservation of antiviral activity of drug te-
nofovir after release from nanofibers without any toxic effects. The
presence of levonorgestrel was shown not to affect the release and
pharmacodynamic profile of tenofovir (Blakney et al., 2014). Ball et al.
have reported preparation of nanofibers of PEO/PLLA blends loaded
either with maraviroc or acyclovir for activity against HIV infection.
Drug release profile for both the drugs was found to be varied based on
the ratio of PEO/PLLA blends. Effective HIV inhibition was reported for
drug-loaded fibers upon in-vitro evaluation (Ball et al., 2012). Zovirex™
is the marketed product of acyclovir used for oral administration; these
acyclovir-loaded nanofibers can provide an easy alternative if bioa-
vailability profiles are similar. Comparison of the prepared formulation
with marketed product in term of release could have provided for easy
comparison.
4.9. Nanofibers in the management of diseases/disorders related to oral
cavity
Candida albicans is one of the very common organisms present in
oral and gastrointestinal tract (GIT) mucosa. Oral cavity environment
change is associated with a change in pathogenic state of the bacteria
which can ultimately lead to acute and/or chronic infections like can-
didal mucositis and denture stomatitis. Santos et al. have reported na-
nocrystal based formulation of a common antifungal ingredient present
in mouthwashes to access the effective concentration of drug along with
the potential of nanofiber-based systems in the delivery of an antifungal
agent for these types of oral infections. PVP/PMMA nanofibers were
used to incorporate cetylpyridinium chloride as antifungal agent and
investigation of antifungal activity has shown the potential of this
system for use in oral infections (Santos et al., 2014).
Chemotherapy/radiation therapy of cancer is associated with
painful inflammation of oral mucosa known as oral mucositis. Tort et al.
have reported preparation of glutamine loaded sodium alginate nano-
fibers with mucoadhesive properties for treatment of oral mucositis.
Drug release profile has shown the release of 85% drug from nanofibers
within 4 h and shown the ability of system for effective mucoadhesion
and drug delivery for prevention of inflammatory disease (Tort and
Acartürk, 2016).
Root canal infection is a very common problem of professionals
working in the field of dentistry. Pankajakshan et al. have reported
triple antibiotic nanofibers for intracanal drug delivery. In this study
polydioxanone nanofibers were prepared with electrospinning tech-
nique and loaded with a combination of triple antibiotics (me-
tronidazole, minocycline and ciprofloxacin) and it's; effect on bacterial
death was evaluated. Results from confocal laser scanning microscopy
have shown significant bacterial death upon exposure to antibiotic
containing nanofibers (Pankajakshan et al., 2016).
4.10. Nanofibers in the management of various types of cancers
Cancer is known to be disease condition characterized by un-
controlled growth of cells which are capable of escaping general de-
struction mechanisms of the body. Statistical reports have suggested an
increase in new cases along with mortality rates of patients suffering
S. Thakkar, M. Misra European Journal of Pharmaceutical Sciences 107 (2017) 148–167

Fig. 12. SEM image showing the morphology of electrospun FBF-loaded PLGA nanofibers (A, B) and corresponding solvent-cast film (C); FBF-loaded PLGA/gelatin (9/1) nanofibers (d–g)
and corresponding film (h).
“Reprinted (adapted) with permission from (Meng et al. Preparation and characterization of electrospun PLGA/gelatin nanofibers as a potential drug delivery system, Colloids Surf. B
84(1) (2011) 97–102.) Copyright (2010) Elsevier.”

from cancer, indicating serious insufficiency of current treatment stra-
tegies available. Nanofibers of various anticancer drugs have been tried
to either increase water solubility or to control the release profile of
drug candidate. Lin et al. have reported preparation of magnetic elec-
trospun chitosan nanofiber composite for treatment of cancer with
hyperthermia. In vitro cell incubation experiments indicated them to be
non-cytotoxic and effective enough to reduce tumor cell proliferation
(Lin et al., 2012). In line to this Wang et al. have reported enhanced
bioavailability and anticancer effect of curcumin loaded electrospun
nanofibers. X-ray diffraction (XRD) studies have shown an even dis-
tribution of curcumin in amorphous form in nanofibers. In-vitro and in-
vivo evaluation have shown enhanced bioavailability and antitumor
efficacy of curcumin nanofibers prepared with PVP as polymer base
(Wang et al., 2015a). In another study by Qui et al. composite nanofi-
bers of doxorubicin-loaded electrospun PLA/mesoporous silica nano-
particles are reported for post-surgical cancer treatment. Studies have
suggested these composite nanofiber scaffolds to be a potential candi-
date for the effective treatment of post-surgical cancer (Qiu et al.,
2013). Zong et al. have reported preparation of cisplatin-loaded mu-
coadhesive nanofibers for local chemotherapy of cervical cancer. Cis-
platin released from nanofiber mats have shown higher accumulation in
the cervical region instead of being accumulated in highly perfused

Fig. 13. A) Nanofibers in management of diabetes, B) nanofibers in the management of rheumatoid arthritis, C) nanofibers in the management of vascular diseases.

163
S. Thakkar, M. Misra European Journal of Pharmaceutical Sciences 107 (2017) 148–167

Table 5
Patents related to drug-loaded polymeric nanofibers by electrospinning.

