2008 Wu BiomaterSciPolymer

J. Biomater. Sci. Polymer Edn, Vol. 19, No. 5, pp.
573– 601 (2008)

 Koninklijke Brill NV, Leiden, 2008.
Also available online - www.brill.nl/jbs
Review
Electrohydrodynamic atomization: a versatile process for

preparing materials for biomedical applications
YIQUAN WU 1,2 and ROBERT L. CLARK 1,2,∗

1 Centerfor Biologically Inspired Materials & Material Systems, Duke University, Durham,
NC 27708, USA
2 Mechanical Engineering and Materials Science, Pratt School of Engineering, Duke University,
Durham, NC 27708, USA
Received 3 September 2007; accepted 25 October 2007
Abstract—Electrohydrodynamic atomization phenomena have increasingly attracted the attention of

researchers who are interested in building micro- or nanometer architectures, such as fibers and en-
capsulated particles with a controllable microstructure. There are two main electrohydrodynamic
atomization techniques: electrospraying and electrospinning. These techniques are unique processes
in that they produce fibers and particles with dimensions that range from micrometers to nanometers
depending on the processing parameters. This paper presents the principles, processes and poten-
tial biomedical applications for electrospraying and electrospinning of biomaterials. Both of these
techniques offer great research opportunities. Emphasis will focus on the effects of processing para-
meters of electrohydrodynamic atomization on morphologies and microstructure of the final products.
In addition, some potential applications are proposed based on the remarkable characteristics of the
biomaterials generated using electrospraying and electrospinning.
Key words: Electrospraying; electrospinning; biomaterials; biomedical application; tissue engineer-

ing; drug delivery.
INTRODUCTION
Electrohydrodynamic atomization is a cost-effective technique that uses a uniform
electrohydrodynamic force to break up the liquids into fine jets [1 –3]. It is
capable of producing particles and fibers through proper selection of the processing
parameters. In a typical electrohydrodynamic process, a liquid precursor is fed
to a nozzle and a droplet forms at the nozzle. When the droplet is exposed to a
strong electric field, a charge is induced on the surface of the droplet. Influenced
by the electrostatic field, the droplet at the tip of nozzle forms a conical shape
∗ Towhom correspondence should be addressed. Tel.: (1-919) 660-5435; Fax: (1-919) 660-5409;
e-mail: rclark@duke.edu
574 Y. Wu and R. L. Clark
spraying mode. From the tip of this cone, a charged jet of liquid precursor
is propelled to the collector, which carries a charge opposite to the droplet or
is grounded. Depending on the specific processing parameters (e.g., working
distance, voltage) these techniques can produce micro- and nano-scale fibers and
particles composed of polymers, ceramics or composites [4, 5]. There are two main
techniques in the electrohydrodynamic atomization processing: electrospraying
and electrospinning. Electrospraying describes a technique where particles are
created while the term electrospinning is used in situations where fibers are created.
Recently, researchers have taken notice of these techniques for their ability to
create micro- and nanometer architectures such as functional tissue scaffolds, drug-
delivery carriers, patterned biochips and bioactive films/coatings [6 –10]. Current
challenges in the field of tissue engineering and drug delivery lie in the design of
scaffolds that mimic the structural and biological functions of natural extracellular
matrix as well as the development of biodegradable drug-encapsulation vessels of
micrometer or nanometer scale [11 –13]. Electrospinning is an attractive possibility
for generating fibers from bio-polymers. It could address a variety of needs in
tissue engineering, such as scaffolds for skin, bone, blood vessels and vascular
grafts [10, 14, 15]. It could also be used in drug delivery systems since drugs and
other small molecules can be easily capsulated directly into electrospun bio-polymer
fibers and membranes [16]. Production and control of particles with a narrow
size distribution are of particular interest for drug delivery [12]. One outstanding
feature of electrospraying is its ability to generate monodispersed droplets whose
size can be varied between hundreds of micrometers and tens of nanometers
by optimizing the processing parameters. The electrohydrodynamic atomization
modes are complicated functions of the applied voltage, the working distance, the
flow rate of the liquid, the nozzle diameter and the physical/chemical properties
of the precursors. As the applied field strength increases, the atomization mode
can be transformed from a dripping mode to a cone-jet to a multi-jet mode [17].
The single cone-jet mode is the preferred atomization mode because it can produce
a uniform, stable, and continuous electrospraying or electrospinning pattern with
a controllable jet size. In this paper, varieties of electrospun and electrosprayed
biomaterials are presented along with their processing parameters. We also report
our investigations related to the electrohydrodynamic atomization processing of
materials having potential biomedical applications. Our emphasis focuses on the
influence of the processing parameters on morphologies and microstructure of the
final products.
BACKGROUNDS AND PRINCIPLES

Electrospraying
The theory describing the electrohydrodynamic atomization of liquids into small
charged droplets under an electrostatic field was formulated by Rayleigh over
100 years ago [18]. He found that a charged droplet is unstable, resulting in the
Electrohydrodynamic atomization 575
Coulombic fission of the liquid droplet into smaller droplets. There is a maximum
limit on the surface charge density, termed the Rayleigh limit [19]. Beyond
this limit, the electrohydrodynamic forces overcome the surface tension forces of
droplets. The atomization modes of electrohydrodynamic processing can be divided
into two groups [9, 17]. The first group includes the modes in which only fragments
of liquid are ejected from the nozzle. The second group includes the modes in
which the liquid ejects from the nozzle in the form of a long continuous jet, which
disintegrates into droplets only at some distance from the tip of the nozzle.
Zeleny was the first researcher to study electrospraying systematically using
a capillary-plate experimental configuration in 1917 [20]. The next significant
contribution to the field came in 1952 by Vonnegut and Neubauer, who reported
the generation of monodispersed aerosol droplets produced by electrospraying [21].
In 1964, Taylor gave the first explanation and theoretical description of the conical
shape of the pending droplet at the capillary exit by investigating the hydrostatic
balance between electrical and surface tension forces [22]. This cone is now
commonly known as the Taylor cone [2]. In 1994, Cloupeau et al. described and
explained the different electrospraying patterns in terms of the electric potentials,
the liquid physical properties, the liquid flow rate and the setup geometry of
system [23]. Also in 1994, Fernandez et al. studied the electric current and the
cone-jet droplet size as they relate to various setup parameters [24]. The multi-jet
electrospraying mode was observed by Shtern et al. in 1994, Jaworek et al. in 1996
and others [25 –29]. Only Jaworek et al. developed a stability map accounting for
the voltage and the flow rate. The field of electrospraying expanded significantly
after these tremendous research works. These works established that solutions with
the right physical properties under certain process parameters could form a conical
meniscus at the exit of a capillary to produce fine aerosol jets from the tip of the
cone. Figure 1 shows the basic principle of the electrospraying phenomena.
In 1997, Gañán et al. carried out the experimental measurement of the current
and the size of the primary droplets by electrospraying a variety of liquids with
different electrical conductivities, surface tension, permittivities, densities and
viscosities [30]. They derived scaling laws for electrospraying currents, as well
as the charges and sizes of the droplets based on a theoretical model of charge
transport. Their experimental results showed that an electrosprayed solution’s
viscosity and conductivity have a significant impact on the resulting current and
Figure 1. Schematic of the basic principle of electrospraying.

