Journal of Controlled Release 185 (2014) 1221

Contents lists available at ScienceDirect

Journal of Controlled Release

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

Review

Electrospinning of polymeric nanobers for drug delivery applications

Xiuli Hu a, Shi Liu a,c, Guangyuan Zhou b, Yubin Huang a,, Zhigang Xie a,, Xiabin Jing a
a
b
c

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China
The University of Chinese Academy of Sciences, Beijing 100049, PR China

a r t i c l e

i n f o

Article history:
Received 19 January 2014
Accepted 10 April 2014
Available online 22 April 2014
Keywords:
Electrospinning
Drug delivery
Wound dressing
Local chemotherapy

a b s t r a c t
Electrospinning has been recognized as a simple and versatile method for fabrication of polymer nanobers. Various polymers that include synthetic, natural, and hybrid materials have been successfully electrospun into ultrane bers. The inherently high surface to volume ratio of electrospun bers can enhance cell attachment, drug
loading, and mass transfer properties. Drugs ranging from antibiotics and anticancer agents to proteins, DNA,
RNA, living cells, and various growth factors have been incorporated into electrospun bers. This article presents
an overview of electrospinning techniques and their application in drug delivery.
2014 Elsevier B.V. All rights reserved.

Contents
1.
2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Electrospinning: setups and process . . . . . . . . . . . . . . . . . . . .
2.1.
The basic setups . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Modication of the setup for electrospinning . . . . . . . . . . . . .
2.2.1.
Modication on the syringe and the spinning liquids . . . . .
2.2.2.
Modication on the collector . . . . . . . . . . . . . . . .
3.
Drug delivery application and release kinetics of electrospun ber formulations .
3.1.
Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Loaded drugs and their release kinetics . . . . . . . . . . . . . . .
3.2.1.
Antibiotics and various antibacterial agents . . . . . . . . .
3.2.2.
Anticancer drugs . . . . . . . . . . . . . . . . . . . . .
3.2.3.
Protein, DNA, RNA and growth factors . . . . . . . . . . . .
3.2.4.
Drug release kinetics . . . . . . . . . . . . . . . . . . .
3.3.
Applications for local chemotherapy . . . . . . . . . . . . . . . . .
4.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.
Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction
Electrospinning is a straightforward method of producing ultrane
bers with micro- to nano-meter range diameters and with controlled

Corresponding author. Tel.: +86 431 85262769.

Corresponding author. Tel.: +86 85262779.
E-mail addresses: ybhuang@ciac.ac.cn (Y. Huang), xiez@ciac.ac.cn (Z. Xie).

http://dx.doi.org/10.1016/j.jconrel.2014.04.018
0168-3659/ 2014 Elsevier B.V. All rights reserved.

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12
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19

surface morphology. The ultrane bers are generated by application

of a strong electric eld on polymer solution or melt.
The use of electrostatic forces to form ultrane bers was traced
back to 100 years ago and was rst patented by Formhals in 1934 [1].
Up until the 1990s, this technique had been known as electrostatic spinning and had gained escalated interest on account of the remarkable
simplicity, versatility, and potential uses in diverse elds. Huang et al. illustrate the development of electrospinning in detail [2]. So far, the notable applications of electrospinning include ltration [35], cosmetic

X. Hu et al. / Journal of Controlled Release 185 (2014) 1221

mask [6,7], military protective clothing [810], nano-sensor [11,12],

energy-related applications [13], wound dressings [1416], drug delivery [17,18], enzyme immobilization [19,20], and tissue engineering
scaffolds [21,22].
Among the various potential applications, drug delivery is one of the
most promising uses. The high loading capacity, high encapsulation efciency, simultaneous delivery of diverse therapies, ease of operation,
and cost-effectiveness are appealing features for electrospinning used
in drug delivery [23,24]. The use of electrospun bers as drug carriers
will be promising in future biomedical applications, especially postoperative local chemotherapy [25,26]. From the rst study on the application
of electrospun nano-bers for the sustained release of a model drug tetracycline hydrochloride using poly(lactic acid) and poly(ethylene-covinyl acetate), as well as their blend as polymeric matrices by Kenawy
et al. [27], electrospun nanobers have been successfully used to
achieve different controlled drug release proles, such as immediate,
smooth, pulsatile, delayed, and biphasic releases [28,29]. And drugs
ranging from antibiotics and anticancer agents to proteins, aptamer,
DNA, and RNA have been incorporated into electrospun bers [26]. To
make this tool more effective, a better understanding of the mechanism
behind electrospinning will improve the control of the electrospun
products. In this paper, a comprehensive review is presented on the researches and developments related to electrospun polymer nanobers
used in drug delivery.

2. Electrospinning: setups and process

2.1. The basic setups
Electrospinning is a method in which materials in solution or melt
are formed into nano- or micro-sized continuous bers. Fig. 1. shows a
schematic illustration of the basic setup for electrospinning. It consists
of three major components: a high-voltage source, a syringe pump,
and a collector.
The basis of electrospinning is application of a strong electric eld.
The polymer solution or melt is hosted in a syringe pump. When a
high voltage is applied, usually between 1 and 30 kV, the pendant
drop of polymer solution will become highly electried and the induced
charges are evenly distributed over the surface. The liquid drop will be
deformed into a conical object known as a Taylor cone by the electrostatic eld [30]. When the voltage surpasses a threshold value, the electric force overcomes the surface tension of the droplet and one or
multiple charged jets of the solution are ejected from the tip of the droplet depending on the electric eld intensity. As the jet moves toward a
collecting metal screen (counter electrode), solvent evaporates and a
nonwoven fabric mat is formed on the screen [31].
The effects of several process parameters, such as the applied electric
eld strength [32], ow rate [33,34], properties of the solution (concentration, viscosity, conductivity, surface tension, homogeneity) [34], distance between syringe and collector, ambient parameters (temperature,

Fig. 1. Schematic illustration of the basic setup for electrospinning.

