-
modifications of electrospun membranes also provide effective
means to render the electrospun scaffolds with controlled
anisotropy and porosity.
2.2. Synthetic copolymers . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1395
3.4. Two-phase electrospinning . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1404
Available online at www.sciencedirect.com
Advanced Drug Delivery Reviews 59 (2007)
13921412www.elsevier.com/locate/addr2.3. Polymer mixtures . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . 13972.3.1. Blends of natural polymers
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . 13972.3.2. Blends of natural and synthetic
polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . 13972.3.3. Synthetic polymer blends based on PLGA
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . 13982.3.4. Synthetic polymer blends containing PEO/PEG . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14002.3.5. Other multi-component polymer systems . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1400
3. New innovations in electrospinning for biomedical
applications . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . 14013.1. Scaffolds with oriented fiber alignment . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . 14023.2. Multilayer electrospinning and mixing
electrospinning . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . 14033.3. Fabrication of dual-porosity scaffolds .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . 1403Keywords: Electrospinning; Nanofiber;
Scaffold; Biomedical applications; Copolymers; Mixtures;
Modifications
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . 13932. Rational design of polymeric materials . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . 1394
2.1. Homopolymers . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13942.1.1. Natural polymers . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13942.1.2. Synthetic polymers . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1395In
this article, we review the materials, techniques and post
modification methods to functionalize electrospun nanofibrous
scaffolds suitable forbiomedical applications. 2007 Elsevier B.V.
All rights reserved.Functional electrospun nanofibrous scaffolds
for biomedical applications
Dehai Liang 1, Benjamin S. Hsiao , Benjamin Chu
Departments of Chemistry and of Biomedical Engineering, Stony
Brook University, Stony Brook, NY 11794-3400, USA
Received 3 January 2007; accepted 15 April 2007Available online
25 August 2007
Abstract
Functional nanofibrous scaffolds produced by electrospinning
have great potential in many biomedical applications, such as
tissue engineering,wound dressing, enzyme immobilization and drug
(gene) delivery. For a specific successful application, the
chemical, physical and biologicalproperties of electrospun
scaffolds should be adjusted to match the environment by using a
combination of multi-component compositions andfabrication
techniques where electrospinning has often become a pivotal tool.
The property of the nanofibrous scaffold can be further
improvedwith innovative development in electrospinning processes,
such as two-component electrospinning and in-situ mixing
electrospinning. Post Corresponding authors. Hsiao is to be
contacted at Tel.: +1 631 632 7793; fax: +1 631 632 6518. Chu,
Tel.: +1 631 632 7928; fax: +1 631 632 6518.E-mail addresses:
[email protected] (B.S. Hsiao), [email protected]
(B. Chu).
1 Current address: College of Chemistry and Molecular
Engineering, Peking University, Beijing, 100871, China.
0169-409X/$ - see front matter 2007 Elsevier B.V. All rights
reserved.doi:10.1016/j.addr.2007.04.021
-
. .
. .
. .
. .
. .
. .
distance between the spinneret and the collecting plate, of
success.
elivtemperature and humidity. These parameters have been
wellstudied and summarized in a recent review [28]. With verysmall
fiber diameters, the yield per spinneret of the electro-spinning
process is extremely low. Recently, multi-jet electro-spinning
[29,30] and blowing-assisted electrospinningtechnology [3032] have
been developed, demonstrating theproduction capability for
fabricating nanofibrous articles on anindustrially relevant
scale.
Besides taking advantage of the materials compositions,
thefabrication process, through which the fiber diameter,
morphol-ogy and scaffold porosity can be manipulated, also plays
animportant role on the scaffold property and functionality.
Forexample, the two-phase electrospinning process provides a
newpathway to incorporate drugs or biopolymers inside the fibercore
that will be suitable for the controlled release over aprolonged
period of time [51]. Physical and chemical modifica-3.5.
Fabrication of core-shelled nanofibers . . . . . . . . .3.6.
Blowing-assisted electrospinning technique . . . . . . .
4. Modifications of post-electrospun scaffolds . . . . . . . . .
.5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . .
.Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . .
.References . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. .
1. Introduction
Electrospinning is a unique technology that can producenon-woven
fibrous articles with fiber diameters ranging fromtens of
nanometers to microns, a size range that is otherwisedifficult to
access by conventional non-woven fiber fabricationtechniques [1,2].
Electrospun nanofibrous scaffolds possess anextremely high
surface-to-volume ratio, tunable porosity, andmalleability to
conform over a wide variety of sizes and shapes.In addition, the
scaffold composition can be controlled toachieve desired properties
and functionality. Due to theseadvantages, electrospun nanofibrous
scaffolds have beenwidely investigated in the past several years
with materials ofdifferent compositions [310] for applications of
varying end-uses, such as filtration [1113], optical and chemical
sensors[1419], electrode materials [2023], and biological
scaffolds[2427].
For small-scale productions (i.e., on a laboratory
scale),electrospinning is a simple method to generate nanoscale
fibers.A basic electrospinning system usually consists of three
majorcomponents: a high voltage power supply, a spinneret (e.g.
apipette tip) and a grounded collecting plate (usually a
metalscreen, plate, or rotating mandrel). When a charged
polymersolution is fed through the spinneret under an external
electricfield, a suspended conical droplet is formed, whereby
thesurface tension of the droplet is in equilibrium with the
electricfield. When the applied electric field is strong enough
toovercome the surface tension, a tiny jet is ejected from
thesurface of the droplet and drawn toward the collecting
plate.During the jet propagation toward the collecting plate,
thesolvent in the jet stream gradually evaporates. The
resultingproduct is a non-woven fibrous scaffold with a large
surfacearea-to-volume ratio and a small pore size (in microns).
Thefiber thickness and morphology can be controlled by
manyparameters, such as solution properties (viscosity,
elasticity,conductivity and surface tension), electric field
strength,
D. Liang et al. / Advanced Drug DThe usage of electrospun
nanofibrous scaffolds for biomedicalapplications has attracted a
great deal of attention in the pastseveral years. For examples,
nanofibrous scaffolds have been. . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . 1404
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 1405
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 1407
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 1408
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 1408
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 1408
demonstrated as suitable substrates for tissue engineering
[2427],immobilized enzymes and catalyst [3336], wound
dressing[37,38] and artificial blood vessels [39,40]. They have
also beenused as barriers for the prevention of post-operative
inducedadhesion [41,42] and vehicles for controlled drug (gene)
delivery[4347]. For a successful application to a specific target,
thenanofibrous scaffold must exhibit suitable physical and
biologicalproperties closely matching the desired requirements.