droplet size. The experimental results fit the theoretical results well. Two
scaling laws can be applied to different solutions with relatively high viscosity and
electrical conductivity or low viscosity and electrical conductivity, depending on a
dimensionless parameter. The parameter governs the liquid acceleration process,
and ultimately the electrospraying current and droplet size. In most cases, the
dimensionless parameter satisfies equation (1):
3 2 1/3
γ ε0
δµ · δ ∼
1/3
, (1)
µ3 K 2 Q
where Q is the flow rate of liquid, ε0 is the permittivity of vacuum, K is the electrical
conductivity, γ is the surface tension and µ is the viscosity of solution.
If δµ · δ 1/3 1, the current, I , and size of the droplets, d, in a cone-jet
electrospraying mode are:
I /I0 = 6.2(Q/(β − 1)1/2 · Q0 )1/2 ;
(2)
d/(β − 1)1/3 d0 = 1.6(Q/(β − 1)1/2 Q0 )1/3 − 1.0.
If δµ · δ 1/3 1, the current, I , and size of the droplets, d, in a cone-jet
electrospraying mode are:
I /I 0 = 11.0(Q/Q0 )1/4 − 5.0; d/d0 = 1.2(Q/Q0 )1/2 − 0.3, (3)
where I0 = (ε0 γ 2 /ρ)1/2 , Q0 = ε0 γ /(ρK), d0 = (γ ε02 (ρK 2 ))1/3 , where β and ρ are
the liquid to vacuum permittivity ratio and the density of liquid, respectively.
Another advance in the understanding of electrospraying came in 1999, when
Hartman et al. developed a model to calculate the shape of the cone-jet [31]. This
model is also capable of calculating the surface charge density on the cone surface,
and the magnitude and direction of the electric field inside and outside the cone-jet.
Electrospinning
The electrospinning process has been used to prepare one-dimensional materials
relatively recently, but the idea was first proposed over 100 years ago [32]. In
one of the earliest electrospinning demonstrations, Cooley patented a setup that
used auxiliary electrodes to direct the electrospinning jet onto a rotating collector
in 1902 [33]. The patent on producing yarns made out of electrospun fibers was
issued to Formhals in 1934, and subsequently he published several other patents
that described electrospinning polymer filaments in the 1930s [34, 35].
More recently, Larrondo and Manley carried out an investigation into polymer
melts in 1981 [36]. Reneker published a paper on electrospinning as a method to
prepare polymer fibers in the early 1990s [37]. Reneker’s work initiated a new
interest in electrospinning from researchers searching for an effective technique for
producing polymeric one-dimensional fibers in the field of nanotechnology during
the past few years [38 –40].
In a typical electrospinning process, the precursor solution is held at the end
of the nozzle in the form of a droplet by its surface tension. As is the case with
electrospraying, a voltage applied to the nozzle results in the formation of a Taylor

cone, from which a jet of the precursor solution will erupt. Although the jet in
a Taylor-cone mode is stable near to the tip of the nozzle, it undergoes a fluid
instability stage that leads to accelerated solidification of the jet and a thinning of
the fibers as the jet approaches the collector [41, 42]. Figure 2 shows the basic
principle of electrospinning. The whole process consists of three stages [5, 43]:
(1) jet initiation with the formation of a Taylor cone, (2) the formation of whipping
instability and the thinning of the jet; (3) elongation and solidification of the jet
into nanofibers. The critical voltage Vc , at which the maximum jet fluid instability
develops, is given in Ref. [44].
Before 1999 the formation of one-dimensional fibers generated by electrospinning
was thought to be a splitting or splaying of the electrified jet [39]. It was believed
that the radial charge repulsion would result the primary jet splitting into multiple
sub-jets as the electrified jet fluid accelerates along its trajectory to the collector.
However, recent studies and experimental observations have demonstrated that the
thinning of a jet is generally caused by the bending instability associated with the
electrified jet, and the key mechanism reducing the jet diameter from the micrometer
to nanometer scale is a non-axisymmetric or whipping instability, which causes
bending and stretching of the jet at very high frequencies [41, 42, 45]. It is
accepted that the electrified jet is initially a straight line in a cone-jet mode and that
becomes unstable in the second stage. Three possible types of instabilities have been
proposed [5, 45 – 47]. The first is referred to as the classical Rayleigh instability,
which is axisymmetric with respect to the jet centerline. The second is referred to
as an axisymmetric instability, where the varicose structures are visible. The third is
the non-axisymmetric, or ‘whipping’ instability, where a non-axisymmetric bending
of the fiber occurs. The third bending instability is considered as the most important
process, because it is responsible for thinning the fibers from the micrometer to
nanometer range. Shin et al. experimentally demonstrated that the so-called
‘inverse cone’ was caused by a bending instability, not by a splitting of the primary
jet into multiple jets [5, 45]. High-speed photography has revealed that the conical
envelope contains a single, rapidly bending, whipping thread. However, in some
cases the splaying and/or splitting of the electrified primary jet can also be observed
as the jet fluid driven by the electric forces is unstable during its trajectory towards
Figure 2. Schematic of the basic principle of electrospinning.