13

humidity, and air ow) [17], have been explored in great detail for
different polymer materials [2,35,36]. In conclusion, the viscosity of
polymer solution and humidity plays a signicant role in
electrospinnability. It was reported that a lower humidity (less than
35%) is ideal for spinning, humidity higher than 35% will make the jet
difcult to spin continuously [37]. Fong et al. found that for poly(ethylene oxide) (PEO) solution in ethanol and water, the viscosities in the
range of 120 P and surface tension between 35 and 55 dyn/cm were
suitable for ber formation [37]. At viscosities above 20 P,
electrospinning was prohibited because of the instability of ow caused
by the high cohesiveness of the solution. Droplets were formed when
the viscosity was too low (b1 P). Zong et al. investigated the effects of
processing parameters of electrospinning on the microstructure of biodegradable amorphous poly(D,L-lactide) (PDLLA) and semi-crystalline
poly(L-lactide) (PLLA) membranes. It was found that mixture of large
beads (drops) and bers was generated by electrospinning the PDLLA
solution at concentrations below 20 wt.%. In contrast, at concentrations
higher than 40 wt.%, the electrospinning process was hard to maintain
due to the high viscosity of the solution [33]. Casper et al. investigated
the inuence of moisture in the air on the surface morphology of
electrospun polystyrene (PS) bers from THF [38]. Electrospinning in
an atmosphere of less than 25% humidity produced smooth bers without any surface defects. When the humidity was above 30%, pores began
to form on the ber surface. Increasing the amount of humidity causes
an increase in the number of pores on the surface, the pore diameter,
and the pore size distribution. It should be noted that the above-mentioned principles are applicable for some of the polymers and these
values need to be established for each type of polymer being
investigated.
2.2. Modication of the setup for electrospinning
The basic setup for electrospinning is so simple that it has already
been established in many research laboratories. Primarily, most of the
systems were utilized for electrospinning from a single polymer solution or melt. However, a variety of polymers could not be electropun
into bers using the basic setup. In order to expand the universality of
electrospinning and tailor the structure of resultant bers, many efforts
have been made on the modication of electrospinning equipments. According to the literature, most of the modication was based on the syringe and the collector. The following will present a more detailed
discussion.
2.2.1. Modication on the syringe and the spinning liquids
Under this catalog, several electrospinning systems were developed,
including co-electrospinning, side-by-side electrospinning, multi-jet
electrospinning, co-axial electrospinning, and emulsion electrospinning.
Co-electrospinning was rst utilized to further tailor the property of
the resultant bers. It includes electrospinning blends of polymers in
the same solvent or mixtures of different polymer solutions using the
traditional electrospinning device. MacDiarmid and his group fabricated
conducting polymer nanobers with sub-30 nm diameters by blending
polyaniline, a conducting polymer, with poly(ethylene oxide) in chloroform [39]. The point is that for a blend of two polymers in the same solvent, the homogeneity of the mixture and the thermodynamic
miscibility of the two polymers should be considered. In another approach, Wikels and his co-workers designed an electrospinning device
where two polymer solutions were electrospun simultaneously in a
side-by-side fashion (Fig. 2) [40]. In this case, the two polymer solutions
do not come in physical contact until they reach the end of the spinneret
where the process of ber formation begins. This side-by-side approach
led to bicomponent bers that had properties from each of the polymeric components. For this bicomponent electrospinning, the key process
parameters are viscosity and conductivity of each of the polymer
solutions.

14

X. Hu et al. / Journal of Controlled Release 185 (2014) 1221

Fig. 2. Schematic illustration of the side-by-side electrospinning setup (Ref. [40]).