Forexample, in tissue engineering, the electrospun scaffold
shouldphysically resemble the nanofibrous features of
extracellularmatrix (ECM) with suitable mechanical properties. It
should alsobe able to promote cell adhesion, spreading and
proliferation. Forwound dressing, the nanofibrous scaffold should
not only serve asa substrate for tissue regeneration, but also may
deliver suitablebioactive agents, including drugs (e.g. antibiotic
agent), within acontrolled manner during healing. The fabrication
of suchfunctional nanofibrous scaffolds for biomedical
applicationsoften requires an interdisciplinary approach combining
physics,chemistry, biology and engineering.
For electrospun nanofibrous scaffolds in biomedical
applica-tions, its physical and biological properties, such as
hydro-philicity, mechanical modulus and strength,
biodegradability,biocompatibility, and specific cell interactions,
are largelydetermined by the materials' chemical compositions.
Based onpolymer physics, copolymerization and polymer blending
aretwo effective means to combine different polymers to yield
newmaterials properties. Thus, by selecting a combination of
propercomponents and by adjusting the component ratio, properties
ofelectrospun scaffolds can be tailored with desired newfunctions.
For example, many kinds of copolymers and polymermixtures, such as
poly(lactide-co-glycolide) [41], poly(ethyl-ene-co-vinyl alcohol)
[48], mixtures of collagen with elastin[49], and mixtures of
chitosan with poly(ethylene oxide) (PEOor PEG when the molecular
weight is small, say less than5000 Da) [50], have been electrospun
to fabricate nanofibrousscaffolds for biomedical applications, but
with varying degrees
1393ery Reviews 59 (2007) 13921412tions of the scaffolds after
electrospinning are also able to renderthe scaffolds with enhanced
properties and suitable functionalityfor specific applications. For
example, the grafting of gelatin
-
onto the surface of a polyethylene terephthalate (PET)
scaffoldafter electrospinning could increase the biocompatibility
andmake the scaffold more suitable for cell adhesion
andproliferation [40].
This review is concerned with the recent progress on the useof
electrospun scaffolds for biomedical applications, withemphasis on
materials, technology, and post treatment of thescaffolds: (1)
rational polymer material design, includingcopolymers and polymer
mixtures, (2) new innovative electro-spinning techniques, and (3)
post-electrospinning modifica-tions. In practice, the three
considerations can be combined
together to generate new functional nanofibrous scaffolds
withenhanced physical and biological properties.
2. Rational design of polymeric materials
2.1. Homopolymers
2.1.1. Natural polymersCompared with synthetic polymers,
naturally occurring
polymers normally exhibit better biocompatibility and
lowimmunogenicity, when used in biomedical applications. All
1394 D. Liang et al. / Advanced Drug Delivery Reviews 59 (2007)
13921412Fig. 1. Field-emission scanning electron microscopic images
of lecithin fibers prconcentration for entanglement). (From Ref.
[77] with permission).epared at different solution concentrations
(from below to above the critical
-
the performance of electrospun scaffolds based on copolymerscan
be significantly improved when compared to that ofhomopolymers. For
example, biodegradable hydrophobicpolyesters generally have good
mechanical properties but lackcell affinity for tissue engineering.
The incorporation of a properhydrophilic polymer segment can
increase the cell affinity.Besides the cell affinity, the
mechanical properties, morphology,structure, pore size and
distribution, biodegradability and otherphysical properties can
also be tailored by using copolymers.Moreover, with amphiphilic
copolymers as protecting mole-cules to encapsulate drug molecules,
electrospun scaffolds canbe used for drug release in a controlled
manner.
PLGA, the random copolymer of glycolide (G) and lactide(L), is a
popular and well-studied system that has been broadlyused as
electrospun scaffolds for biomedical applications. Aslisted in
Table 1, the mechanical properties and the degradationrate of PLGA,
being dependent on the L/G ratio, are quitedifferent from PGA and
PLA homopolymers. The in vitro
elivfour major classes of biopolymers: proteins,
polysaccharides,DNAs and lipids, have been fabricated into
electrospunscaffolds. Protein fibers, mainly from collagen,
gelatin, elastinand silk fibroin, have been well studied in recent
years [5255].For example, collagen is the principal structural
element of theextracellular matrix (ECM) in tissues, where three
types ofcollagen, types I, II and III, have been fabricated
intonanofibrous scaffolds for studies of cell growth and
penetration[5658]. Wnek et al. have electrospun human or
bovinefibrinogen fraction I, dissolved in
1,1,1,3,3,3-hexafluoro-2-propanol (HFP) with minimal essential
medium (Earle's salts),and used the resulting scaffolds for
tissue-engineering applica-tions [59]. Min et al. have prepared
silk fibroin (SF) electrospunscaffolds with fiber diameters of
around 80 nm [60]. They foundthat normal human keratinocytes and
fibroblasts seeded on theSF nanofibers were able to attach and
grow, indicating that theSF nanofibers may be a good candidate for
wound dressing andtissue engineering [60,61]. The treatment of the
scaffold bywater vapor induced a conformational transition of SF
fromrandom coil to beta-sheet structures, thereby the
mechanicalstrength and the cellular compatibility were improved
[62,63].In addition, Huang et al. have electrospun gelatin
intonanofibers with diameters ranging from 100 to 340 nm
using2,2,2-trifluoroethanol as the solvent [64].
Recently, our group has demonstrated the
successfulelectrospinning of hyaluronic acid (HA) in aqueous
solutions[65]. HA is essentially an associating polymer in
aqueoussolution, often exhibiting very high solution viscosity.
Conse-quently, typical electrospinning processes could not be
usedsuccessfully to develop a steady jet stream. The sample has to
bespun with the assistance of air flow at elevated
temperatures,thereby broadening the processing window. This process
istermed blowing-assisted electrospinning, which has beendescribed
elsewhere [32,65] and will not be elaborated on in thisreview. The
electrospun HA nanofibrous scaffolds with asuitable degree of
post-crosslinking will be suitable for cartilagerepair, since
hyaluronan is an abundant polysaccharide foundalmost exclusively in
articular joints, allowing the cells to attachfor cartilage
regeneration. Other polysaccharides, such asdextran [66], chitosan
(chitin) [6770] and cellulose acetate[7175], have also been
fabricated to form nanofibers byelectrospinning. Besides proteins
and polysaccharides, calfthymus Na-DNA in an aqueous solution was
electrospun toform nanofibers with diameters of around 5080 nm
[76].However, no specific biomedical applications of such
DNAnanofibers have been reported. Recently, McKee M. et al.reported
the non-woven membranes from electrospinninglecithin solutions in a
single processing step [77]. Atconcentrations above the critical
concentration for entangle-ment, Ce, electrospun fibers with
diameters ranging from 1 to5 m were fabricated (Fig. 1). Such
scaffolds offered manypotential applications, such as tissue growth
and engineeringvehicles, as well as drug-delivery platforms.