the collector. Using more advanced experimental equipment, the phenomena of

splaying and splitting have been observed by a number of research groups [48 –50].
The observed bending instability has also been described with proposed mathe-
matical models. Fridrikh et al. studied the thinning rate of the electrified jet in the
bending instability region and derived the equation of motion for the electrified jet
[51]. Reneker et al. modeled the instabilities of an electrified liquid jet as a system
of connected, viscoelastic dumbbells [41]. The interactions between the beads of the
dumbbells followed Coulomb’s law and had a Maxwellian viscoelastic resistance to
elongation. They modeled the three-dimensional trajectory of the electrified liquid
jet using linearized Maxwell’s equations, and the results provided a fundamental
interpretation for the mechanism of bending instability. Rutledge et al. developed
a different model to study electrospinning by considering the electrified liquid jet
as a long, slender object [42]. The modeled results exhibited the rapidly whipping
liquid jet phenomenon.
These modeling studies provide a better understanding of how these mechanisms
generate one-dimensional nanomaterials. Optimizing the electrospinning process
requires considering several of the process parameters such as the flow rate of the
solution, the electric field strength, the working distance and the ambient conditions.
In addition to the process parameters, a number of properties of the solution must be
taken into account including viscosity, concentration, electric conductivity, surface
tension, molecular weight and the molecular-weight distribution of the polymer.
Generally, the solution should have a concentration high enough to cause molecular
entanglements for electrospinning, but not so high that the viscosity will prevent the
solution from being electrospun under a reasonable applied electric field.
PREPARATION OF MATERIALS FOR BIOMEDICAL APPLICATIONS
The versatility of electrohydrodynamic atomization has been demonstrated through

several published results from many fields. In this section, various techniques
are discussed in the context of potential biomedical applications that they may
impact. This section also includes additional observations from our recent research
activities. These techniques can potentially be used in many different areas where
the production of particles and fibers in a controllable fashion is desirable.
Electrospraying of materials
Drug-delivery microspheres. Preparation of drug carriers still remains one of
the important challenges in medicine, and various fabrication techniques have been
studied in the pursuit of generating size-controllable and well-dispersed (i.e., not
clumped together) delivery carriers with high encapsulation efficiency [52, 53].
Targeted drug delivery directs therapeutic agents to specific organs or locations
in the body in a site-specific manner [54 –56]. Recently, significant efforts have
been devoted to developing novel technologies for preparing drug-delivery carriers
that offer suitable means for delivering low-molecular-weight drugs, as well as

macromolecules such as proteins, peptides, or genes [57 –59]. Electrospraying is
a promising technique for preparing drug-delivery carriers.
One of the significant potential advantages of the electrospraying technique is its
ability to prepare micro- and nano-sized particulate drug-delivery systems such as
microspheres and microcapsules, in which the biological agents can be encapsulated
or distributed into biodegradable polymer particles [60, 61]. The biodegradable
particles prepared using electrospraying can have a fairly narrow size distribution
and are well dispersed. The nanometer delivery particles can pass through small
intercellular openings to target the treated tissues or organs. In addition, antibodies
coupled to electrosprayed particles would achieve more efficient targeting and
get more predictable drug release profiles [62]. Figure 3 shows a schematic
representation of drug-delivery particles.
We synthesized polycaprolactone (PCL) particles by electrospraying a PCL
solution. Figure 4 shows a schematic experimental setup of electrospraying
for preparing drug delivery carriers. Figure 5a shows an SEM image of the
electrosprayed PCL particles. It can be seen that the individual particles have
smooth surfaces. The particle sizes range from 4.8 ± 0.2 to 17.7 ± 0.5 µm. The
particle size distribution is shown in Fig. 5b, revealing that 44% of the particles
fall within the range of 8 to 11 µm. Poly(methyl methacrylate) (PMMA) polymer
Figure 3. Schematic representations of particulate drug-delivery carriers. This figure is published in

colour at http://www.ingenta.com
Figure 4. Schematic diagram of an experimental setup for electrospraying. This figure is published
in colour at http://www.ingenta.com
Figure 5. (a) SEM image and (b) particle size distribution of electrosprayed PCL microspheres. Flow
rate 3 ml/h, spraying voltage 8 kV, concentration 7% (w/v).
Figure 6. SEM images of (a) PMMA microparticles and (b) PCL nanoparticles generated by
electrospraying techniques.
was also electrosprayed. The SEM image in Fig. 6a reveals a different particle
size and morphology when compared with the electrosprayed PCL particles. The
PMMA average particle size was 1.8 ± 0.3 µm, which is smaller than that of PCL
particles. The PMMA particles also displayed a very uniform size distribution. In
addition, with the right flow rate, PMMA nanoparticles could be achieved. The sizes
of particles fabricated in the present work ranged from 740 ± 4 nm to 100 ± 5 nm,
with an average size of 310 ± 6 nm, as shown in Fig. 6b. The experimental
results demonstrated that when the processing parameters were optimized, the
polymer particles prepared by electrospraying had a smooth surface and uniform
morphology, which are important characteristics for applications in drug delivery.
Surface smoothness influences particle adhesion because the adhesion forces vary
with roughness [63]. Rough surfaces are more favorable for colloid deposition
due to the fact that stronger attractive van der Waals interactions can be generated
by rough surfaces than that by smooth surfaces [64]. Compared with particles
fabricated by other methods such as spray-drying and emulsion evaporation, the
electrosprayed microspheres have a better spherical microstructure and uniform size
distribution [4, 7].
Figure 7. Schematic of an electrospraying setup with a water bath collector. This figure is published
Porous biopolymeric particles. In the last decade, porous biopolymer particles