In order to solve the inefciency problem of the electrospinning

caused by the slow ow rates of polymer solution (usually less than
1 mL/h), an array of multiple needles has been demonstrated by Chu
and co-workers [41]. This multiple-jet equipment overcomes the drawback of single jet spinning in low productivity and offers the potential
for mass production [42]. Shiratori et al. also reported the preparation
of blend biodegradable nanobrous mats comprising poly(vinyl alcohol) (PVA) and cellulose acetate (CA) via multi-jet electrospinning
[43]. Meanwhile, uniform thickness of blend nanobrous mats with
good dispersibility of multi-component was achieved by using a movable multi-jet and rotatable grounded tubular collector. The above
side-by-side and multi-jet approaches can be used to fabricate blend
nanobrous mats with bi- or multi-component polymers which cannot
be dissolved in the same solvent or kept in the same container.
One of the most signicant technical breakthroughs is coaxial
electrospinning, in which a concentric spinneret with two different diameters is used. Two polymer solutions were added to the inside and
outside spinneret, respectively. Similar to single-nozzle electrospinning,
coaxial electrospinning employs electric forces acting on both polymer
solutions and resulting in signicant stretching of polymer jets due to
a direct pulling and growth of the electrically driven bending perturbations. By adjusting the liquid ow rates and applied voltage, core-shell
structure nanobers were obtained. Coaxial electrospinning is of particular interest for those core materials that cannot form bers via
electrospinning by themselves. In 2001, Loscertales et al. rst reported
this coaxial electrospinning technique to generate monodisperse capsules containing water soluble drug [44]. Soon, Sun et al. obtained
core-shell polymer nanobers by coaxial electrospinning [45]. The outstanding work on coaxial electrospinning came from Xia and his coworkers. Various hollow nanobers with walls made of inorganic/polymer composites or ceramics were prepared by electrospinning two immiscible liquids through a coaxial, two-capillary spinneret, followed by
selective removal of the cores [4648]. For example, they obtained hollow bers by using heavy mineral oil and an ethanol solution of poly(vinyl pyrrolidone) (PVP) and Ti(OiPr)4 as the materials for core and
sheath, respectively [49]. The Ti(OiPr)4 was added into the PVP/alcohol
solution as a solgel precursor, which was found to be necessary for the
formation of stable, coaxial jets. PVP was used to increase the viscosity
and to control the viscoelasticity of the solution. After the solution was
electrospun into a thin jet, the metal alkoxide immediately started to
hydrolyze by reacting with the moisture in surrounding air to generate
a continuous gel network within the polymer matrix. As a result, nanobers consisting of an inorganic/polymer composite were obtained. Ceramic nanobers with hollow structure would be readily obtained by
removing the organic phase via calcination of these composite bers
at elevated temperatures in air [48].
Different from single-nozzle electrospinning, coaxial electrospinning
requires a coreshell nozzle attached to a double-compartment syringe

and a supply of two polymer solutions by means of two separate pumps

and pipelines leading to a coreshell nozzle. It was reported that core
shell polymer nanobers were possible from an ordinary single-nozzle
electrospinning setup if an emulsion of two polymer solutions was used
as the working liquid [5054]. Jing and his co-workers reported the preparation of core-sheath composite nanobers by single-nozzle
electrospinning of a water-in-oil emulsion [55], in which the aqueous
phase consisted of a poly(ethylene oxide) (PEO) solution in water and
the oily phase was a chloroform solution of an amphiphilic poly(ethylene
glycol)poly(L-lactic acid) (PEG-PLA) diblock copolymer. The obtained bers were composed of a PEO core and a PEGPLA sheath with a sharp
boundary in between. The schematic mechanism for emulsion
electrospinning is shown in Fig. 3. Similar coreshell bers were obtained
by Megaridis and his coworkers by electrospinning blends of poly(methyl
methacrylate) (PMMA)/polyacrylonitrile (PAN) solutions in
dimethylformamide (DMF) using a single-nozzle technique [56].
2.2.2. Modication on the collector
For most electrospinning devices, electrospun bers are often deposited on the surface of a at collector as randomly oriented nonwoven
mats. Well-aligned and highly ordered architectures are often required
for expanded application. In the past few years, a number of approaches
have been demonstrated to obtain aligned polymer bers by modication of the collector or the distribution of the local electric eld, such
as using a rotating cylinder collector [56], a frame collector, a wheellike disk [57], or an auxiliary electrode/electrical eld [58]. The aligned
polymer bers were mostly useful in tissue engineering and the above
methods have been reviewed in several papers [2,58,59] and thus are
not described here in detail.
3. Drug delivery application and release kinetics of electrospun
ber formulations
Various delivery systems have been investigated to improve the
therapeutic effect and to reduce the toxicity of conventional dosage
forms. Nanoscale formulations such as liposomes, polymeric micelles,
complexes, and nanobers attracted special attention during the last
decade. Compared with other formulations, electrospinning affords
great exibility in selecting materials and drugs for drug delivery application. And its high loading capacity, high encapsulation efciency, simultaneous delivery of diverse therapies, ease of operation, and costeffectiveness are also appealing features for use in drug delivery, especially for wound-dressing materials and in postoperative local
chemotherapy.
Various carrier materials including natural [6062] and synthetic
(biodegradable and non-degradable) polymers and a blend of both
[63,64] have been used for electrospinning and many drugs from

Fig. 3. Schematic mechanism for the formation of core-sheath composite bers during
emulsion electrospinning (Ref. [55]).

X. Hu et al. / Journal of Controlled Release 185 (2014) 1221

anticancer drugs [6567] and antibiotics [68,69] to protein [7072],

DNA [73,74], and RNA [75,76] have been investigated. And the drug release behavior is determined by drug diffusion and degradation of the
carrier polymer. The above mentioned electrospinning techniques are
used to control the distribution state of the drug in the bers and thus
to improve drug release kinetics.