Patent title Area of invention/final product description Advantage/applications/claims Reference

Electrospunamorphous
Pharmaceutical compositions
Modulation of drug release rate
From electrospun fibers
Electrospun pharmaceutical
Compositions
Biodegradable drug-polymer
Delivery system
Fiber-based nano drug delivery
Systems (NDDS)
Medical device applications of
nanostructured surfaces
Polymeric nanofibers for tissue engineering
and drug delivery
Nanofiber surfaces for use in
Enhanced surface area applications
Antibacterial nanofiber material and
preparation method thereof
Method for producing shell-core structure
medicament nanofibre with coaxial
electrostatic spinning technology
Stabilization of solid dispersions of amorphous drugs
in polymeric nanofibers
Control of release rate of any additive in nanofibers
by electrospinning
Field of invention is nanofibers of drug particles
Field of invention is polymeric or cyclodextrin
containing nanofibers loaded with drug
Invention relates to processes for creating extruded
fibers containing a mixture of drugs and
pharmaceutically acceptable polymers such that the
drugs form nanofibers
Invention pertains to medical devices and methods
comprising nanofibers
Invention is related to medical applications of
polymer fibers and particularly the use of polymeric
nanofibers in tissue engineering, medical devices
and drug delivery
The patent is mentions invention related to
nanofibers, and nanofiber structures having
enhanced surface areas, as well as to the use of such
nanofibers and nanofiber structures in various
pharmaceutical applications
Invention belongs to the field of nano-fiber and its
preparation, and more particularly to an
antibacterial nanofiber material and preparation
method
This patent discloses shell - core structure of the drug
Preparation as nanofiber, particularly to a coaxial
electrospinning technique for preparing shell - core
structure
Patent claims enhancement of solubility of poorly (Ignatious and Sun,
water soluble pharmaceutical actives along with 2006)
formation of amorphous solid dispersions of drugs in
nanofiber form to make them stabilized
Patent claims co-electrospinning of one or two (Shastri and Sy,
polymers of additives (active pharmaceuticals) to 2008)
modulate release of incorporated drug candidates
Patent claims enhanced solubility of active (Ignatious and
pharmaceuticals by a novel and alternative Baldoni, 2003)
technique of solubility enhancement
Biodegradable sustained release nanofibers have (Davis et al., 2005)
been claimed and certain embodiments contain
cyclodextrins as fiber forming content; these fibers
can be used for the treatment of ocular diseases/
disorders
A drug delivery system in the form of homo- (Pourdeyhimi et al.,
component, bi-component or multi-component 2009)
fibers wherein one of the components comprise a
drug compounded with a polymer carrier
Invention claims formation of various medical (Dubrow et al.,
devices based on nanofibers and may include use of 2005)
antimicrobial agent in it
Polymeric nanofibers either biodegradable or non- (Laurencin et al.,
biodegradable can be made with various blends of 2007)
polymers
In some aspects the current invention comprises a (Dubrow and
substrate comprising at least a first surface, a Daniels, 2009)
plurality of nanofibers attached to the first surface,
and, one or more specific moiety attached to one or
more member of the plurality of nanofibers
Invention claims use of polymers or polymeric (Long et al., 2009)
blends for nanofiber formulation containing
antibacterial drug candidate
Patent claims nanofiber formulation by co-axial (Qian Zhou et al.,
electrospinning of drug bovine serum albumin, 2009)
heparin, doxorubicin, paclitaxel, tetracycline
hydrochloride, griseofulvin, vitamin C, vitamin E, or
vitamin B2

peripheral organs like kidney, liver and others. This advantage of ac-
cumulation at the local site when compared to intravenous route has
shown the ability of mucoadhesive nanofiber mat to deliver drug at the
site of action. Another advantage achieved is a better balance between
anticancer activity and systemic safety in equal drug dose as compared
to intravenous route (Zong et al., 2015). As described previously
homogeneity of the drug must be taken into account in case of highly
potent drugs like anticancer ones; which is not addressed in most of the
reports.
4.11. Nanofibers as wound dressing materials
Wound dressing materials are the ones designed for creating and
maintaining an environment which is most suitable for wound healing
by providing easy gaseous exchange, absorbing exudates from the
wound site and providing a sterile environment which does not support
microbial growth (Li et al., 2017). Use of antibiotic-loaded nanofibers
as wound dressing material serves several advantages due to porosity,
high surface area to volume ratio and biocompatibility. This area of
drug delivery with nanofibers is very well explored and will be de-
scribed only in brief. Recently Li et al. have reported thermosensitive
nanofibers loaded with ciprofloxacin as antibacterial wound dressing
materials. Ciprofloxacin (broad spectrum antibiotic) was loaded in
thermoresponsive electrospun fiber mats containing poly(di(ethylene
glycol) methyl ether methacrylate). Post electrospinning drug was
found to be in amorphous form. By virtue of their thermal sensitivity;
fibers could promote the proliferation of fibroblasts, and by varying the
temperature cells could easily be attached to and detached from the
fibers. In vivo investigations on rats indicated aforementioned nanofi-
bers to have much more potent wound healing properties than com-
mercial gauze (Li et al., 2017).
In the same year Alavarse et al. have reported tetracycline hydro-
chloride-loaded electrospun nanofiber mats based on PVA and chitosan
for wound dressing. Burst delivery of drug during the first 2 h was re-
ported to allow an effective antibacterial activity on the Gram-negative
Escherichia coli as well as on the Gram-positive Staphylococci epidermidis
and Staphylococcus aureus (Alavarse et al., 2017).