have been of great interest in the field of bioengineering. They have been used
in a variety of applications in tissue engineering, drug delivery and biomolecular
analysis due to their designed porous microstructure, large surface area and con-
trollable pore size [65 –67]. Porous bio-polymer particles have been studied as po-
tential drug-delivery carriers and in tissue engineering as scaffolding for certain
orthopedic applications [68, 69]. Designing and arranging bioactive substances in
the pores can result in biological materials with unique properties for specific ap-
plications [70]. Further research into various functionalized porous bio-polymer
particles could uncover new applications that they are well suited for in the field
of bionanotechnology. Currently, a number of approaches for their fabrication
are employed: supercritical carbon dioxide emulsification, colloidal particles self-
assembly, aerosol-spray techniques and controlled solvent evaporation [71 –74].
Experimentally, electrospraying has been demonstrated to be capable of generating
highly charged droplets, which consequently result in self-repelled, small particles
without coalescence. In the micro- or nanometer range, the capability of producing
bio-polymer particles with controllable porous microstructures through the electro-
spraying technique would be unmatched by other aerosol processing methods. The
capability to electrospray porous bio-polymer particles is demonstrated in this pa-
per. Figure 7 shows a schematic experimental setup.
To prepare electrosprayed PCL particles, several solutions with different concen-
trations were prepared by dissolving PCL in chloroform solvent [7]. The prod-
ucts prepared by electrohydrodynamic processing show different microstructures
and morphologies depending on the solvents used for the polymer solution. When
selecting a solvent there are general principles to consider: fast solvent evapora-
tion and phase separation results in pore formation; solvents with low boiling points
yield irregular pore morphologies and large pore dimensions; and solvents with
high densities and boiling points result in smaller fiber diameters [75, 76]. Pat-
Figure 8. SEM images of PCL particles electrosprayed into a water bath using different solution
concentrations. Flow rate 3 ml/h, working distance 10 cm, spraying voltage 8 kV.
tamaprom et al. investigated the spinnability of solvents for polystyrene and found
that solvents with the highest spinnability all had a high dipole moment, low mole-
cular weight, and low-to-moderate viscosity, density and surface tension [77]. The
morphologies and pore microstructures of electrosprayed PCL particles were char-
acterized by SEM. Figure 8a shows an SEM image of PCL particles synthesized by
electrospraying PCL solution into a water bath. The particles had an average size of
4 ± 0.3 µm in diameter. From the SEM image, some particles were observed to ad-
here to each other, which was due to the surface tension of water acting on the PCL
particles during drying. The PCL particles had two kinds of isolated pores, small,
mostly rounded pores in the nanometer range and pores larger than 1 µm having a
hexagonal shape.
When the concentration of PCL in chloroform was increased to 4% (w/v), the
pores became smaller, more circular and more homogenously distributed, as shown
in Fig. 8b. The PCL particles had an average size of approximately 8 ± 0.5 µm,
with pore sizes ranging from 10 to 310 nm. It is believed that thermally-induced
phase separation and evaporation-induced phase separation are the pertinent phase-
separation processes for pore formation in porous electrosprayed PCL particles
[78, 79]. Figure 9 is an illustration of the formation of porous particles by this
method. Another mechanism under consideration as a source for the formation
of porous electrosprayed PCL particles is the cooling caused by rapid solvent
evaporation [7]. As the surface temperature of the electrosprayed jet cools, water
droplets could condense on the polymer particles. The pores in the dried particles
would be the remaining imprints left where the water droplets had formed.
Electrostatic deposition of bio-coatings. In biomedical applications, bio-

coatings have been deposited onto implants to promote cellular in-growth and re-
duce the mechanical mismatch between implanted devices and new tissues [80, 81].
Electrospraying is capable of producing uniform coatings with controllable thick-
nesses and microstructures using inexpensive equipment in a typical atmospheric
environment. A recent review summarizes electrospraying applications in film de-
Figure 9. An illustration of phase separation resulting in different porous microstructures. This figure
is published in colour at http://www.ingenta.com
position, details numerous laboratory experiments and offers examples of electro-

spraying’s practical significance [82]. Huang et al. employed electrospraying to
deposit silicon substituted hydroxyaptite bio-coatings, which could offer great po-
tential for the creation of bioactive surfaces that provide improved interfacial bond-
ing with host tissues [83]. Siebers et al. prepared calcium phosphate coatings using
electrostatic spray deposition to evaluate the biocompatibility of coated implants
with various degrees of crystallinity [84]. In addition, some bio-polymeric coat-
ings have been deposited on the electrode surface of biosensors to enhance their
biocompatibility. For example, collagen, an extracellular matrix protein, has been
successfully deposited on a metallic surface to enhance the bioactivity and biocom-
patibility [85]. Native biomaterials have also been prepared as coating materials for
biomedical applications, such as biosensors, wound dressing/skin repair materials,
and scaffolds designed for cell culture and tissue engineering [86, 87]. Doubtlessly,
the bioactive coatings fabricated by electrospraying will find applications in the
fields of biosensors, microfluidic devices, antifouling surfaces and biocompatible
surfaces for biomedical devices. Electrospraying can be used to prepare dense or
porous coatings at low cost and with high efficiency [88, 89]. Figure 10 shows a
schematic experimental setup for preparing bio-coatings using the electrospraying
technique.
To prepare bioactive coatings, a cone-jet spraying mode is preferred due to the
wide potential range of sizes that can be achieved and the narrow size distribution for
a particular set of process parameters [90, 91]. When electrospraying bio-coatings,
it is also important to consider the evaporation of solvents and the spreading of
the aerosol droplets on substrates that are influenced by the depositing temperature.
The spreading behavior of the droplets on the substrate plays an important role in
the development of the bio-coating microstructure [92, 93]. Figure 11 shows the
effect that temperature had on the microstructure of a series of deposited PCL bio-
coatings. Electrospraying offers potential advantages in the deposition of bioactive
coatings by being cost-effective and applicable to a wide choice of precursors. In
addition, mixing precursor materials and solvents is an easy way to control the
composition of the biomedical coatings. Electrospraying has already been used
Figure 10. A diagram of an electrospraying setup for preparing bio-coatings. This figure is published
Figure 11. The influences of depositing temperatures on the microstructural development of PCL
bio-coatings.
to deposit bioceramic coatings with a variety of chemical properties [94, 95] to