3.1. Materials
Various materials including natural polymers, synthetic polymers
and hybrid blends of the two have been used to obtain electrospun bers. Synthetic polymers have great exibility in synthesis and modication, but these polymers lack cell afnity because of their low
hydrophilicity and lack of surface cell recognition sites. Compared to
synthetic polymers, natural polymers exhibit better biocompatibility
and low immunogenicity, and some exhibit intrinsic antibacterial properties and better clinical functionality. Typical natural polymers include
polysaccharides (cellulose, chitin, chitosan, dextrose), proteins (collagen, gelatin, silk, etc.), DNA, as well as some biopolymer derivatives
and composites and their applications in electrospinning have been reported or summarized in a few papers [36,62,77]. For example, Lee et al.
summarized the characteristics of various polysaccharides such as alginate, cellulose, chitin, chitosan, hyaluronic acid, starch, dextran, and
heparin that can be used for electrospinning and their biomedical applications for tissue engineering, wound dressings, drug delivery, and enzyme immobilization [78]. Chitosan has shown good anticancer
activity, mainly due to its polycationic nature. Quaternized derivatives
of chitosan are known for their good in vitro anticancer activity against
HeLa, Hep3B and SW480 cells [79,80].
Secondly, synthetic polymers, especially biodegradable polymers,
attracted special attention in electrospinning due to the elimination of
a second surgery to remove the implanted carrier. Polymers such as
poly(lactic acid) (PLA), poly(-caprolactone) (PCL), poly(ethylene
oxide), and copolymers, such as poly(L-lactide-co-caprolactone)
(PCLA) and poly(lactic-co-glycolic acid) (PLGA), have been extensively
investigated to fabricate bers with desired properties for tissue engineering and drug delivery applications. Additionally, the rate of degradation can be controlled to some extent by altering parameters such
as polymer blend composition and ratio of amorphous to crystalline
segments. For example, the hydrophobic nature of PLA and PLGA is serious problem in a predominantly hydrophilic bioenvironment. Kim
et al. investigated the control of degradation rate and hydrophilicity of
poly(D,L-lactide) nanobers by adding PLGA (LA/GA = 50/50) random
copolymer, PLA-b-PEG-b-PLA triblock copolymer and lactide [81]. Of
the four components, high molecular weight (HMW) PLA was to provide the overall mechanical strength, PLGA was to grossly tune the degradation rate, lactide was to ne tune the degradation rate and PLA-bPEG-b-PLA copolymer was to control the hydrophilicity. Finally, they
found that the electrospun nanobers containing the four components
(40 wt.% of HMW PLA, 15 wt.% of lactide, 20 wt.% of PLA-b-PEG-b-PLA
and 25 wt.% of lower molecular weight PLGA) exhibited an ideal
biodegradation prole, a good hydrophilicity, and stable mechanical
properties in aqueous conditions. Zong et al. prepared poly(glycolideco-lactide) (GA:LA = 90:10) electrospun bers and investigated their
microstructure, morphology and texture, and the inuence of postdrawing and thermal treatment on their degradation and mechanical
properties [82]. When annealed at elevated temperatures without
drawing, the membrane bers showed a higher degree of crystallinity
with distinct lamellar structure but no overall orientation. The crystal
orientation was improved signicantly when the membrane was
drawn and annealed. The tensile strength of the electrospun membranes was greatly improved by post-treatments (stretching and annealing). The tensile retention time for the membranes annealed
under a strain of 300% at 90 C for 20 min increased from 2 to 12 days
during in vitro degradation.

15

Thirdly, in most cases, it is desirable to fabricate composite nanobers comprising both synthetic polymers for the backbone and natural
polymers for cellular attachment. Stitzel et al. examined the use of a hybrid blend of type I collagen (45%), PLGA (40%), and elastin (15%) to
form a vascular prosthesis via electrospinning [83]. The addition of
PLGA was shown to improve mechanical properties such as burst
strength and compliance of the prosthesis as compared to bers composed solely of type I collagen and elastin (which are both components
of the natural ECM of blood vessel walls). Park et al. examined the generation of novel biodegradable bers by electrospinning a hybrid blend
consisting of poly(glycolic acid) (PGA) and chitin [84]. In vitro degradation results indicated that PGA in PGA/chitin blend nanobers were degraded faster than pure PGA nanobers, which was attributed to the
hydrophilicity of chitin. The cell attachment and spreading onto the
PGA/chitin blend nanobers showed relatively promising results for
the normal human broblasts.
Currently, bioactive materials which can intentionally interact with
the biological environment are often incorporated into the electrospun
bers of synthetic, natural, or hybrid materials [85]. Grafahrend et al.
presented a degradable extracellular matrix-mimetic carrier by
electrospinning poly(D,L-lactide-co-glycolide) with a functional, amphiphilic macromolecule based on star-shaped poly(ethylene oxide) to
suppress non-specic protein adsorption on the bers' surface [86].
And the subsequent covalent attachment of cell-adhesion-mediating
peptides to the hydrophilic bers promotes specic bioactivation and
enables adhesion of cells. Lancuski et al. reported efcient and versatile
surface-glycosylated PCL electrospun bers by CuAAC click-chemistry
and investigated their interaction with specic lectins [87].
3.2. Loaded drugs and their release kinetics
The above mentioned unique properties of electrospun bers such
as high surface area, high loading, simultaneous delivery of diverse therapies, ease of operation, and cost-effectiveness expanded their use in
drug delivery. Of the various applications, wound-dressing and local
cancer treatments are two of the most investigated area. Table 1
presents some of the representative drugs loaded into electrospun
bers for drug delivery.
3.2.1. Antibiotics and various antibacterial agents
Antibiotics and various antibacterial agents are the most preferred
biocides to be loaded in nanobers to afford antibacterial properties.
Ignatova et al. summarized various antibiotics, such as tetracycline
hydrochloride, ciprooxacin, levooxacin, and moxioxacin, and antibacterial agents (e.g., 8-hydroxyquinoline derivatives, itraconazole,
benzalkonium chloride (BC), fusidic acid or silver nanoparticles) encapsulated in nanobers for wound-dressing [89]. In most cases, PLA, PLGA,
and PCL were used as the carrier polymers, and other synthetic or natural polymers were added to regulate the biodegradability and hydrophilic nature of the bers, thus regulating the release behavior. For
example, in the early study on application of electrospun nano-bers
for drug delivery by Kenawy et al. [27], tetracycline hydrochloride was
used as a model drug and poly(ethylene-co-vinyl acetate), poly(lactic
acid) and their blends were used as polymeric carriers. The results demonstrated that drug release behavior was inuenced by the nature of
polymeric carrier and drug content. Smooth and regulated drug release
over approximately 5 days was obtained by electrospinning 50/50
blend with relatively low drug content (5 wt.%). Higher drug content
(25 wt.%) induced much more rapid release than the 5 wt.% sample,
due to the more surface-segregation of the drug in the former case.
3.2.2. Anticancer drugs
Various anticancer drugs such as doxorubicin (Dox), paclitaxel
(PTX), platinum complexes [67], and dichloroacetate have been
electrospun into bers and used for postoperative local chemotherapy.
For example, Xu et al. reported preparation of ultrane Dox-