D. Liang et al. / Advanced Drug D2.1.2. Synthetic
polymersSynthetic polymers often offer many advantages over
natural
polymers in that they can be tailored to give a wider range
ofproperties and predictable lot-to-lot uniformity.
Moreover,synthetic polymers are cheaper and represent a more
reliablesource of raw materials. Typical synthetic polymers used
inbiomedical applications are hydrophobic biodegradable
polye-sters, such as polyglycolide (PGA)[76,78,79], polylactide
(PLA)[10,8083] and poly(-caprolactone) (PCL) [8487], whichhave all
been electrospun into nanofibrous scaffolds. Table 1 liststhe
physical properties of some popular biodegradable polyestersand
their copolymers [88]. Other hydrophilic biodegradablepolymers,
such as polyurethane [89,90], poly(vinyl alcohol)[91,92], PEO [93],
polydioxanone [94] and polyphosphazenederivatives [95,96] have also
been electrospun into nanofibrousscaffolds for biomedical
applications.
2.2. Synthetic copolymers
The use of copolymers is a viable scheme to generate
newmaterials of desirable properties. When properly
implemented,
Table 1Biodegradable polymers for biomedical applications
Polymer name Melting point(C)
Glass transitiontemperature(C)
Modulus(Gpa)a
Degradation time(Month)b
PGA 225230 3540 7.0 6 to 12L-PLA 173178 6065 2.7 N24D,L-PLA
Amorphous 5560 1.9 12 to 16PCL 5863 (65) (60) 0.4 N24PDO N/A (10) 0
1.5 6 to 1285/15 PLGA Amorphous 5055 2.4 5 to 675/25 PLGA Amorphous
5055 2.0 4 to 565/35 PLGA Amorphous 4550 2.0 3 to 450/50 PLGA
Amorphous 4550 2.0 1 to 2
aTensile or flexural modulus.bTime to complete mass loss. Rate
also depends on geometry.PGA: poly(glycolide); PLA: poly(lactide);
PCL: poly(-caprolactone); PDO:poly(dioxanone); PLGA: copolymer of
PGA and DL-PLA, ratio is PLA/PGA.
1395ery Reviews 59 (2007) 13921412degradation rate of
electrospun PLGA scaffold at different L/Gcomposition has been
investigated by our group. Thenanofibrous PLGA scaffolds generally
degrade faster than the
-
regular casting film with the same dimensions and composi-tion,
mainly due to the high surface area-to-volume ratio andthe high
water adsorption ability (both decrease the inductiontime during
hydrolysis) [41]. Recently, Laurencin et al. havestudied the
potential use of PLGA nanofibrous scaffolds as anantibiotic
delivery vehicle for the treatment of wounds [44].They demonstrated
that PLGA nanofibers could be tailored todesired diameters through
modifications in processing para-meters, such as orifice diameter
(needle gauge), polymersolution concentration and voltage per unit
length, where theantibiotic drugs, such as cefazolin, could be
incorporated intothe nanofibers.
The lactide component can also be copolymerized
with-caprolactone. The degradation rate of the copolymer,
P(LA-CL),is between those of the two homopolymers (PLA and PCL),
whichare significantly longer than that of PGA. Its degradation
ratecan also be controlled by the composition ratio. The
potentialuse of electrospun P(LA-CL) scaffolds in tissue
engineeringhas been investigated by several groups [97100]. For
example,Kwon et al. [97] electrospun P(LA-CL) scaffolds using
differentL/CL molar ratios (70/30, 50/50, 30/70) and
systematcallyinvestigated the scaffold structure, mechanical
properties andcell adhesion ability. They found that the human
umbilical veinendothelial cells (HUVECs) could adhere and
proliferate on
1396 D. Liang et al. / Advanced Drug Delivery Reviews 59 (2007)
13921412Fig. 2. Electrospun scaffolds from 5 wt.% total
concentration of mixtures with PEO to10% concentration. (From Ref.
[108] with permission).casein ratio at (a) 100:0, (b) 80:20, (c)
50:50, (d) 20:80, (e) 5:95, and (f) 20:80 at
-
elivthe P(LA-CL) nanofibers with the average diameter
rangingfrom 300 nm to 1.2 m. Mo et al. [99] studied the
interactionsof smooth muscle cells and endothelial cells with
P(LA-CL)nanofibrous scaffolds. They found that both cell adhesion
andproliferation took place after 7 days on the electrospun
P(LA-CL) scaffold with a LA/CL ratio of 75/25. Their
resultsindicated that P(LA-CL) nanofibrous scaffolds have
excellentbiocompatibility and they are potentially very useful in
tissueengineering applications.
Electrospun scaffolds based on DegraPol, a degradableblock
polyester-urethane, containing crystalline blocks of
poly((R)-3-hydroxybutyric acid)-diol and blocks of
poly(-capro-lactone-co-glycolide)-diol linked with a diisocyanate,
wasstudied as a potential scaffold for skeletal muscle
tissueengineering [26]. As a block copolymer, DegraPol combinedthe
characteristics of traditional polyesters with good process-ibility
and distinct elasticity of polyurethanes; it also exhibitedgood
affinity with tissue cells. Electrospun DegraPol nanofi-brous
scaffolds showed satisfactory mechanical properties andpromising
cellular response in preliminary cell adhesion anddifferentiation
experiments. It has now been considered as oneof the most promising
scaffolds for skeletal muscle tissueengineering [26].
Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) is
abiodegradable and biocompatible copolymer derived frommicrobial
polyesters; it has also been fabricated into nanofi-brous scaffolds
recently. By controlling the electrospinningparameters, nanofibers
with an average diameter of around185 nm were fabricated. Compared
with the PHBV cast films,electrospun PHBV nanofibrous scaffolds
provided a much moresuitable environment for the attachment and
growth ofchondrocytes derived from rabbit ears [101]. Choi et al.
foundthat the fiber diameter of PHBV was decreased by addition of
asmall amount of benzyl trialkylammonium chlorides in thesolution
before electrospinning, and the degradation rate ofPHBV fiber was
also accelerated, probably due to a significantincrease in the
surface area of PHBV nanofibers [102].