improve the biological performance. The biological characterization demonstrated
that electrospraying capable of manufacturing bioceramic surface coatings with a
variety of chemical properties and morphologies. Biological membranes have also
been prepared on electrodes using electrospraying to prevent fouling of the electrode
surface by discriminating against macromolecular species [96]. The deposition of
protein and other biomolecular coatings onto an electrode surface is a necessary step
in fabrication of biosensors for biomedical applications. Morozov et al. were the
first to prepare functionally active protein coatings using electrospraying [97]. The
experiments showed that the electrospraying process neither destroyed the native
structure of protein molecules nor irreversibly inactivated them, demonstrating it is
a feasible technique for fabricating protein coatings for biomedical applications.
In this effort, an electrospraying setup was employed to prepare PCL bio-coatings.
The electrospraying unit included a high voltage power supply to generate a high
potential difference between the nozzle and the substrate, a metal nozzle to supply
Figure 12. SEM images of PCL bio-coatings prepared via electrospraying at different temperatures:
(a) room temperature and (b) 40◦ C. Flow rate 0.2 ml/h, spraying voltage 5 kV, working distance
14 mm.
the precursor and a substrate holder to fix the substrate and collect the materials.
The precursor solutions were prepared by dissolving PCL in dichloromethane
solvent. Figure 12 shows SEM images of PCL coatings deposited on a glass
substrate at room temperature and at 40◦ C. The results showed that the PCL coatings
prepared at 40◦ C were porous, but the coatings deposited at room temperature were
smooth, dense and homogeneous. The porous microstructure is attributed to the
fast evaporation of solvent on the heated substrate, causing a slow spreading of the
electrosprayed droplets on substrate. In general, dense coatings are produced when
the electrosprayed droplets on the substrate have enough time to spread whereas
porous microstructures are formed when the droplets were dried quickly [98].
Electrospinning of materials
PGA tissue templates. Tissue engineering is rapidly emerging as a promising
therapeutic strategy to repair or reconstruct damaged tissue or organs that fail to
regenerate or heal spontaneously [99, 100]. It has been defined by Langer and Va-
canti as an interdisciplinary field that applies biological, chemical and engineering
principles towards the development of biological substitutes that restore, maintain,
or improve tissue function using biomaterials, cells and factors alone or in com-
bination [101]. Figure 13 shows a schematic illustration of the tissue engineering
principle.
One aspect of tissue engineering involves the fabrication of three-dimensional
scaffolds with specific mechanical and biological properties similar to the native
extracellular matrix (ECM). These scaffolds can accommodate and deliver inductive
molecules/cells to the repair site and guide their growth into a specific tissue
[102]. The tissue scaffolds can modulate cellular activities such as migration,
proliferation, differentiation and gene expression. These activities are essential for
cellular growth functions in vitro and in vivo as they are directly involved in the
transport of oxygen and nutrient supports to the cells. In general, the ideal tissue
scaffolds should have the following characteristics to promote cellular functions
Figure 13. The basic principle behind tissue engineering. This figure is published in colour at
http://www.ingenta.com
[103 –105]: (1) biocompatibility and biodegradability to integrate with the host
tissue without eliciting a major immune response; (2) appropriate levels of porosity
and interconnected pores to allow for the exchange of nutrients; (3) sufficient
surface area and a variety of surface chemistries to carry the biomolecular signals
that promote cell adhesion, growth, migration and differentiation; (4) adequate
mechanical strength to support new tissue growth; and (5) a degradation rate to
closely match the regeneration rate of the desired natural tissue. Moreover, many
researches have demonstrated that fibrous scaffolds with fiber diameters down to the
nanometer scale are suitable for replicating the structure and functions of the ECM,
and have an important effect on regulating cell behavior.
Based on the above features, electrospinning is an appropriate technique for
preparing tissue scaffolds with fibers ranging from nanometer to micrometer scale
that mimic a natural extracellular matrix, and has the potential for large-scale pro-
duction of continuous nanofibers for biomedical applications [106]. Only recently
has electrospinning been revitalized and gained popularity with the biomedical en-
gineering community as a potential means of producing scaffolds for tissue engi-
neering applications. Figure 14 is a schematic showing an experimental setup for
preparing tissue scaffolds. Compared to other techniques for synthesizing nanome-
ter fibers, electrospinning is a straightforward way to produce continuous nano-
featured scaffolds with large surface area/volume ratio and an interconnected pore
structure [9, 10]. To date, electrospinning has been used most extensively to prepare
non-woven and aligned tissue scaffolds because various mono-polymers, blends of
polymers and compositions of polymers with other materials (e.g., inorganic sub-
stances, growth factors, cell regulatory biomolecules and living cells) can be elec-
trospun into tissue scaffolds for biomedical applications. Electrospinning has also
been employed to prepare bioceramic fibers and fibrous mats, including hydrox-
yapatite mats and bioactive glass fibers. These bioceramic structures have many
potential uses in the repair and treatment of bone defects, drug delivery, and tissue
engineering [49, 107, 108]. Moreover, electrospinning has emerged as a leading
technique for generating biomimetic, fibrous, extracellular matrix scaffolds made
Figure 14. Schematic diagram of an experimental setup for electrospinning. This figure is published
Table 1.
Processing parameters for electrospinning PGA fibers
Parameter
Applied voltage 18 kV
Flow rate 2.0 ml/h
Working distance 15 cm
Solvent Hexafluoro-2-propanol
Concentration 12% (w/v)
Figure 15. (a) Digital image and (b) SEM image of an electrospun PGA scaffold. Flow rate 2.0 ml/h,
electrospinning voltage 18 kV, working distance 15 cm.
of natural polymers, such as chitin nanofibers, silk fibroin, collagen, solubilized

alpha-elastin and recombinant human tropoelastin [109 –114]. The case study of
PGA scaffolds prepared using electrospinning is demonstrated herein.
Poly(glycolic acid) (PGA) has been electrospun into fibers suitable for tissue
scaffolds because along with being biocompatible and biodegradable, it is the
simplest form of linear aliphatic polyester. This makes it attractive for a wide variety
of biomedical applications [113]. The electrospinning conditions in our experiment
are detailed in Table 1. Figure 15a shows a digital image of the electrospun
PGA tissue template, which demonstrated that electrospinning was capable of

generating smooth tissue scaffolds mats. The microstructure of electrospun PGA
scaffolds was characterized using SEM, as shown in Fig. 15b. The SEM images
revealed that these PGA fibers formed a non-woven mat structure with apparently
random fiber orientation. The fiber diameters were in the range of 90 ± 10 nm
to 350 ± 6 nm with an average diameter of 180 ± 5 nm. The fibrous PGA
mat revealed a high porosity, which is ideal for tissue scaffolds because the high
surface area allows for a high percentage of cellular attachment. Furthermore,
the synthetic PGA bio-polymers also afford greater ability to tailor mechanical
properties and degradation rates, which is an indispensable element in engineered
tissue scaffolds [114]. Precise design and control of the fiber diameter will be
necessary for better recreating the function of native extracellular matrix. By
employing special collectors and controllable electric field, the synthetic bio-
polymer tissue scaffolds can be built with aligned fiber microstructure and improved
mechanical properties [115].
Electrospun elastin-like polypeptide fibers. Natural bio-polymers have been