16

X. Hu et al. / Journal of Controlled Release 185 (2014) 1221

Table 1
Some of the representative drugs loaded into electrospun bers.
Polymer

Drugs

Solvent

Spinning type

Ref.

PLA, PEVA and PLA/PEVA

PLA/PCL
PCL
PCL-co-PCLEEP

Tetracycline hydrochloride
Tetracycline hydrochloride
siRNA
Human glial cell-derived neurotrophic
factor (GDNF)
Human -nerve growth factor (NGF)
siRNA
Fusidic acid and rifampicin

Chloroform
Chloroform and dimethylformamide (DMF)
2, 2,2-Triuoroethanol (TFE)
Dichloromethane (DCM)

Single nozzle
Single nozzle
Single nozzle
Single nozzle

[27]
[88]
[75]
[72]

Single nozzle
Single nozzle
Single nozzle

[70]
[76]
[68]

Tetracycline hydrochloride
Ketoprofen (KET)

DCM
RNase-free water
Tetrahydrofuran (THF) and
dimethylformamide (DMF)
1,1,1,3,3,3-Hexauoro-2-propanol
Ethanol aqueous solution

Single nozzle
Single nozzle

[69]
[107]

Ibuprofen

DMF

Side-by-side-electrospinning

[97]

Ketoprofen (KET)
Mefoxin
Bovine serum albumin (BSA)
Lysozyme
Human-nerve growth factor (NGF)
Doxorubicin hydrocloride (Dox)
Doxorubicin hydrochloride
Doxorubicin
Hydroxycamptothecin (HCPT)
DNA
Fenbufen
HRP encapsulated liposomes
Paclitaxel
Cisplatin
Dichloroacetate (DCA)
1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU)

Ethanol aqueous solution

DMF
Deionized water
Chloroform
Chloroform
Chloroform
Water-in-oil (W/O) emulsions
ChloroformCH3OHDMSO
DMSO
DMF
2,2,2-Triuoroethanol
Polyvinyl alcohol
DCM and DMF
DCM
Chloroform
Chloroform

Sequential electrospinning
Single nozzle
Single nozzle
Emulsion electrospinning
Emulsion electrospinning
Single nozzle
Emulsion electrospinning
Single nozzle
Emulsion electrospinning
Single nozzle
Single nozzle
Coaxial electrospinning
Single nozzle
Single nozzle
Single nozzle
Single nozzle

[108]
[94]
[12]
[51]
[71]
[65]
[52]
[25]
[113]
[74]
[105]
[92]
[111]
[67]
[112]
[53]

PCL-co-PCLEEP
PCLEEP
PLGA
Poly(ester urethane) urea (PEUU) and PLGA
Ethyl cellulose (EC) and polyvinylpyrrolidone
(PVP)
PLGA poly(ethylene glycol)-g-chitosan
(PEG-g-CHN)
PVP/zein
PLGA
Poly(ethylene oxide) (PEO)
PLA
Poly(L-lactide-co-caprolactone)
PEGPLA
PEGPLA
PLLA
2-Hydroxypropyl--cyclodextrin (HPCD)
PLAPEG and PLGA
PLGA/gelatin
PCL/PVA
PLGA
PLA/PLGA
PLA
PEGPLLA

containing PEGPLLA bers by electrospinning a water-in-oil emulsion,

in which the aqueous phase contained the water-soluble drugs and the
oily phase was a chloroform solution of PEGPLLA. The results indicated
that the Dox was entirely encapsulated inside the electrospun bers
[52]. Afterwards, they successfully loaded hydrophobic PTX and hydrophilic Dox simultaneously into PEGPLA nanober mats by the
emulsion-electrospinning method, and realized multi-drug delivery
[90]. Xie et al. fabricated cisplatin-loaded PLA/PLGA (30/70) bers for
long-term sustained delivery of cisplatin to treat C6 glioma in vitro
[67]. The drug encapsulation efciency was more than 90% and the
cisplatin-loaded bers showed sustained release for more than 75
days without initial burst release.
3.2.3. Protein, DNA, RNA and growth factors
Along with the development of electrospinning technique, more and
more bioactive molecules such as protein, DNA, RNA, and growth factors
have been incorporated into electrospun bers. The challenge is to ensure the bioactivity or functional efciency of these drugs during the
electrospinning process. By careful selection of materials and processing
conditions, desired encapsulation efciency, as well as preserved bioactivity of the therapeutic agents can be achieved. The incorporation of
such bioactive molecules was mostly by means of blend electrospinning
or coaxial electrospinning. In blend electrospinning, the carrier polymer
and biomolecules are mixed prior to electrospinning, which always
causes localization of bioactive molecules on the surface of bers, and
consequently bioactivity reduction. Chew et al. encapsulated human
nerve growth factor (hNGF) along with BSA as a carrier protein into
nanobers composed of a copolymer of PCL and poly(ethyl ethylene
phosphate) (PCLEEP) [70]. The protein was uniformly dispersed in the
polymer solution as aggregates. The induction of PC12 cells into the
neuronal lineage by the released hNGF indicated a partial retention of
the bioactivity of the growth factor in the electrospinning process. A
sustained release of hNGF over three months was demonstrated. The
same group demonstrated the feasibility of delivering smallinterfering RNA (siRNA) and transfection reagent (TKO) complexes
within nanobers comprising a copolymer of caprolactone and ethyl