Bhattarai et al. [103,104] developed a novel block
copolymerbased on
poly(p-dioxanone-co-L-lactide)-block-poly(ethyleneglycol)
(PPDO/PLLA-b-PEG) that could be electrospun intoscaffolds for
applications of tissue engineering and drug-release. The random
disposition of the PPDO and PLLAsegments, as well as the
incorporation of PEG oligomers,significantly improved the
biodegradability and hydrophilicityof the electrospun scaffolds.
For example, NIH 3T3 fibroblastcells were found to grow and
proliferate on the scaffold after10 days, which showed a six-fold
increase in the cell populationafter incubation when compared with
the same environmentwithout the scaffold [104]. Kenawy et al. [48]
combined thehydrophilicity of the vinyl-alcohol repeating unit with
thehydrophobicity of the ethylene repeating unit in
electrospunpoly(ethylene-co-vinyl alcohol) nanofibrous scaffolds,
alsoresulting in improved biocompatibility. The hydroxyl group
inthe vinyl-alcohol repeating unit could offer opportunities
for
D. Liang et al. / Advanced Drug Dchemical modifications either
before or after electrospinning.Without modification, the
electrospun poly(ethylene-co-vinylalcohol) scaffold was found to be
readily able to support theculturing of smooth muscle cells and
fibroblasts. In addition, thederivatives of poly(ethylene-co-vinyl
alcohol), poly(ethylene-co-vinylacetate) [105], as well as
poly(L-lactic acid-co-succinicacid-co-1,4-butane diol) [106] have
also been fabricated intoelectrospun nanofibers that appeared to be
suitable for varyingtissue engineering applications.
2.3. Polymer mixtures
2.3.1. Blends of natural polymersPolymer mixtures (or blends)
have an advantage over
copolymers in that they are not limited by suitable
syntheticschemes. Therefore, nanofibrous scaffolds formed by
mixingdifferent polymers become an appealing option, which
isespecially true for natural polymers, as their chemical mono-mers
are often more difficult to modify. Blending of naturalpolymers may
provide a straightforward pathway to combinedifferent bioactivities
for biomedical applications. For example,Boland et al. [49]
demonstrated the electrospinning of micro-and nano-fibrous
scaffolds based on collagen and elastinmixtures in order to develop
viable vascular tissue engineeredconstructs. Collagen/elastin
scaffolds could replicate thecomplex architecture of a blood vessel
wall and withstandhigh pressures under the pulsatile environment
induced by thebloodstream. Therefore, such scaffolds could have the
potentialto create a suitable environment for in vitro generation
ofvascular replacements [49]. The thermal stability of
thecollagen/elastin scaffolds was able to be improved by
cross-linking of
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimidehydrochloride and
N-hydroxysuccinimide (NHS) [107].
2.3.2. Blends of natural and synthetic polymersAs regenerated
natural polymers usually possess weak
mechanical properties, blends of natural and synthetic
polymerscan overcome this problem and combine two desired
character-istics, i.e., the strength and durability of a synthetic
polymer,and the specific cell affinity of a natural polymer.
Electrospunscaffolds based on blends of natural and synthetic
polymers canenhance both physical properties and biological
functionality.One example was the electrospinning of casein or
lipasesuspensions, mixed with synthetic PEO or PVA [108].
Thestand-alone suspensions of casein and lipase were not
suitablefor electrospinning. However, their mixtures with PEO or
PVAcould significantly facilitate the electro-spinning process.
Fig. 2shows the scanning electron microscopic (SEM) images
ofelectrospun scaffolds from PEO/casein mixtures. With the PEO(Mv,
600 KDa) concentration below 5%, a non-fibrous scaffoldwas obtained
(Fig. 2e). However, this situation could besignificantly improved
by increasing the PEO content to 80%,as illustrated in Fig. 2b
[108]. To maintain casein concentrationas high as 80%, an increase
in the total mixture concentration to10% appeared to be capable of
producing fine fibers byelectrospinning (Fig. 2f). Their study also
showed that lipasecould be electrospun together with PEO or PVA,
and the
1397ery Reviews 59 (2007) 13921412catalytic activity on the
hydrolysis of olive oil in lipase/PVAelectrospun scaffolds was 6
times higher than that in cast filmwith similar compositions [108].
Furthermore, the crosslinking
-
elivof polymer/lipase scaffolds using a dialdehyde could
signifi-cantly improve the water stability. The pH level of the
reactionmedia during crosslinking was found to play an important
rolein the activity of the immobilized lipase [34].
Zhang et al. [109] mixed 10% w/v gelatin with 10%w/v PCLin
2,2,2-trifluoroethanol (TFE) at a ratio of 50:50 to produce
agelatin/PCL nanofibrous scaffold by electrospinning. Thescaffold
showed enhanced mechanical properties and morefavorable wetability
than those obtained from either PCL orgelatin scaffolds alone.
Bone-marrow stromal cells (BMSC)were found to attach and grow well
on the surface of the blendnanofibrous scaffold. In addition, BMSCs
were found to be ableto migrate inside the scaffold up to a depth
of 114 m within1 week of culture, suggesting the potential use of
compositegelatin/PCL fibrous scaffolds for preparation of the
three-dimensional tissue construct.
The mixture of heparin and PEG was also electrospun toprepare
nanofibrous scaffolds [110]. The presence of PEG in theelectrospun
scaffolds prolonged the release of heparin, whichcould closely
match the time scale needed for use in wounddressings. The
composition of the scaffold is also suitable fordrug delivery. It
is evident that the mixtures of type I collagenand PEO can provide
a convenient, non-toxic and non-denaturing way to generate
collagen-containing nanofibrousscaffolds that may have good
potential in biomedical applica-tions [111]. A blend of wool
keratin and PEO in aqueoussolutions was also fabricated into
nanofibers in a similar fashion[112].
Electrospinning of synthetic polymers followed by thecoating of
natural material has also been demonstrated as apractical approach
to yield desired functional features. Forexample, He et al
fabricated the collagen-coated
poly(L-lacticacid)-co-poly(-caprolactone) (P(LLA-CL) 70:30)
scaffoldwith a porosity of 64-67% and a fiber diameter of 470 nm
byelectrospinning followed by plasma treatment and collagencoating
[113]. The coating of collagen was found to improve
thebiocompatibility of the scaffold, thus enhancing the
spreading,viability and attachment of the human coronary
arteryendothelial cells and preserving the cells' phenotype [113]
inthe scaffold. The properties of the electrospun
collagen-coatedpoly(L-lactic acid)-co-poly(-caprolactone) scaffold
are quitesuitable for engineered vascular graft.