electrospun into fibers because of their enhanced biocompatibility and biofunctional
qualities. For instance, collagen and chitosan have been prepared into nanofibrous
tissue scaffolds using the electrospinning technique [116, 117]. In our work,
elastin-like polypeptide (ELPs) has been electrospun into one-dimensional fibers.
ELPs, inspired by the amino-acid sequence of natural elastin, are bio-polymers
comprised of oligomeric repeats of the pentapeptide sequence Val-Pro-Gly-X-Gly
(VPGXG), where the guest residue, X, can be any combination of natural amino
acids except Pro [118]. ELPs are genetically encoded and synthesized by using
recombinant DNA methods, which offer the ability to precisely control the ELP
sequence, and in turn, the microstructure and function of ELP biomaterials at the
molecular level [119]. The materials can exhibit a broad range of mechanical
and viscoelastic responses ranging from plastic to elastic. However, only the
pentapeptide ELPs exhibit elastic behavior with spectroscopic features, undergoing
high deformation without rupture, storing energy involved in deformation, and then
recovering to their original state when the stress is removed [120]. The force
generation capabilities have potential applications as microactuator materials in bio-
microelectromechanical systems (Bio-MEMS) [121]. ELPs could be useful as drug-
delivery carriers and tissue-engineering scaffolds. If ELP scaffolds for artificial
organs and other engineered tissues are found to be useful, electrospinning is a
strong candidate for the manufacturing of such fibers and fabrics.
Trifluoroethanol (TFE) was the selected solvent for the electrospinning of ELPs.
The solution was prepared by dissolving the ELP protein in TFE, which is a
good solvent for both the hydrophobic and hydrophilic blocks of protein at room
temperature. The key factors of the electrospinning process are given in Table 2.
The morphologies of the electrospun ELP fibers were observed using SEM. The
SEM image is shown in Fig. 16a, which reveals that the ELP fiber diameters are
Table 2.
Processing parameters for electrospinning ELP fibers
Parameter
Applied voltage 15 kV
Flow rate 1.0 ml/h
Working distance 15 cm
Solvent Trifluoroethanol
Concentration 15% (w/v)
Figure 16. (a) SEM image and (b) fiber diameter distribution of electrospun ELPs.
in the order of nanometers and the surfaces of the fibers are smooth. The diameter
distribution of electrospun ELP fibers is shown in Fig. 16b. The diameters covered
a range of 90–190 nm. The average diameter was 140 ± 8 nm. The surface
topography of the ELP fibers was also examined with tapping mode atomic force
microscopy (AFM) to check for any influence that the SEM’s electron beam might
have on the ELP fibers. Figure 17 shows the AFM image, which reveals that
the SEM process does not noticeably alter the fibers. The electrospun ELP fibers
imaged by AFM also had smooth surface with a uniform cylindrical structure, and
the fiber diameters were in the range of 80 ± 10 to 185 ± 7 nm.
Electrospun biomedical sutures. While electrospinning has attracted a lot of

interest as a technique to produce fibers in a random orientation, the manufacture
of aligned electrospun fibers is also of interest. Aligned fibers could be used in
biomedical applications involving the nervous system, tendons and muscles. In
particular, the yarns made of aligned electrospun fibers are of interest as sutures
for medical applications [122 – 124]. Some groups have used oriented assemblies
of electrospun fibers to control the regeneration of cells. Cells cultured on oriented
fiber scaffolds have been shown to proliferate in the direction of the fiber orientation
[115, 123, 125, 126]. Various devices have been developed to collect aligned
electrospun fibers such as a rotating drum collector, a rotating metal frame collector,
a collector based on the sharp edge of a rotating wheel and auxiliary electrode-
Figure 17. AFM image of the electrospun ELPs. This figure is published in colour at
http://www.ingenta.com
assisted aligned assembly, amongst others [5, 115]. However, limited studies have
been conducted on the manufacturing of yarn using electrospinning techniques. Ko
et al. produced continuous yarns of composites of polymers and carbon nanotubes
by a co-electrospinning process [127]. Dalton et al. prepared multi-filament yarn
by placing two grounded rings equidistantly from the spinneret to form an array of
fibers between the collecting rings. After collecting the fibers, rotating one of the
collecting rings created a wound multi-filament yarn [128]. Smit et al. obtained
continuous uniaxial fiber bundle yarns by electrospinning polymers onto a water
reservoir collector and then drawing the resulting non-woven web of fibers across
the water to elongate and align the fibers [129].
Another simple and inexpensive technique was used to prepare oriented yarns in
our work. The schematic process of yarn formation is illustrated in Fig. 18. Firstly,
focused aligned fibrous sheets were electrospun onto a single rotating drum with
an aid of an auxiliary electric field. As the electrospinning needle moved along the
axis of the collector, the aligned sheets were collected along the rotating drum from
one side to other side. A multi-filament yarn can then be created by removing the
aligned fibrous sheets off the collector and then rotating one end of the sheet. If
the electrospinning needle reciprocates, a long, aligned sheet could be formed on
the drum through layer-by-layer assembly. This technique could be used to prepare
multi-composition yarns by simultaneously electrospinning two different polymers
onto the rotating drum.
The solution was prepared by dissolving 8 wt% PCL in dichloromethane. A mo-
torized drum collector was set to run at a rotating speed equivalent to a linear take-up
of the electrospun fibers. The translating needle deposited an aligned sheet of fibers
across the surface of the collector. Figure 19a shows an SEM image of the sheets
obtained using a rotating collector, exhibiting a high degree of fiber alignment.
Figure 18. Schematic illustrations of processes for manufacturing yarns using an electrospinning
technique. This figure is published in colour at http://www.ingenta.com
Figure 19. SEM images of (a) PCL aligned sheets and (b) PCL yarn.
The diameters of the electrospun fibers in the obtained sheet were in a range of
3.5–6.0 µm, with an average diameter of about 4.3 ± 0.2 µm. To manufacture a yarn
the resulted aligned sheet was slowly removed from the collector and then rotated at
one end of the sheet until a single yarn was produced. Figure 19b shows an SEM im-
age of the PCL yarn with a diameter of 125 ± 8 µm. The SEM micrograph revealed
that the PCL yarn was uniform, demonstrating that the electrospinning process is
capable of preparing an aligned yarn for biomedical suture applications.
Porous structural electrospun fibers. As discussed previously, electrospinning