ethylene phosphate (PCLEEP) [76]. Co-encapsulation of siRNA and

TKO within PCLEEP bers resulted in a sustained release of bioactive
siRNA for at least 28 days. The copolymerization of EEP with
caprolactone enhanced siRNA delivery rate and gene knockdown efciency as compared to PCL.
In coaxial electrospinning, both polymer and biomolecules are coaxially and simultaneously electrospun to produce bers with a coreshell
structure. The shell polymer not only contributes to the sustained and
prolonged release of the therapeutic agent, but also plays an essential
role in protecting the core ingredient from direct exposure to the biological environment. Saraf and co-workers constructed nanobers containing plasmid DNA (pDNA) within the core and the non-viral gene carrier
poly(ethylenimine)-hyaluronic acid (PEI-HA) within the sheath by coaxial electrospinning [91]. Extended release of the gene over a period
of 60 days was obtained by changing the parameters such as concentration of the pDNA. And the transfection efciency of the pDNA can be
tuned by changing the concentration and molecular weight of the core
polymer. In order to protect the activity of biomolecules, Mickova
et al. proposed combined use of liposome and bers as drug delivery
system [92]. Core/shell nanobers containing intact liposomes were
successfully fabricated by using coaxial electrospinning. Due to the
shielding effect of the lipid sphere, enzymes encapsulated in liposomes
can better survive the electrospinning process.
3.2.4. Drug release kinetics
For most non-biodegradable polymer nanobers, diffusion plays a
leading role in the release behavior, and it becomes complicated if the
carrier is biodegradable. The diffusion of drug molecules from the ber
and the degradation of the carrier should be considered together. For
example, Jing et al. encapsulated rifampin into poly(L-lactic acid) bers
and surfactants were used to adjust the diameter size and uniformity
[31]. The drug release in the presence of proteinase K followed nearly
zero-order kinetics, on the other hand, no drug was detected in the buffer solution without proteinase K, which indicated that the drug release
in the presence of proteinase K was mainly due to the degradation of the
PLLA bers, not due to the diffusion or permeation of drug molecules

X. Hu et al. / Journal of Controlled Release 185 (2014) 1221

through the PLLA carrier. No burst release was observed, implying

perfect inclusion of the drug inside the bers. Dave et al. prepared
endogenously triggered electrospun bers for controlled antibiotic
release by encapsulating antibiotic gentamicin sulfate (GS) and a
polymer-degrading enzyme (lipase) in polycaprolactone (PCL)-based
electrospun bers simultaneously [93]. By modulating the concentration of lipase, they obtained different GS release systems and the lifetime of the bers could also be tuned (10 h to 25 days). Antibiotic
drug Mefoxin was reported to be loaded into PDLLA nanobers with
loading efciency of 90% using a similar method. However, burst release
of Mefoxin in PDLA nanobers was observed in the rst 3 h and complete release occurred within 48 h, which indicated that the drug was
attached only on the surface of the nanobers. In another study [94],
the burst release of Mefoxin in poly(lactide-co-glycolide) (PLGA)based nanobers at earlier time points was reduced by introduction of
an amphiphilic PEG-b-PLA block copolymer and sustained drug release
system was obtained (up to 1 week). The above studies indicate that
the drug distribution state in the ber has important inuence on its release. In order to attain successful encapsulation of a drug into the
electrospun nanobers, the physicochemical properties of polymers as
well as their interaction with drug molecules must be precisely considered, as they signicantly affect drug-encapsulation efciency, drug distribution inside the bers, and kinetics of drug release [26]. The general
principle is that hydrophobic drugs such as rifampicin and paclitaxel
should be loaded into hydrophobic polymers and hydrophilic drugs
like Dox should be loaded into hydrophilic polymers.
Recently, Yohe et al. proposed using air as a barrier component in a
porous electrospun mesh by using superhydrophobic polymers to control the drug release rate [95,96]. They fabricated poly(-caprolactone)
electrospun ultrane bers containing 050 wt.% poly(glycerol
monostearate-co--caprolactone) (PGC-C18) as a hydrophobic polymer
dopant. SN-38 (7-ethyl-10-hydro-xycampthothecin) was encapsulated
into the bers as a model drug. PCL electrospun bers doped with 10
wt.% PGC-C18 showed nearly linear sustained release over 70 days
whereas pure PCL electrospun bers showed relative fast drug release
for the rst 10 days and reached maximum cumulative release of
about 70% after 20 days. The delay of drug release by the hydrophobic
bers is through the reduced drug diffusion and increased stability of
the entrapped air layer.
Covalent conjugation of the drug to polymers represents another
method to modulate drug release. Jiang et al. used a PLGA/PEG-g-chitosan blend for delivery of ibuprofen [97]. The PEG-g-chitosan component
was used to mediate the mechanical properties and ibuprofen release
rate from the electrospun membranes. They further conjugated ibuprofen to the side chains of PEG-g-chitosan, and the drug release prolonged
for more than two weeks. Zou et al. incorporated functional ketone
groups into PDLLA backbone through copolymerization with functional
PCL-based monomers [98]. Subsequently heparin molecules were conjugated to electrospun bers through arm molecules. Heparinized bers
could efciently bind bFGF, gradually release bFGF and preserve the bioactivity during incubation.
However, this conjugate method needs to select carrier polymers
with desired functional groups. A relatively simple method to reduce
the burst release was coaxial electrospinning and emulsion
electrospinning. Xu et al. reported the preparation of ultrane Doxcontaining PEGPLLA bers by electrospinning a water-in-oil emulsion
[52], in which the aqueous phase contained the water-soluble drugs and
the oily phase was a chloroform solution of PEGPLLA. The Dox was entirely encapsulated inside the electrospun bers. The release of Dox
from the medicated bers followed a combined mechanism of diffusion
and enzymatic degradation. At the early stage, the diffusion mechanism
was predominant and a certain time later, the enzymatic degradation
mechanism became predominant. There was much less burst release
in the very beginning compared with the suspension-electrospun bers.
In their following both Dox- and PTX-loaded system [90], the release behaviors of both drugs from the same ber mats were mainly relied on