2.3.3. Synthetic polymer blends based on PLGABlends of synthetic
polymers have been routinely used in
electrospinning to produce new scaffolding materials. As PLGAhas
been widely used in biomedical applications from sutures,medical
devices to tissue regeneration, its mixtures with othersynthetic
polymers are reviewed here. By mixing PLGA withanother polymer
material, the physical properties of PLGA,such as hydrophobicity,
degradation rate, shrinkage behavior inbody fluids and mechanical
modulus, can be altered to specificbiomedical applications, such as
carriers for drugs or DNAwithcontrolled-release capability.
1398 D. Liang et al. / Advanced Drug D2.3.3.1. PLGA with
dextran. PLGA is a hydrophobic polymerwhile dextran is a
hydrophilic polymer that is highly soluble inan aqueous medium. By
mixing PLGA and dextran together at a1 to 1 ratio, Jiang et al.
[66] produced a hydrophobic/hydrophilicelectrospun composite
scaffold. With a portion of dextranmethacrylated in advance, they
could also photo-crosslink thedextran phase in the solid state to
fabricate water-resistantnanofibrous scaffolds with improved
hydrophilicity. The cross-linked PLGA/dextran scaffolds may be used
as substrates fortissue engineering. However, no further
information on thestructure control and cell growth has been
reported on thissystem yet.
2.3.3.2. PLGA with PEG-g-CHN. It is difficult to
incorporatehydrophilic drugs into the hydrophobic scaffolds (e.g.
PLGA)by electrospinning. Jiang et al. [43] synthesized a
graftcopolymer, poly(ethylene glycol)-g-chitosan (PEG-g-CHN)that
could encapsulate most hydrophilic drugs, such asibuprofen (an
anti-inflammatory agent), and was also compat-ible with the PLGA
matrix. The unique structure of PEG-g-CHN also showed the
controlled release capability ofhydrophilic drugs from electrospun
PLGA scaffolds. In theirstudy [43], mixtures of PEG-g-CHN and PLGA
with varyingratios were used to fabricate medicated electrospun
scaffolds. Itwas found that the addition of PEG-g-CHN decreased the
glasstransition temperature of PLGA, resulting in a decrease in
thetensile strength at break and an increase in the tensile strain
ofthe scaffold. The shrinkage behavior of the electrospun
com-posite scaffold at 37 C in the body fluid was also improvedwhen
compared with that of the pure PLGA scaffold (e.g. whenthe content
of PEG-g-CHN reached 30 wt.%, only a 3% de-crease in the area of
the composite scaffold was detected, whilethe shrinkage change of
the pure PLGA electrospun scaffoldcould be more than 50% in some
cases [43]). More importantly,the presence of PEG-g-CHN
significantly slowed down theinitial release rate of ibuprofen from
the scaffold and prolongedthe release of ibuprofen for over two
weeks. Specifically, at5 wt.% loading of ibuprofen to scaffold, the
initial amount ofdrug release reached 45% after day 4, and
continuedgradually up to 70% over the next two weeks. This datawas
in contrast with the same weight percentage of ibuprofen inPLGA
alone, which rapidly reached85% after day 4. Becauseof its desired
sustained release rate, Jiang et al. concluded thatthese polymer
scaffolds, being mechanically strong andcompliant, could be
suitable candidates for the prevention ofpost-surgery induced
atrial fibrillation when applied to thesurface of the heart
[43].
Co-electrospinning of PLGA/1,1,1,3,3,3-hexafluoro-2-pro-panol
(HFP) solution and chitin/formic acid solution at a weightratio of
80/20, Min et al. [114] generated a compositenanofibrous scaffold
with chitin nanoparticles evenly distribut-ed and strongly adhered
to the PLGA nanofibers. Both normalhuman keratinocytes and
fibroblasts were used to test theefficacy of this unique scaffold
for tissue engineering. ThePLGA/chitin composite scaffolds showed
better results thanpure PLGA scaffolds on normal human
keratinocytes. Howev-
ery Reviews 59 (2007) 13921412er, on fibroblasts, PLGA/chitin
and PLGA showed similarperformance, with no improvement observed on
the PLGA/chitin electrospun scaffold [114].
-
2.3.3.3. PLGA with PEG-PLA copolymers. Amphiphilicblock
copolymers, containing hydrophobic PLA blocks andhydrophilic
poly(ethylene glycol) (PEG) blocks, have showngreat promise in the
applications of drug delivery. Thesecopolymers (e.g. diblock
PEG-PLA, triblock PEG-PLA-PEG orPLA-drug PEG-PLA) are suitable to
encapsulate and protectdrug or DNA molecules, whereby the
encapsulated drug (gene)/polymer aggregates can be incorporated
into the nanofibrousPLGA scaffolds by electrospinning. Since PLGA
and PEG-PLA are compatible with each other, the addition of even
asmall amount of PLA-PEG block copolymer can significantlychange
the hydrophobicity and the degradation rate ofelectrospun
PLGA-based scaffolds [115]. Blending PEG-PLAcopolymers is, thus, an
effective way to fine-tune the propertiesof PLGA-based scaffolds
for different biomedical applications.
For drug delivery, our group has recently demonstrated thatthe
release of cefoxitin sodium (Mefoxin), a hydrophilicantibiotic
drug, could be modulated by the addition of a diblockPEG-b-PLA
copolymer (Mw of PEG and PLA are 5 K and 4.6 K,respectively) in an
electrospun PLGA scaffold [45]. Fig. 3 showsthe effect of PEG-b-PLA
on the cefoxitin sodium release profile.
D. Liang et al. / Advanced Drug DelivFig. 3. Drug (cefoxitin
sodium) release profiles (cumulative curve-top anddifferential
curve-bottom) from medicated electrospun scaffolds. The data
represents the meanS.D. (n=5 scaffolds): (a) medicated PLGA with
1 wt.%drug, (b) medicated PLGA/PLA/PEG-b-PLA blend with 5 wt.%
drug, and(c) medicated PLGA with 5 wt.% drug. (From Ref. [45] with
permission).Without the block copolymer, about 75% of cefoxitin
sodiumwas released in one day; while with 15 wt.% of PEG-b-PLA,only
about 60% of cefoxitin sodiumwas released in one day. Therapid
initial burst release was designed to prevent bacteriainfection
immediately after surgery, but the prolonged secondarydelivery
profile was also desirable in order to minimize potentialbacteria
growth. The efficacy of released cefoxitin sodium waschecked by an
inhibition study using S. aureus bacteria culture.The results
showed that the process of electrospinning did notcompromise the
efficacy of this drug. In other words, thestructure and bioactivity
of cefoxitin sodiumwas retained duringthe processes of drug
incorporation and electrospinning [45].