5. Clinical trials of drug containing nanofibers
Nanofiber drug delivery systems are at the preliminary stages of
clinical trials supported by a small number of the literature in this re-
gard. These have been clinically verified for their use only in the area of
dentistry. Chaturvedi et al. have reported a clinical study of doxycy-
cline-loaded PCL nanofibers for their use in patients with chronic per-
iodontitis. Drug-coated nanofibers have shown to be having first order
release kinetics up to a period of 11 days.7 patients (4 females and 3
males) aged between 20 and 50 years were divided into 2 treatment
groups as one group having SRP (Scaling and Root Planing) alone and
another one with SRP + doxycycline nanofibers. Patients are reported
to be evaluated continuously for probing depth, plaque index, and
gingival index. Results revealed that treatment group with SRP
+ doxycycline nanofibers demonstrated better improvement in probing
depth, plaque index, and gingival index as compared to control group

164
S. Thakkar, M. Misra
(Chaturvedi et al., 2013). The same group has reported a clinical study
of metronidazole loaded PCL nanofibers for their use in patients with
chronic periodontitis. 7 patients (4 females and 3 males) aged between
20 and 50 years were divided into 2 treatment groups as one group
having SRP (Scaling and Root Planing) alone and another one with SRP
+ metronidazole nanofibers. Patients are reported to be evaluated
continuously for probing depth, plaque index, and gingival index. Re-
sults revealed that treatment group with SRP + metronidazole nanofi-
bers demonstrated better improvement in probing depth, plaque index,
and gingival index as compared to control group (Chaturvedi et al.,
2012).
6. Patents related to drug containing nanofibers
Several patents have been granted in the area of drug delivery of
various pharmaceutically active substances in the form of polymeric
nanofibers. These are mainly based on the pattern and type of drug
release needed along with the use of nanofibers as solubility enhance-
ment technique for various classes of compounds. Some patents are
related to the particular form of drug and release profile accordingly as
amorphous or crystalline ones. Table 5 describes some of the patents
related to drug delivery with polymeric nanofibers.
7. Challenges in drug delivery with electrospun nanofibers
Although nanofibers have shown great potential for drug delivery
applications; still there are certain challenges which need to be cir-
cumvented before nanofibres obtained using electrospinning can be
used as drug delivery vehicle. Till date certain major factors, including
drug loading, the stability of active ingredients, initial burst release, the
amount of residual solvents and industrial scale-up are crucial bottle-
necks, which needs to be overcome before bringing this technology into
mainstream drug delivery technologies. Though several reports cite
greater extent of drug loading with certain polymers for extended re-
lease, however uneven distribution of the drug in nanofibers often re-
sults in initial burst effect, which still needs a lot of fine-tuning.
Polymers (either synthetic or natural) which are a common ingredient
to provide the backbone for nanofibers and are reported to cause
amorphization of crystalline drug candidates. The presence of an active
ingredient in suitable form whether amorphous or crystalline will have
a major impact on stability, especially in the case of drugs, where
regulatory norms are very stringent and require that polymorphic form
of the drug be specified at all crucial stages, including stability. Apart
from this, drug loading in polymer solution may adversely affect its
viscosity and surface tension rendering it unsuitable for electrospinning
(Yu et al., 2009).
Scale-up of nanofiber production by electrospinning technique is
again questionable. Laboratory scale machines are generally dealing
with small volumes in milliliters and when it comes to liters in in-
dustrial scale the thing presents lots of challenges and there is room for
further improvement of process and machinery (Persano et al., 2013).
In the case of textile industries other applications beyond drug delivery
even large-scale production is possible by proper optimization of the
process but for drug delivery nanofiber commercialization by electro-
spinning presents huge challenges for technology development scien-
tists. Hence it is desirable that all these challenges must be well un-
derstood and controlled before nanofibres obtained using
electrospinning could be used in mainstream drug delivery technologies
offering desired drug release profile and adequate drug loading.
8. Conclusion
Electrospun nanofibers have shown great potential for drug delivery
as well as control of release pattern. Proper selection of polymers/
polymeric blends/materials to provide the backbone and effective un-
derstanding of various CPPs and CMAs enable formulation scientist to
165
European Journal of Pharmaceutical Sciences 107 (2017) 148–167
control numerous properties associated with nanofibers. Drug/drug
nanoparticles can be easily incorporated by direct as well as an indirect
method of fabrication which has surely widened the scope for the use of
nanofibers in the field of pharmaceuticals and medical devices. Though
this technique has accomplished considerable success in the field of
pharmaceuticals including antimicrobial applications, wound healing,
cancer treatment, periodontics and tissue engineering still there are
some challenges likes drug loading, the stability of therapeutic in-
gredient and control over undesired release profile, which needs to be
addressed. Advances in electrospinning technology with stringent
control over various parameters can overcome these challenges.
Formulation scientists are expanding its use for diseases/disorders of
brain, ear, eye, lungs and joints still further investigations are required
in terms of preclinical and clinical trials of these drug-loaded nanofibers
for easy commercialization in the pharmaceutical field.
Conflict of interest
Authors report no conflicts of interest.
Acknowledgement
Shreya would like to thank Department of Pharmaceuticals,
Ministry of Chemicals and Fertilizers, Government of India for pro-
viding financial assistance in form of Ph.D fellowship.