17

their solubility properties and distribution status in the bers. Due to

its high hydrophilicity, Dox was easy to diffuse out from the bers,
and its release rate was faster than that of hydrophobic PTX. Moreover,
the release rate of PTX was accelerated by Dox's release from the same
drug-loaded bers. (See Fig. 4.)
Rather than emulsion electrospinning mentioned above, another
way to develop drug loaded polymer nanobers for controlled drug
release is coaxial electrospinning. Two or more components can be coaxially electrospun through different capillary channels and are integrated into a coreshell structured composite ber. With this, drugs or
biologically active molecules can be released through the skin of the
bicomponent nanober if the carrier polymer is permeable to the
drugs wrapped, or can be released over a certain period of time while
a biological degradation of the carrier polymer is taking place. Another
advantage of the coaxially electrospun nanobers is that it provides
temporal protection for certain bioactive substances such as growth factors which need to be protected for a certain period of time prior to
playing their role in the early stage of wound healing. Zhang et al. prepared (uorescein isothiocyanate-conjugated bovine serum albumin)encapsulated poly(-caprolactone) core-sheath nanobers. It was
found that these core-sheath nanobers pronouncedly alleviated the
initial burst release for higher protein loading and gave better sustainability compared to single-nozzle electrospun bers [99].
Cross-linking is another method to prevent burst release of drug
from nanobers. Several physical and chemical methods have been
employed by researchers for effective crosslinking of the nanobers, including UV-irradiation [100,101], dehydrothermal treatment [102], and
treatment with chemicals such as glutaraldehyde, formaldehyde and
carbodiimide [103,104]. Meng et al. prepared drug (Fenbufen, FBF)loaded poly(D,L-lactide-co-glycolide) (PLGA) and PLGA/gelatin nanobers and the subsequent crosslinking treatment depressed effectively
the burst release of FBF at initial release stage of PLGA/gelatin (9/1)
[105]. Tang et al. reported the preparation of cross-linked poly(vinyl
alcohol) (PVA) nanobers using chemical cross-linking agent, glutaraldehyde (GA), with hydrochloric acid (HCl) as a catalyst [103].
In order to better meet the needs of clinical application, a high control over the release rate, i.e., a biphasic delivery system, has sprung up
in recent years [106108]. This system contains a fast release that can
produce a rapid rise of drug concentration in the plasma for promptly
exercising the therapeutic effect, followed by a sustained release in
order to avoid repeated administration. This biphasic drug release system can be realized by multi-layered nanober mats that were produced by sequential electrospinning of different polymers. Huang
et al. described a tri-layered nanober mat realizing time-engineered
biphasic release using the sequential electrospinning method [106].
Two polymers (polyvinylpyrrolidone (PVP) and ethyl cellulose (EC))
were used as polymer carriers and ketoprofen (KET) was used as
model drug that was loaded into the ber mats. The drug release behavior can be controlled by the order of the nanober mesh, morphological
features of electrospun products, such as the ber diameter and mesh
thickness. The similar multilayered nanober mats have also been investigated and a more intelligent drug delivery system can be realized.
Okuda et al. demonstrated time-programmed dual release nanobers
using four-layered nanober mats [109]. The four layers were (1)
drug-loaded ber, (2) barrier bers (3) second drug-loaded ber, and
(4) basement ber (bottom). Time programmed controlled release of
dual drugs was achieved using this tetra-layered nanober meshes.
3.3. Applications for local chemotherapy
The fundamental aspect of electrospinning such as principle, parameter, electrospinning technique, loading method and their application in
tissue-engineering scaffold [110], wound dressing [14], and ltration
have been investigated extensively and reviewed excellently. However,
the application of electrospinning ber mats for local chemotherapy became popular only recently. Compared with other dosage forms like