Using a triblock PLA-PEG-PLA copolymer (Mw of PEG andPLA are 3.4
K and 0.6 K, respectively), our group also reportedthatDNAmolecules
could be incorporated and then released fromelectrospun scaffolds
in a controlled manner [47]. With additionof 1015 wt.% PLA-PEG-PLA,
the release of -galactosidaseencoding plasmid DNA from the
gene-containing electrospunPLGA scaffold was sustained over 20
days, with the maximumamount of release occurring within about 2 h.
The cumulativerelease profiles indicated that the amount of DNA
released wasapproximately 6880% of the initial load. Fig. 4 shows
thetransfection activity of the released DNA from the
electrospunscaffold. Results indicated that DNA released directly
from thePLGA scaffolds was indeed intact, capable of cellular
transfectionand successfully encoding the protein -galactosidase
[47].
Our group also evaluated the potential use of a
compositescaffold containing PLGA, PEG-PLA diblock copolymer
andcefoxitin sodium to prevent surgery-induced adhesion [42].Acting
as a physical barrier but with drug delivery capability,this
electrospun medicated PLGA-based scaffold was able tocompletely
prevent any adhesion formation after 28 days usingan objective rat
model. The combined advantages of thecomposition adjustment,
drug-loading capability, and easyplacement handling ability in the
body (the material is relativelyhydrophobic) have made these
scaffolds potential candidates forfurther clinical evaluations
[42].
A composite scaffold formed by electrospinning of a
multi-component mixture containing PLA, PLGA, triblock copoly-mer
of PLA-b-PEG-b-PLA and lactide was fabricated by ourgroup [115].
The objective of choosing multi-components wasto precisely control
the physical and biological properties of thescaffold, with each
component providing a different function.For example, PLA of high
molecular weight provided theoverall mechanical strength,
PLA-PEG-PLA affected thehydrophilicity, PLGA coarse-tuned and
lactide fine-tuned thedegradation rate[115]. We found that a
scaffold containing40 wt.% high molecular weight PLA, 25 wt.% low
molecularweight PLGA, 20 wt.% PLA-PEG-PLA and 15 wt.% lactideshowed
a suitable degradation profile, good hydrophilicity, andstable
mechanical properties in aqueous solution (and bodyfluids) for the
prevention of post-operative adhesion [115].
2.3.3.4. PLGA with other polymers. Many other biocompat-
1399ery Reviews 59 (2007) 13921412ible and biodegradable
polymers have been mixed together withPLGA based polymers to form
nanofibrous scaffolds byelectrospinning. For example, mixtures of
PLA with poly
-
eliv1400 D. Liang et al. / Advanced Drug D(vinylpyrrolidone)
[116], and of PLA with poly(ethylene-co-vinylacetate) [117] were
fabricated into nanofibrous scaffoldsby electrospinning for
biomedical applications.
2.3.4. Synthetic polymer blends containing PEO/PEGPoly(ethylene
oxide) (PEO) or poly(ethylene glycol) (PEG,
when the molecular weight is small, say less than 5000 Da) is
aunique polyether diol, which is amphiphilic and can bedissolved in
both organic solvents and aqueous solutions,including pure water.
PEO/PEG is non-toxic and can beeliminated by renal and hepatic
pathways, making it suitable formany biomedical applications. Thus
far, PEO/PEG has beenused as the electrospun scaffold mainly for
two reasons: (1) toimprove the fiber property and functions (e.g.
hydrophilicity),and (2) to facilitate electrospinning of other more
difficult toprocess biomaterials as a processing aid. For example,
in firstapplications, PEG has been incorporated in the
electrospunscaffolds in the form of copolymers, such as PEG-g-CHN
[43]and PEG-PLA [45,118] described earlier. Duan et al.
[50]fabricated nanofibrous scaffolds by co-electrospinning
mixturesof chitosan and PEO in aqueous solutions containing 2
wt.%acetic acid. With the PEO/chitosan mass ratio of 2:1 or 1:1,
finefibers with two diameter distributions (the diameter ranged
from80 nm to 180 nm) were obtained from solutions of 46
wt.%chitosan/PEO concentrations. They found that thick and
thinfibers were formed mainly by PEO and chitosan,
respectively[50]. Spasova et al. [119] applied electrospun
chitosan/PEOscaffolds for delivery of potassium
5-nitro-8-quinolinolate
Fig. 4. Bioactivity of released DNA in the transfection of MC3T3
cells. (a) Naked DN(Fugene 6), (c) DNA containing scaffold
incubated with cell for 4 h, then removed,(From Ref. [47] with
permission).ery Reviews 59 (2007) 13921412(K5N8Q), an antimicrobial
and antimycotic drug. They showedthat the drug had an effect on the
production of fiber diameterand fiber morphology. With 1 wt.% K5N8Q
loading in thescaffold based on the chitosan/PEO ratio of 1:1, the
resultingnanofibrous mat showed antibacterial and antimycotic
activityagainst E. coli, S. aureus and C. albicans [119]. The
molecularweight of PEG as a processing aid for electrospinning
wasrelatively high, usually larger than 5000 Da. This is because
thelower molecular weight PEG has the form of a liquid. Forexample,
Xie et al. used oligomeric PEG to facilitate theelectrospinning of
two natural proteins: casein and lipaseenzyme [108]. Jin et al.
also showed that the addition of a smallamount of oligomeric PEG
was able to improve the process-ibility of silkworm fibroin
solutions [120].
2.3.5. Other multi-component polymer systemsOther mixtures of
biocompatible and biodegradable poly-
mers have also been electrospun into nanofibrous scaffolds,such
as polyether imide/poly(3-hydroxybutyrate-co-3-hydroxyvalerate)
[6]. In addition to polymer blends, blends of syntheticpolymers and
inorganic particles, such as silver particles[74,121], calcium
carbonate [122], calcium phosphate [123],and hydroxy-apatite
[124,125] were also used to preparenanofibrous scaffolds, which
were found to be useful inbiomedical applications. Since elemental
silver and silver saltshave been used for decades as antimicrobial
agents in curativeand preventive health care, Son et al. [74]
electrospun celluloseacetate fibers containing AgNO3, which was
further reduced to
A added directly to cell medium, (b) cells transfected with
control DNA complex(d) released DNA from scaffold complexed with
Fugene 6. Scale bar 100 m.