has been accepted as a promising technique to prepare one-dimensional materials
allowing control of the fiber diameter. By tuning the process parameters, other
important aspects of the microstructure of the fibers can be manipulated, specifically
the porosity. The microstructure of electrospun fibers is important when considering
their applications. Porous structures will have larger surface area-to-volume ratios,
which is beneficial for many applications. For example, porous electrospun fibers
can be generated with increased surface area for applications such as controlled drug
release, body fluid filtering and purification, biological sensors, tissue scaffolds and
biocatalyst carriers [130 –133]. There have been a few reports on the preparation
of porous electrospun fibers with micrometer or nanometer-sized pores. In such
studies, highly porous fibers were prepared via electrospinning with a modified low
temperature collector placed in liquid nitrogen, which induced a phase separation
between the polymer and the solvent [130]. Porous fibers can also be generated by
electrospinning polymer blends followed by selective dissolution. For example,
porous ultrafine poly(glycolic acid) fibers were prepared by electrospinning a
mixture solution to obtain poly(glycolic acid)/poly(L-lactic acid) composite fibers,
and then the poly(L-lactic acid) composition was removed via a selective dissolution
technique using chloroform [131]. In addition, some research groups have reported
that porous fibers or fibers with unusual surface microstructures can be obtained
when a highly volatile solvent was used [132, 133]. In this research effort,
porous PCL fiber was prepared to demonstrate the capability of electrospinning
for generating porous electrospun fibers. The porous microstructure was induced
by phase separation resulting from the rapid evaporation of the solvent during the
electrospinning process.
To prepare electrospun PCL fibers, PCL was dissolved in chloroform solvent and
then stirred magnetically before electrospinning. Figure 20 shows the SEM image
of porous PCL fibers prepared by electrospinning a solution into a water bath.
The diameter of the fibers is approximately 3 ± 0.4 µm. The porous PCL fibers
contained a high density of circular pores with diameters ranging from 300 to
800 nm. The pore size distribution is relatively narrow. It is believed that
Figure 20. SEM image of electrospun porous PCL fiber.

phase separation plays an important role in the formation of pores. During the
solvent evaporation, the solution became thermodynamically unstable and the
electrospun fibers separated into polymer-rich and polymer-poor phases [78, 79].
The polymer-poor phase formed the pores. The experimental work demonstrated
that electrospinning can also be used to prepare polymer fibers with porous
microstructures based on phase separation.
Hybrid electrospinning and electrospraying of materials

Functional tissue scaffolds. Conventionally, tissue and organ malfunction is
treated by tissue or organ transplantation; however, this is hindered by donor short-
age and immunological problems associated with infectious diseases [134, 135].
Recently, regenerative medicine, a new therapy based on the induction of tissue re-
generation through cells and tissue engineering, is becoming a third therapy option
after reconstructive surgery and organ transplantation [136]. The regeneration of
tissues and organs is naturally induced by artificially accelerating the proliferation
and differentiation of cells. Therefore, functional tissue scaffolds must be fabricated
to provide living cells with a local in vivo environment of artificial extracellular ma-
trix [137]. This field requires the development of techniques for manufacturing
functional three-dimensional biomedical scaffolds by producing and assembling
bio-polymer scaffolds encapsulated with living cells and bioactive substances si-
multaneously. Electrohydrodynamic atomization processing is a very attracting and
promising method for realizing this objective [138]. We have developed a tech-
nique to build functional biomedical scaffolds by simultaneously electrospraying
living cells (chondrocytes) and bioactive substances into the electrospun scaffolds.
The process is advantageous for producing functional scaffolds because the living
cells can be homogenously embedded within the scaffolds, regardless of their size.
The functionalized PCL scaffolds were manufactured using an improved instru-
ment, which consisted of a rotating collector, a high-voltage power supply, a pre-
cursor supply system and electrodes for producing the desired electric field. Fig-
ure 21 shows a schematic diagram of a modified electrohydrodynamic atomiza-
tion processing setup. This hybrid process was designed for homogenous delivery
of living cells into an electrospun PCL fibrous mat layer-by-layer. Confocal mi-
croscopy was used to visualize the living cells embedded in the functional scaffolds
after being cultured in the cell media for a set time. The experimental results re-
vealed that 80% of the cells were still viable after the electrohydrodynamic process,
demonstrating the potential for this hybrid process in manufacturing functional tis-
sue scaffolds. The functional biomedical scaffolds can play an important role in
modulating tissue growth and response behavior of the encapsulated living cells.
The scaffolds serve not only as a template for cell attachment, growth, and prolifer-
ation but also to facilitate the cell migration and assembly into a three-dimensional
structure [139]. Figure 22 shows an illustration of the application of the electrohy-
drodynamic process to manufacture the functional tissue scaffolds for biomedical
applications.
Figure 21. Diagram of an experimental setup of an electrohydrodynamic atomization process. This

figure is published in colour at http://www.ingenta.com
Figure 22. Electrohydrodynamic processing of functional scaffolds. This figure is published in colour
at http://www.ingenta.com
Self-electrospun microstructured scaffolds. Research in tissue engineering is

advancing at a remarkable pace with a variety of methods under development for
preparing tissue scaffolds to substitute for defective or lost tissues and organs.
To maintain biological functions and accelerate tissue regeneration, it would be
useful for these tissue scaffolds to be used in combination with cells and/or
Figure 23. Diagram of a tissue scaffold with localized and controlled delivery functions. This figure
is published in colour at http://www.ingenta.com
Figure 24. Schematics of an electrospraying and self-electrospinning process. This figure is published
signaling molecules such as growth factors, cytokines, chemokines and genes, and
release essential signaling molecules into the wound tissue for the regenerating
tissue [140 –142]. Drug-delivery systems can be employed to locally deliver
biological agents by encapsulating the agents within a scaffold matrix or within
microspheres [136, 143]. Figure 23 shows a concept diagram of tissue scaffolds
with controlled release functions. To develop localized and controlled delivery of
agents from scaffolds, we have proposed a design and preparation of bead and fiber
microstructured scaffolds generated by a hybrid electrospinning and electrospraying
technique. Figure 24 shows an illustration of the self-electrospinning process. In
the hybrid process, a mixture of biological substances and bio-polymer solution
will be electrosprayed into droplets, which carry charges on their surface. When
the charged droplets are ejected onto the substrate, provided the charge density
is high enough to breakup the droplets, fibers will be electrospun directly from
the droplets due to their high viscosity and the polymer chain entanglement.
Kessick et al. [144] demonstrated this by making nanofibers by alternately