18

X. Hu et al. / Journal of Controlled Release 185 (2014) 1221

liposomes, micelles, hydrogels, and nanoparticles, electrospun mats can

reduce the system toxicity and increase the local drug concentration. Especially in the case of solid tumors, a combination of surgical operation
for removing the tumor with subsequent chemotherapy or radiation
therapy is the normal procedure to reduce the probability of recurrence.
Local chemotherapy is a good choice for the treatment of unresectable
cancer or for the prevention of post-surgery tumor recurrence. Liu
et al. prepared Dox encapsulated nanobers using PLLA as the carrier
and examined its efcacy as a local chemotherapy system against secondary hepatic carcinoma (SHCC) [25]. The results indicated that the
majority of the loaded Dox in the bers was released and diffused into
the tumor site underneath the ber mat, leading to a great inhibitory
effect on tumor growth and little damage to other organs. These results
provide an encouraging prospect of using drug-loaded electrospun
nanobers in local chemotherapy, especially for those patients
receiving complete tumor resection or cytoreductive surgery. Similarly,
Ranganath et al. prepared paxlitaxel-loaded nanobers and evaluated
their post-surgical chemotherapy effect against malignant glioma
[111]. Liu et al. incorporated dichloroacetate (DCA) into the polylactide
(PLA) non-woven fabrics by electrospinning. These DCA-loaded
electrospun mats were directly implanted to cover the solid tumor
[112]. Results indicated that totally a tumor suppression degree of 96%
was achieved in less than 19 days. The solid subcutaneous tumors
completely disappeared from 50% of the tumor-bearing mice (Fig. 5).
Luo prepared hydroxycamptothecin loaded poly(benzaldehyde-poly
(ethylene glycol))-poly(D,L-lactide) (PBELA) bers for intratumoral
implantation and superior antitumor activity and fewer side effects
were observed [113].
4. Conclusions
Electrospinning is an old technology for the fabrication of continuous nanobers with simple setup. However, it attracted renewed focus
of biomedical applications and other nano-techniques in recent years.
Its inherent high surface to volume ratio, ease of operation, and costeffectiveness are all appealing features for biomedical application.
With the development of electrospinning techniques, such as co- and
multi-nozzle electrospinning, co-axial electrospinning and emulsion
electrospinning, a rich variety of materials, including natural polymers,
synthetic polymers, and their composites have been electrospun into ultrathin bers with controllable diameters and morphologies. This paper
summarizes the modication of the eletrospinning setups and the effect
of process parameters on the bers, discusses their application in drug
delivery, including carrier materials, loaded drugs and their release kinetics, and illustrates their application for local chemotherapy. To
date, the majority of the studies on the release of antibacterial agents
or anticancer drugs from electrospun bers were conducted in vitro. In
depth and systemic in vivo studies are necessary before clinical translation or commercialization can be realized, especially those on in vivo
drug release kinetics and dynamics, effects of drug dosage and release
kinetics on therapy efcacy, bio-distribution of the released drugs and
possible toxic effect on other organs, possible operation protocols, and
metabolism of the carrier polymers.
5. Perspective
The past few decades have witnessed tremendous progress in
electrospinning. Due to the achievements in the comprehension of the
basic and various parameters of electrospinning, in diversifying the
setups for electrospinning, such as co-axial electrospinning, emulsion
electrospinning, side-by-side electrospinning, and combination of
electrospinning with other techniques, a rich variety of polymers, ceramics and composite materials have been electrospun into ultrathin bers with controllable diameters. By careful selection of materials and
processing conditions, various antibacterial agents and anticancer

Fig. 4. Release proles of (A) Dox (a) and PTX (b) from (1.0 wt.% Dox + 1.0 wt.% PTX)/
PEGPLA composite bers, and release prole of PTX from 1.0 wt.% PTX/PEGPLA bers
(c) in 0.05 mol/L TrisHCl buffer solutions in the presence of proteinase (4 g/ml) at
37 C or (B) in the absence of proteinase K, respectively (Ref. [90]).

drugs have been successfully encapsulated into these nanobers and investigated for tissue engineering and drug delivery.
In spite of the signicant progress in using electrospun bers for
drug delivery, a great number of problems need to be solved. First of
all, it remains a challenge to ensure uniform nanobers to be fabricated
repeatedly and massively with the desired morphological, mechanical
and chemical properties, especially in industrial scale; Second, up to
now most of the studies on the release of antibacterial agents or anticancer drugs from electrospun bers have been conducted in vitro,
and in vivo studies have been rarely seen. In addition to those mentioned in the previous section, a number of other issues need to be addressed, such as proper drug loading content and efciency, removal
of residual organic solvent, bioactivity retention of the incorporated
drugs during preapplication procedures such as sterilization, effect of
the initial burst drug release, assurance of a required release prole,
and probable impacts such as brosis, or other immunological
responses.
The profound studies in these areas are crucial for the translation of
this promising technology from the laboratory to the industrial scale. It
needs cooperation of researchers in interdisciplinary elds, including
chemistry, physics, biology, pharmacy and clinical medicine.

Acknowledgments
This project was supported by the National Natural Science Foundation of China (Project Nos. 91227118 and 51373167).

X. Hu et al. / Journal of Controlled Release 185 (2014) 1221

19

Fig. 5. Suppression results on tumor growth. Changes of the tumor volume (a), tumor weight (b) and tumor suppression degree (c) on the 7th, 14th and 19th days; and photographs of
tumors of groups C, O, P and D on the 19th day (d). No solid tumors were observed in 5 of the 10 tumor-bearing mice in group D, as indicated in the red circle in (d). In all the four gures,
groups C, O, P and D represent the control group, the blank PLA mat group, the oral group and the DCA-loaded mat group, respectively (Ref. [112]).

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