-
the porosity through the electrospinning processing
technology.In this section, we describe several innovative
electrospinningtechniques to enhance the functions and properties
of electro-spun nanofibers. The new development includes
multilayeredelectrospinning, core-shelled electrospinning,
two-phase elec-trospinning, blowing-assisted electrospinning and
post-align-ment methods. Furthermore, some of these techniques
are
1401elivery Reviews 59 (2007) 13921412silver nanoparticles by a
photo-reduction technique using UVirradiation. Silver nanoparticles
in cellulose acetate fibers werestabilized by interactions with
carbonyl oxygen groups oncellulose acetate and showed very strong
antimicrobial activity.Recently, Melaiye et al. [121] prepared
Tecophilic nanofibers (afamily of hydrophilic polyether-based
thermoplastic aliphaticpolyurethanes), containing up to 75 wt.%
silver-imidazolecyclophane gem-diol complex by electrospinning. The
nanofi-brous mat encapsulated the silver particles and released
them ina sustained profile over a long period of time. Therefore,
the rateof bactericidal activity of the silver particles was
greatly im-proved and the amount of silver used was much reduced.
Suchelectrospun organic/inorganic hybrid scaffolds were found to
bevery effective againstE. coli, P. aeruginosa, S. aureus, C.
albicans,A. niger and S. cerevisiae [121].
Fujihara et al. demonstrated that the incorporation of
calciumcarbonate (CaCO3) in the electrospun PCL scaffold was able
toassist the bone cell regeneration [122]. To achieve the
desiredmechanical stability, two layered structures, one formed by
neatPCL and one formed by the mixture of PCL and CaCO3 atdifferent
compositions, were employed. Good cell attachmentand proliferation
was observed in such composite scaffolds. Fanet al. incorporated
b-tertiary calcium phosphate (b-TCP) intoelectrospun PLA scaffolds
[123]. Compared with pure PLAscaffold, the incorporation of b-TCP
increased the hydrophili-city of the scaffold and improved cell
adhesion and prolifer-ation, greatly improving its potential for
use in tissue engineering.
Bioceramic hydroxy-apatite and PLA were fabricated
intonanocomposite nanofibers by electrospinning [124]. A
surfac-tant, hydroxysteric acid (HSA), was added in the system
toeffectively disperse hydrophilic hydroxy-apatite powders in
thePLA solutions in chloroform. As a result, continuous and
uni-form nanofibers with diameters about 12 m were
generated.Cellular assay experiments indicated that this scaffold
hadexcellent cell attachment and proliferation properties as well
asenhanced expression of alkaline phosphatase at 7 days
ofculturing. Tomimic the human bonematrix, Kim et al. fabricateda
nanocomposite nanofibrous scaffold by electrospinningmixtures of
gelation and hydroxy-apatite nanocrystals [125].The
hydroxy-apatite/gelatin mixture was lyophilized anddissolved in the
organic solvent HFP and then electrospununder controlled
conditions. With this method, the hydroxy-apatite nanocrystals were
well distributed within the gelatinfibers. Compared to pure
gelatin, the nanocomposite nanofiberssignificantly improved the
bone-derived cellular activity, thushaving good potential in the
application of guided tissue (bone)regeneration [125].
3. New innovations in electrospinning forbiomedical
applications
Using the schemes of copolymerization and polymermixtures,
desirable physical and biological properties ofelectrospun
nanofibrous scaffolds can be obtained. However,
D. Liang et al. / Advanced Drug Dthe performance of the
electrospun scaffold can be furthercontrolled by adjusting the
diameter and morphology of thenanofibers, desirable 3D patterns
(e.g., layered structures) andFig. 5. Confocal micrographs of
immunostained myosin filaments in SMCs after
1 day of culture; (a) on aligned nanofibrous scaffold, (b) on
aligned nanofibrousscaffold, overlay image on the aligned fiber,
and (c) on tissue culture polystyreneas control. (From Ref. [100]
with permission).
-
highly complementary in nature and can be combined togenerate
new hybrid materials in the platform of nanofibrousscaffolds with
specific and desired properties. The selectedexamples represent
only a snapshot of current activities reportedin the community of
electrospinning. Without a doubt, there willbe many more innovative
developments on the fabricationmethods based on electrospinning
technology in the future.
3.1. Scaffolds with oriented fiber alignment
During electrospinning, as the velocity of the fiber jet near
thecollector is very high (e.g. near a fraction of the speed of
sound),the resulting nanofiber is usually collected in a random
fashionwithout preferred orientation (i.e., non-woven structure).
Forcertain applications in tissue engineering, scaffolds with
alignedfibers are often more desirable to guide the cell growth
with
desired anisotropy [27,53,100,126,127]. Several fiber
collectionmethods, including (1) auxiliary electrode/electrical
field [128130], (2) thin wheel with sharp edge collector [131], and
(3)frame collector [28], have been developed to align the fibers
onthe collector. The most practical method to align the
electrospunscaffold is perhaps by mechanical drawing (e.g.
uniaxialdrawing or sequential biaxial drawing) [132]. However, it
hasbeen found that with the increase in the stretching
extensionratio, the porosity of the scaffold would decrease
correspond-ingly. If this is a concern, the sequential biaxial
stretchingprocess with asymmetric draw ratios can be effectively
used tocontrol both orientation and porosity of the electrospun
scaffold.
The use of oriented electrospun scaffolds has beendemonstrated
in several studies. For example, Xu et al. [100]investigated the
P(LA-CL) nanofibrous scaffold with alignedfibrous structure and
found that human coronary artery smooth
1402 D. Liang et al. / Advanced Drug Delivery Reviews 59 (2007)
13921412Fig. 6. (a) SEM images of cardiac myocytes cultured on
uniaxially stretched align(c) electrical response of cardiac
myocytes on electrospun scaffolds (action potentialoptical
recording system). (From Ref. [133] with permission).ed PLLA
electrospun scaffolds, (b) corresponding confocal micrograph of
(a);s were measured using a voltage-sensitive dye di-8-ANEPPS and a
micro scale
-
muscle cells (SMCs) attached and migrated along the axis of
thealigned nanofibers and expressed a spindle-like
contractilephenotype. Fig. 5 illustrates that the distribution and
organiza-tion of smooth muscle cytoskeleton proteins inside SMCs
wereparallel to the direction of nanofibers. They also found that
theadhesion and proliferation rate of SMCs on the
alignednanofibrous scaffold was significantly improved when
com-pared with those on solid polymer films [100].