References
Abadeer, N.S., Murphy, C.J., 2016. Recent progress in cancer thermal therapy using gold
nanoparticles. J. Phys. Chem. C 120, 4691–4716.
Adibkia, K., et al., 2016. Anti pneumococcal activity of azithromycin-Eudragit RS100
nano-formulations. Adv. Pharm. Bull. 6, 455.
Alavarse, A.C., et al., 2017. Tetracycline hydrochloride-loaded electrospun nanofibers
mats based on PVA and chitosan for wound dressing. Mater. Sci. Eng. C 77, 271–281.
Angammana, C.J., Jayaram, S.H., 2016. Fundamentals of electrospinning and processing
technologies. Part. Sci. Technol. 34, 72–82.
[19-09-2016]. Available from http://www.nanofibersolutions.com/products.html.
[18-09-2016]. Available from http://www.nicast.com/index.aspx?id=2930.
Ball, C., et al., 2012. Drug-eluting fibers for HIV-1 inhibition and contraception. PLoS One
7, e49792.
Baumgarten, P.K., 1971. Electrostatic spinning of acrylic microfibers. J. Colloid Interface
Sci. 36, 71–79.
Begum, S.R., et al., 2012. Enhancement of dissolution rate of piroxicam by electrospin-
ning technique. Adv. Nat. Sci. Nanosci. Nanotechnol. 3, 045012.
Bhardwaj, N., Kundu, S.C., 2010. Electrospinning: a fascinating fiber fabrication tech-
nique. Biotechnol. Adv. 28, 325–347.
Bhattarai, N., Zhang, M., 2007. Controlled synthesis and structural stability of alginate-
based nanofibers. Nanotechnology 18, 455601.
Blakney, A.K., et al., 2014. Delivery of multipurpose prevention drug combinations from
electrospun nanofibers using composite microarchitectures. Int. J. Nanomedicine 9,
2967.
Bognitzki, M., et al., 2001a. Nanostructured fibers via electrospinning. Adv. Mater. 13,
70–72.
Bognitzki, M., et al., 2001b. Preparation of fibers with nanoscaled morphologies: elec-
trospinning of polymer blends. Polym. Eng. Sci. 41, 982–989.
Boland, E.D., et al., 2004. Electrospinning collagen and elastin: preliminary vascular
tissue engineering. Front. Biosci. 9, e32.
Caruso, R.A., et al., 2001. Titanium dioxide tubes from sol–gel coating of electrospun
polymer fibers. Adv. Mater. 13, 1577–1579.
Cejkova, J., et al., 2016. Treatment of alkali-injured cornea by cyclosporine A-loaded
electrospun nanofibers–an alternative mode of therapy. Exp. Eye Res. 147, 128–137.
Celebioglu, A., Uyar, T., 2011. Electrospinning of polymer-free nanofibers from cyclo-
dextrin inclusion complexes. Langmuir 27, 6218–6226.
Chaturvedi, T.P., et al., 2012. Evaluation of metronidazole nanofibers in patients with
chronic periodontitis: a clinical study. Int. J. Pharm. Invest. 2, 213.
Chaturvedi, T., et al., 2013. Doxycycline poly e-caprolactone nanofibers in patients with
chronic periodontitis–a clinical evaluation. J. Clin. Diagn. Res. 7, 2339.
Chen, R., et al., 2008. Fabrication of the silver/polypyrrole/polyacrylonitrile composite
nanofibrous mats. Mater. Lett. 62, 4031–4034.
Chen, Z., et al., 2016. Electrospun nanofibers for cancer diagnosis and therapy. Biomater.
Sci. 4, 922–932.
Cho, K., et al., 2010. Synthesis and characterization of electrospun polymer nanofibers
incorporated with CdTe nanoparticles. Synth. Met. 160, 888–891.
Choi, J.S., et al., 2011. Coaxial electrospun nanofibers for treatment of diabetic ulcers
with binary release of multiple growth factors. J. Mater. Chem. 21, 5258–5267.
Chou, S.-F., Woodrow, K.A., 2017. Relationships between mechanical properties and drug
release from electrospun fibers of PCL and PLGA blends. J. Mech. Behav. Biomed.
S. Thakkar, M. Misra
Mater. 65, 724–733.
Chou, S.-F., et al., 2015. Current strategies for sustaining drug release from electrospun
nanofibers. J. Control. Release 220, 584–591.
Cui, W., et al., 2006. Investigation of drug release and matrix degradation of electrospun
poly (DL-lactide) fibers with paracetanol inoculation. Biomacromolecules 7,
1623–1629.
Davis, M.E., et al., 2005. Biodegradable Drug-polymer Delivery System. US 2005/
0276841A1. United States.
Demir, M.M., et al., 2004. Palladium nanoparticles by electrospinning from poly (acry-
lonitrile-co-acrylic acid)-PdCl2 solutions. Relations between preparation conditions,
particle size, and catalytic activity. Macromolecules 37, 1787–1792.
Demirci, S., et al., 2014. pH-responsive nanofibers with controlled drug release proper-
ties. Polym. Chem. 5, 2050–2056.
Doshi, J., Reneker, D.H., 1993. Electrospinning process and applications of electrospun
fibers. In: Industry Applications Society Annual Meeting, 1993. Conference Record of
the 1993 IEEE. IEEEpp. 1698–1703.