spraying positively and negatively charged droplets onto a substrate. The nanofibers
were observed to form between oppositely charged droplets without the need
for the application of an external potential. Presumably, this indicates that the
charges on the droplets overcame the surface tension and formed a small Taylor
cone.
Biological agents can also be embedded with the fibers by electrospinning a
solution of the matrix biomaterials and the agents. Either the biological sub-
stances are distributed within the small fibers or they attached to the surface of
the nanofibers. However, in both case, the biological agents are be exposed to the
conditions within the body that cause them to degrade quickly. This is disadvan-
tageous when the goal is for the biological agents to remain in the tissue scaf-
folds for an extended time to assist in the regeneration of new tissue [145]. In
the hybrid bead and fiber tissue scaffolds, the biological agents can be stored in
the beads which are much larger in diameter than the fibers. Therefore, biolog-
ical agents will persist over a longer time period and deliver the signaling mole-
cules more gradually. The prominent characteristic of the hybrid scaffolds is that
biological agents can be protected against quick biodegrading reactions and prote-
olysis when incorporated in an appropriate reservoir. This results in a prolonged
retention of activity in vivo [146]. The potential advantages of electrosprayed/self-
electrospun tissue scaffolds are that: (1) a high surface area and porosity can
be achieved; (2) a bead structure protects the released bioactive ingredients in
vivo; (3) they offer novel control of the hybrid microstructures; (4) they can pro-
vide growth factors, drugs, therapeutics and genes to stimulate tissue regeneration.
An SEM image of a self-electrospun microstructured PCL scaffold is shown in
Fig. 25, which reveals that the average size of beads is 1.6 ± 0.2 µm and the av-
erage diameter of the fibers is 120 ± 8 nm. Self-electrospun scaffolds are still in
early stages of exploration, but they offer promising future research opportuni-
ties.
Figure 25. SEM of a self-electrospun fiber and bead microstructure.

CONCLUSIONS
Within the past several years, there have been considerable efforts in electrohy-
drodynamic atomization processing to prepare nanostructured, biological materials
for various biomedical applications. Electrospinning and electrospraying are cost-
effective and versatile techniques for creating fibrous and particulate structures that
could revolutionize biomaterials for numerous applications. An overview of some
potential applications of biomaterials prepared using electrohydrodynamic atomiza-
tion processing has been presented in this paper, including (functionalized) tissue
scaffolds, drug-delivery carriers, surface functionalization of medical implants and
preservation of bioactive substances within scaffolds. Most of these applications are
still in their infancy. In vivo and clinical studies are required to further understand
and improve the efficacy of these biomaterials. The ability to control the processing
parameters of electrospinning and electrospraying allows for the development and
preparation of biomaterials with well-controlled microstructures and biofunctional
properties. These preliminary research results have doubtlessly demonstrated the
capability and merits of electrohydrodynamic atomization processing for manufac-
turing materials applied in biomedical applications. In order to advance the applica-
tions of electrospinning and electrospraying in the biomedical fields, future research
in this area will require greater interdisciplinary collaboration between researchers
working in fields ranging from materials science, medicine, biology, chemistry and
engineering.
Acknowledgements
The authors are very grateful to Prof. Ashutosh Chilkoti’s group in the Department
of Biomedical Engineering at Duke University for help in preparing ELP materials
and Prof. Farshid Guilak’s group at Duke University Medical Center for providing
the living cells for electrospraying and cell characterization.
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J. Biomater. Sci. Polymer Edn, Vol. 19, No. 5, pp.

573– 601 (2008)

Electrohydrodynamic atomization: a versatile process for

YIQUAN WU 1,2 and ROBERT L. CLARK 1,2,∗

Received 3 September 2007; accepted 25 October 2007

Abstract—Electrohydrodynamic atomization phenomena have increasingly attracted the attention of

Key words: Electrospraying; electrospinning; biomaterials; biomedical application; tissue engineer-

BACKGROUNDS AND PRINCIPLES

Figure 1. Schematic of the basic principle of electrospraying.

electrospraying, a voltage applied to the nozzle results in the formation of a Taylor

Figure 2. Schematic of the basic principle of electrospinning.

the collector. Using more advanced experimental equipment, the phenomena of

PREPARATION OF MATERIALS FOR BIOMEDICAL APPLICATIONS

The versatility of electrohydrodynamic atomization has been demonstrated through

that offer suitable means for delivering low-molecular-weight drugs, as well as

Figure 3. Schematic representations of particulate drug-delivery carriers. This figure is published in

Porous biopolymeric particles. In the last decade, porous biopolymer particles

Electrostatic deposition of bio-coatings. In biomedical applications, bio-

position, details numerous laboratory experiments and offers examples of electro-

to deposit bioceramic coatings with a variety of chemical properties [94, 95] to

of natural polymers, such as chitin nanofibers, silk fibroin, collagen, solubilized

PGA tissue template, which demonstrated that electrospinning was capable of

Electrospun elastin-like polypeptide fibers. Natural bio-polymers have been

Electrospun biomedical sutures. While electrospinning has attracted a lot of

Porous structural electrospun fibers. As discussed previously, electrospinning

Figure 20. SEM image of electrospun porous PCL fiber.

Hybrid electrospinning and electrospraying of materials

Figure 21. Diagram of an experimental setup of an electrohydrodynamic atomization process. This

Self-electrospun microstructured scaffolds. Research in tissue engineering is

Kessick et al. [144] demonstrated this by making nanofibers by alternately

Figure 25. SEM of a self-electrospun fiber and bead microstructure.

12. K. S. Soppimath, T. M. Aminabhavi, A. R. Kulkarni and W. E. Rudzinski, J. Control. Rel. 70,

128. P. D. Dalton, D. Klee and M. Moller, Polymer 46, 611 (2005).

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