Dubrow, R., Daniels, R.H., 2009. Nanofiber Surfaces for use in Enhanced Surface Area
Applications. United States.
Dubrow, R.S., et al., 2005. Medical Device Applications of Nanostructured Surfaces. US
2005/0038498A1. United States.
Dzenis, Y., Wen, Y., 2001. Continuous carbon nanofibers for nanofiber composites. In:
MRS Proceedings. Cambridge Univ Press, pp. U5. 4.1.
Eltayeb, M., et al., 2016. Electrosprayed nanoparticle delivery system for controlled re-
lease. Mat. Sci. Eng. C-Bio. S 66, 138–146.
Fang, X., Reneker, D., 1997. DNA fibers by electrospinning. J. Macromol. Sci. Part B Phys.
36, 169–173.
Frenot, A., Chronakis, I.S., 2003. Polymer nanofibers assembled by electrospinning. Curr.
Opin. Colloid. In. 8, 64–75.
Frenot, A., et al., 2007. Electrospinning of cellulose-based nanofibers. J. Appl. Polym. Sci.
103, 1473–1482.
Garg, T., et al., 2014. Development and characterization of nano-fiber patch for the
treatment of glaucoma. Eur. J. Pharm. Sci. 53, 10–16.
Gencturk, A., et al., 2016. Polyurethane/hydroxypropyl cellulose electrospun nanofiber
mats as potential transdermal drug delivery system: characterization studies and in
vitro assays. Artif. Cell Nanomed. Biotechnol. 1–10.
Goonoo, N., et al., 2014. Drug loading and release from electrospun biodegradable na-
nofibers. J. Biomed. Nanotechnol. 10, 2173–2199.
Haider, A., et al., 2015. A comprehensive review summarizing the effect of electrospin-
ning parameters and potential applications of nanofibers in biomedical and bio-
technology. Arab. J. Chem.
He, D., et al., 2009. Large-scale synthesis of flexible free-standing SERS substrates with
high sensitivity: electrospun PVA nanofibers embedded with controlled alignment of
silver nanoparticles. ACS Nano 3, 3993–4002.
Hedenquist, J.W., Lowenstern, J.B., 1994. The role of magmas in the formation of hy-
drothermal ore deposits. Nature 370, 519–527.
Hrib, J., et al., 2015. Nanofibers for drug delivery–incorporation and release of model
molecules, influence of molecular weight and polymer structure. Beilstein J.
Nanotechnol. 6, 1939–1945.
Hsu, C.-Y., Liu, Y.-L., 2010. Rhodamine B-anchored silica nanoparticles displaying white-
light photoluminescence and their uses in preparations of photoluminescent poly-
meric films and nanofibers. J. Colloid Interface Sci. 350, 75–82.
Hsu, P.-C., et al., 2012. Passivation coating on electrospun copper nanofibers for stable
transparent electrodes. ACS Nano 6, 5150–5156.
Hsu, P.-C., et al., 2013. Performance enhancement of metal nanowire transparent con-
ducting electrodes by mesoscale metal wires. Nat. Commun. 4.
Hsu, K.-H., et al., 2016. Hybrid electrospun polycaprolactone mats consisting of nanofi-
bers and microbeads for extended release of dexamethasone. Pharm. Res. 33,
1509–1516.
Huan, S., et al., 2015. Effect of experimental parameters on morphological, mechanical
and hydrophobic properties of electrospun polystyrene fibers. Materials 8,
2718–2734.
Huang, Z.-M., et al., 2003. A review on polymer nanofibers by electrospinning and their
applications in nanocomposites. Compos. Sci. Technol. 63, 2223–2253.
Huang, C.-H., et al., 2014. Preparation of a thermo-and pH-sensitive nanofibrous scaffold
with embedded chitosan-based nanoparticles and its evaluation as a drug carrier.
Cellulose 21, 2497–2509.
Husain, O., et al., 2016. Investigating the particle to fibre transition threshold during
electrohydrodynamic atomization of a polymer solution. Mat. Sci. Eng. C-Bio. S 65,
240–250.
Ignatious, F., Baldoni, J.M., 2003. Electrospun Pharmaceutical Compositions. US 2003/
0017208 A1. United States.
Ignatious, F., Sun, L., 2006. Electrospunamorphous Pharmaceutical Compositions. US
2006/0013869 A1. United States.
Ikegame, M., et al., 2003. Template synthesis of polypyrrole nanofibers insulated within
one-dimensional silicate channels: hexagonal versus lamellar for recombination of
polarons into bipolarons. Angew. Chem. Int. Ed. 42, 2154–2157.
Jaeger, R., et al., 1998. Electrospinning of ultra-thin polymer fibers, macromolecular
symposia. Wiley Online Library 141–150.
Jang, C.H., et al., 2015. Antibacterial effect of electrospun polycaprolactone/polyethylene
oxide/vancomycin nanofiber mat for prevention of periprosthetic infection and
biofilm formation. Int. J. Pediatr. Otorhinolaryngol. 79, 1299–1305.
Jiang, H., et al., 2004. Optimization and characterization of dextran membranes prepared
by electrospinning. Biomacromolecules 5, 326–333.
Jin, Y., et al., 2009. Fabrication of necklace-like structures via electrospinning. Langmuir
26, 1186–1190.
Kaiser, S., et al., 2014. Porous perovskite fibers–preparation by wet phase inversion
166
European Journal of Pharmaceutical Sciences 107 (2017) 148–167
spinning and catalytic activity. Chem. Eng. Technol. 37, 1146–1154.
Kang, Y., et al., 2002. Manufacturing the cellulose web by using electro-spinning and in-
vitro behaviour of oxidized cellulose web. J. Korean Fiber Soc. 39, 14–20.
Kenawy, E.R., Abdel-Fattah, Y.R., 2002. Antimicrobial properties of modified and elec-
trospun poly (vinyl phenol). Macromol. Biosci. 2, 261–266.
Kessick, R., et al., 2004. The use of AC potentials in electrospraying and electrospinning
processes. Polymer 45, 2981–2984.
Konwarh, R., et al., 2013. Electrospun cellulose acetate nanofibers: the present status and
gamut of biotechnological applications. Biotechnol. Adv. 31, 421–437.
Kowalewski, T., et al., 2005. Experiments and modelling of electrospinning process. Tech.
Sci. 53, 385–394.
Laurencin, C.T., et al., 2007. Polymeric Nanofibers for Tissue Engineering and Drug
Delivery. United States.
Li, W.J., et al., 2002. Electrospun nanofibrous structure: a novel scaffold for tissue en-
gineering. J. Biomed. Mater. Res. 60, 613–621.
Li, D., et al., 2004. Photocatalytic deposition of gold nanoparticles on electrospun na-
nofibers of titania. Chem. Phys. Lett. 394, 387–391.
Li, Y.F., et al., 2016. Light responsive hybrid nanofibres for on-demand therapeutic drug
and cell delivery. J. Tissue Eng. Regen. Med.
Li, H., et al., 2017. Thermosensitive nanofibers loaded with ciprofloxacin as antibacterial
wound dressing materials. Int. J. Pharm. 517, 135–147.
Lin, T.-C., et al., 2012. In vitro feasibility study of the use of a magnetic electrospun
chitosan nanofiber composite for hyperthermia treatment of tumor cells. Acta
Biomater. 8, 2704–2711.
Liu, K.-S., et al., 2015a. Sustained release of vancomycin from novel biodegradable na-
nofiber-loaded vascular prosthetic grafts: in vitro and in vivo study. Int. J.
Nanomedicine 10, 885.
Liu, W., et al., 2015b. Electrospinning of grooved polystyrene fibers: effect of solvent
systems. Nanoscale Res. Lett. 10, 1–10.
Liu, L., et al., 2016. Controlled release from thermo-sensitive PNVCL-co-MAA electrospun
nanofibers: the effects of hydrophilicity/hydrophobicity of a drug. Mater. Sci. Eng. C
67, 581–589.
Long, H.C., et al., 2009. Antibacterial Nano Fiber Material and Preparation Method
Thereof. China.
Luo, C., et al., 2012. Electrospinning versus fibre production methods: from specifics to
technological convergence. Chem. Soc. Rev. 41, 4708–4735.
Mahalingam, S., Edirisinghe, M., 2013. Forming of polymer nanofibers by a pressurised
gyration process. Macromol. Rapid Commun. 34, 1134–1139.
Mahanta, N., Valiyaveettil, S., 2011. Surface modified electrospun poly (vinyl alcohol)
membranes for extracting nanoparticles from water. Nano 3, 4625–4631.
Maity, S., et al., 2011. Embedded metal nanoparticles as localized heat sources: an al-
ternative processing approach for complex polymeric materials. Polymer 52,
1674–1685.
Matthews, J.A., et al., 2002. Electrospinning of collagen nanofibers. Biomacromolecules
3, 232–238.
McKeon-Fischer, K., Freeman, J., 2011. Characterization of electrospun poly (L-lactide)
and gold nanoparticle composite scaffolds for skeletal muscle tissue engineering. J.
Tissue Eng. Regen. Med. 5, 560–568.
Megelski, S., et al., 2002. Micro-and nanostructured surface morphology on electrospun
polymer fibers. Macromolecules 35, 8456–8466.
Meng, Z., et al., 2011. Preparation and characterization of electrospun PLGA/gelatin
nanofibers as a potential drug delivery system. Colloids Surf. B 84, 97–102.
Mengistu Lemma, S., et al., 2016. Preparation of pure and stable chitosan nanofibers by
electrospinning in the presence of poly (ethylene oxide). Int. J. Mol. Sci. 17, 1790.
Min, B.-M., et al., 2004. Chitin and chitosan nanofibers: electrospinning of chitin and
deacetylation of chitin nanofibers. Polymer 45, 7137–7142.
Modgill, V., et al., 2015. Transmucosal delivery of linagliptin for the treatment of type-2
diabetes mellitus by ultra-thin nanofibers. Curr. Drug Deliv. 12, 323–332.
Natu, M.V., et al., 2010. Effects of drug solubility, state and loading on controlled release
in bicomponent electrospun fibers. Int. J. Pharm. 397, 50–58.
Nayak, R., et al., 2011. Recent advances in nanofibre fabrication techniques. Text. Res. J
0040517511424524.
Neamnark, A., et al., 2006. Electrospinning of hexanoyl chitosan. Carbohydr. Polym. 66,
298–305.
Noh, H.K., et al., 2006. Electrospinning of chitin nanofibers: degradation behavior and
cellular response to normal human keratinocytes and fibroblasts. Biomaterials 27,
3934–3944.
Ohkawa, K., et al., 2004. Electrospinning of chitosan. Macromol. Rapid Commun. 25,
1600–1605.
Paaver, U., et al., 2015. Electrospun nanofibers as a potential controlled-release solid
dispersion system for poorly water-soluble drugs. Int. J. Pharm. 479, 252–260.
Pankajakshan, D., et al., 2016. Triple antibiotic polymer nanofibers for intracanal drug
delivery: effects on dual species biofilm and cell function. J. Endod. 42, 1490–1495.
Parhizkar, M., et al., 2016a. Electrohydrodynamic encapsulation of cisplatin in poly
(lactic-co-glycolic acid) nanoparticles for controlled drug delivery. Nanomedicine 12,
1919–1929.
Parhizkar, M., et al., 2016b. Electrohydrodynamic encapsulation of cisplatin in poly
(lactic-co-glycolic acid) nanoparticles for controlled drug delivery. Nanomed.
Nanotech. Biol. Med. 12, 1919–1929.
Park, J.-Y., Lee, I.-H., 2011. Controlled release of ketoprofen from electrospun porous
polylactic acid (PLA) nanofibers. J. Polym. Res. 18, 1287–1291.
Park, W.H., et al., 2004. Effect of chitosan on morphology and conformation of electro-
spun silk fibroin nanofibers. Polymer 45, 7151–7157.
Park, K.E., et al., 2006a. Biomimetic nanofibrous scaffolds: preparation and character-
ization of chitin/silk fibroin blend nanofibers. Int. J. Biol. Macromol. 38, 165–173.
Park, K.E., et al., 2006b. Biomimetic nanofibrous scaffolds: preparation and
S. Thakkar, M. Misra
characterization of PGA/chitin blend nanofibers. Biomacromolecules 7, 635–643.
Park, J.-Y., et al., 2015. Fabrication and characterization of antimicrobial ethyl cellulose
nanofibers using electrospinning techniques. J. Nanosci. Nanotechnol. 15,
5672–5675.
Persano, L., et al., 2013. Industrial upscaling of electrospinning and applications of
polymer nanofibers: a review. Macromol. Mater. Eng. 298, 504–520.
Pina, M.F., et al., 2017. The generation of compartmentalized nanoparticles containing
siRNA and cisplatin using a multi-needle electrohydrodynamic strategy. Nano 9,
5975–5985.
Polat, Y., et al., 2016. Solution blowing of thermoplastic polyurethane nanofibers: a facile
method to produce flexible porous materials. J. Appl. Polym. Sci. 133.
Pourdeyhimi, B., et al., 2009. Fiber-based Nano Drug Delivery Systems (NDDS). US
7.491.407 B2. United States.
Qian Zhou, L.X., Yan, Su, Xiumei, Mo, 2009. Method for Producing Shell-core Structure
Medicament Nanofibre With Coaxial Electrostatic Spinning Technology. China.
Qiu, K., et al., 2013. Doxorubicin-loaded electrospun poly (L-lactic acid)/mesoporous
silica nanoparticles composite nanofibers for potential postsurgical cancer treatment.
J. Mater. Chem. B 1, 4601–4611.
Reardon, P.J., et al., 2017. Electrohydrodynamic fabrication of core–shell PLGA nano-
particles with controlled release of cisplatin for enhanced cancer treatment. Int. J.
Nanomedicine 12, 3913.
Rujitanaroj, P.-O., et al., 2008. Wound-dressing materials with antibacterial activity from
electrospun gelatin fiber mats containing silver nanoparticles. Polymer 49,
4723–4732.
Santos, V.A.d., et al., 2014. Antifungal effect of electrospun nanofibers containing ce-
tylpyridinium chloride against Candida albicans. Braz. Oral Res. 28, 1–6.
Schiffman, J.D., Schauer, C.L., 2008. A review: electrospinning of biopolymer nanofibers
and their applications. Polym. Rev. 48, 317–352.
Schiffman, J.D., et al., 2009. Chitin and chitosan: transformations due to the electro-
spinning process. Polym. Eng. Sci. 49, 1918–1928.
Schreuder-Gibson, H., et al., 2002. Protective textile materials based on electrospun na-
nofibers. J. Adv. Mater. 34, 44–55.
Shaddock, E.J., 2016. How and when to use common biomarkers in community-acquired
pneumonia. Pneumonia 8, 17.
Shao, H., et al., 2015. Effect of electrospinning parameters and polymer concentrations on
mechanical-to-electrical energy conversion of randomly-oriented electrospun poly
(vinylidene fluoride) nanofiber mats. RSC Adv. 5, 14345–14350.
Shastri, V.P., Sy, J.C., 2008. Modulation of Drug Release Rate From Electrospun Fibers.
US 2008/0220054A1. United States.
Shi, W., et al., 2013. Hydrothermal synthetic strategies of inorganic semiconducting na-
nostructures. Chem. Soc. Rev. 42, 5714–5743.
Shin, Y., et al., 2001. Experimental characterization of electrospinning: the electrically
forced jet and instabilities. Polymer 42, 09955–09967.
Shukla, S., et al., 2005. Electrospinning of hydroxypropyl cellulose fibers and their ap-
plication in synthesis of nano and submicron tin oxide fibers. Polymer 46,
12130–12145.
Siafaka, P.I., et al., 2016. Novel electrospun nanofibrous matrices prepared from poly
(lactic acid)/poly (butylene adipate) blends for controlled release formulations of an
anti-rheumatoid agent. Eur. J. Pharm. Sci. 88, 12–25.
Sill, T.J., von Recum, H.A., 2008. Electrospinning: applications in drug delivery and tissue
engineering. Biomaterials 29, 1989–2006.
Singh, B., et al., 2015. Development, optimization, and characterization of polymeric
electrospun nanofiber: a new attempt in sublingual delivery of nicorandil for the
management of angina pectoris. Artif Cell Nanomed. Biotechnol. 1–10.
Stojanovska, E., et al., 2016. A review on non-electro nanofibre spinning techniques. RSC
Adv. 6, 83783–83801.
167
European Journal of Pharmaceutical Sciences 107 (2017) 148–167
Sulejczak, D., et al., 2014. Electrospun nanofiber mat as a protector against the con-
sequences of brain injury. Folia Neuropathol. 52, 56–69.
Švachová, V., et al., 2016. Novel electrospun gelatin/oxycellulose nanofibers as a suitable
platform for lung disease modeling. Mater. Sci. Eng. C 67, 493–501.
Taghavi, S., Larson, R., 2014. Regularized thin-fiber model for nanofiber formation by
centrifugal spinning. Phys. Rev. E 89, 023011.
Tan, G., et al., 2016. Synthesis and characterization of silver nanoparticles integrated in
polyvinyl alcohol nanofibers for bionanotechnological applications. Turk. J. Biol. 40,
643–651.
Teo, W.-E., et al., 2011. Technological advances in electrospinning of nanofibers. Sci.
Technol. Adv. Mater. 12, 013002.
Theron, S., et al., 2004. Experimental investigation of the governing parameters in the
electrospinning of polymer solutions. Polymer 45, 2017–2030.
Toncheva, A., et al., 2012. Antibacterial fluoroquinolone antibiotic-containing fibrous
materials from poly (l-lactide-co-d, l-lactide) prepared by electrospinning. Eur. J.
Pharm. Sci. 47, 642–651.
Torres, B., 2001. Ultrafine fibers of polystyrene dissolved in tetrahydrofuran prepared
using the electrospinning method. In: Proceeding of the National Conference on
Undergraduate Research, pp. 15–17.
Tort, S., Acartürk, F., 2016. Preparation and characterization of electrospun nanofibers
containing glutamine. Carbohydr. Polym. 152, 802–814.
Vellayappan, M., et al., 2016. Electrospinning applications from diagnosis to treatment of
diabetes. RSC Adv. 6, 83638–83655.
Wang, J., Nain, A.S., 2014. Suspended micro/nanofiber hierarchical biological scaffolds
fabricated using non-electrospinning STEP technique. Langmuir 30, 13641–13649.
Wang, C., et al., 2015a. Enhanced bioavailability and anticancer effect of curcumin-
loaded electrospun nanofiber: in vitro and in vivo study. Nanoscale Res. Lett. 10, 1.
Wang, J., et al., 2015b. Heparin and vascular endothelial growth factor loaded poly (L-
lactide-co-caprolactone) nanofiber covered stent-graft for aneurysm treatment. J.
Biomed. Nanotechnol. 11, 1947–1960.
Wang, X., et al., 2016. Enhancing the electrospinnability of low molecular weight poly-
mers using small effective cross-linkers. Macromolecules 49, 891–899.
Wnek, G.E., et al., 2003. Electrospinning of nanofiber fibrinogen structures. Nano Lett. 3,
213–216.
Wu, X., et al., 2005. Effect of solvent on morphology of electrospinning ethyl cellulose
fibers. J. Appl. Polym. Sci. 97, 1292–1297.
Wu, H., et al., 2013. A transparent electrode based on a metal nanotrough network. Nat.
Nanotechnol. 8, 421–425.
Xie, J., Hsieh, Y.-L., 2003. Ultra-high surface fibrous membranes from electrospinning of
natural proteins: casein and lipase enzyme. J. Mater. Sci. 38, 2125–2133.
Xie, J., et al., 2015. Electrohydrodynamic atomization: a two-decade effort to produce
and process micro-/nanoparticulate materials. Chem. Eng. Sci. 125, 32–57.
Xu, L., et al., 2015. Semi-interpenetrating network (sIPN) co-electrospun gelatin/insulin
fiber formulation for transbuccal insulin delivery. Pharm. Res. 32, 275–285.
Yao, C., et al., 2007. Electrospinning and crosslinking of zein nanofiber mats. J. Appl.
Polym. Sci. 103, 380–385.
Yu, D.-G., et al., 2009. Electrospun nanofiber-based drug delivery systems. Health 1, 67.
Zampetti, E., et al., 2011. Effects of temperature and humidity on electrospun conductive
nanofibers based on polyaniline blends. J. Nanopart. Res. 13, 6193–6200.
Zhang, C.-L., Yu, S.-H., 2014. Nanoparticles meet electrospinning: recent advances and
future prospects. Chem. Soc. Rev. 43, 4423–4448.
Zhao, Y., et al., 2006. TiO2 micro/nano-composite structured electrodes for quasi-solid-
state dye-sensitized solar cells. Nanotechnology 17, 2090.
Zong, S., et al., 2015. The use of cisplatin-loaded mucoadhesive nanofibers for local
chemotherapy of cervical cancers in mice. Eur. J. Pharm. Biopharm. 93, 127–135.