Our group has investigated the structural and functionaleffects
of oriented electrospun scaffolds on the growth ofcardiac myocytes
(CM) [133]. The orientation was achieved byusing a post-drawing
process after electrospinning. Scanningelectron microscopy (SEM)
revealed that the fine fiberarchitecture of the non-woven matrix
allowed the cardiomyo-cytes to make extensive use of provided
external cues forisotropic or anisotropic (oriented) growth, and to
some extent tocrawl inside and pull on fibers (Fig. 6a). Structural
analysis byconfocal microscopy indicated that CM had a preference
forrelatively hydrophobic surfaces (Fig. 6b). Cardiac myocytes
on
Fig. 7a, such a process could produce a multilayered
non-wovennanofibrous mesh, in which a hierarchically ordered
structurecomposed of different polymer meshes could be obtained.
Inmixing electrospinning, two different polymer solutions
weresimultaneously electrospun from different syringes under
differentprocessing conditions. The spun polymer fibers were mixed
on thesame target collector, resulting in the formation of mixed
fibermesh (Fig. 7b). Three layered scaffolds, containing
segmentedpolyurethane, styrenated gelatin and type I collagen,
fabricated byusing the multilayered electrospinning technique, and
co-minglednanofibrous scaffold, containing segmented polyurethane
and poly(ethylene oxide), fabricated by using the mixing
electrospinningtechnique, have been demonstrated [134]. The
multilayer electro-spun scaffolds have been further used for guided
bone regeneration[122] and biohemostat [135] studies.
3.3. Fabrication of dual-porosity scaffolds
The presence of clay nanoparticles is capable of enhancing
the
1403D. Liang et al. / Advanced Drug Delivery Reviews 59 (2007)
13921412electrospun poly(L-lactide) (PLLA) scaffolds developed
maturecontractile machinery (sarcomeres). Functionality
(excitability)of the engineered constructs was confirmed by optical
imagingof electrical activity using voltage-sensitive dyes (Fig.
6c). Thestudy clearly indicates that engineered cardiac tissue
structureand function could be modulated by the chemistry and
geometryof the provided nano- and micro-textured surfaces.
3.2. Multilayer electrospinning and mixing electrospinning
Recently, Kidoaki et al. [134] demonstrated two novel
electro-spinning techniques: (1) multilayer electrospinning and (2)
mixingelectrospinning (Fig. 7), to fabricate composite scaffolds
contain-ing different polymers. In multilayer electrospinning,
eachpolymer was electrospun to form its individual layer and
wassequentially collected on the same target collector. As shown
inFig. 7. Schematic diagram of (a) multilayer electrospinning and
(bstrength, stiffness, resistance to heat, andmechanical and
physicalproperties of the polymer matrix. Lee et al. [136] used
thecombination of electrospinning, based on suspensions
containingPLA, solvent and clay nanoparticles, and salt addition,
to fabricatea nanofibrous composite. After the salt leaching/gas
formingprocess, a unique dual-porosity nanofibrous scaffold based
onPLA/clay nanocomposites was generated. As shown in Fig. 8,
thescaffold exhibited a 3-D structure with nano-sized pores at
theinterstices of the entangled fibers (Fig. 8a) and micro-sized
(50300 m) pores formed by the salt particles and gas bubbles(Fig.
8b). Such morphology is desired for scaffolding in
tissueregeneration, as the large holes will enable the
transportation oftypical cells (in tens of microns) and the small
holes will enablethe perfusion of smaller size molecules (e.g.
nutrients, growthfactors). The biological activity of the
dual-porosity scaffold,however, has not been reported.) mixing
electrospinning. (From Ref. [134] with permission).
-
could be immobilized for a long time and then released in
acontrolled manner. Therefore, the techniques may offerpotentially
useful advantages over other electrospinning techni-ques in the
applications of drug delivery and tissue engineering.
3.5. Fabrication of core-shelled nanofibers
The fabrication of core-shelled nanofibers by electrospinningwas
first reported by Sun et al. [137]. Using this technology,some
difficult-to-process polymer solutions could be co-electrospun to
form an ultra-fine core within the shell of otherpolymer materials
[138]. Fig. 10 shows a typical setup used togenerate the
core-shelled structures by electrospinning. Basi-cally, two polymer
solutions were co-electrospun without directmixing. Zhang et al.
[139] reported the fabrication of a
elivery Reviews 59 (2007) 139214121404 D. Liang et al. /
Advanced Drug D3.4. Two-phase electrospinning
Immiscible polymer solutions, such as poly(ethylene-co-vinyl
acetate) in dichloromethane and bovine serum albumin(BSA) in
phosphate-buffered saline (PBS) at a 40:1 ratio, havebeen
electrospun to form a fibrousmat, containing a distinct two-phase
structure in the resulting fibers [51]. The morphology ofsuch
fibers is illustrated in Fig. 9 (left). The incompatible waterphase
(BSA in PBS) was encapsulated in the matrix of
poly(ethylene-co-vinyl acetate). In Fig. 9 (right), the
florescent-labeled protein in PBS could be visualized directly by
bothvisible and ultraviolet light, exhibiting different
spectroscopicproperties from the polymer matrix [51]. The
two-phaseelectrospinning process, using a single spinneret,
provides aviable means to incorporate small molecules and/or
macro-molecules, including drugs and proteins in the
nanofibrousscaffolds, provided that the molecules could withstand
theelectrospinning process. The encapsulated bioactive
molecules
biodegradable core-shelled structure with PCL being the shelland
gelatin being the core. Transmission electron microscopy(TEM)
images and X-ray photoelectron spectroscopy (XPS)analysis confirmed
the encapsulation of the gelatin within thePCL phase. This
technique can be particularly useful inproducing surface-modified
nanofibers, functional nanocompo-sites, and even continuous hollow
fibers.
Another advantage of the core-shelled fiber is that the
shell
Fig. 8. SEM image of PLA/clay nanocomposite scaffold by
electrospinning andsalt leaching/gas foaming methods. (From Ref.
[136] with permission).protects the material in the core during the
electrospinningprocess. This feature is even more attractive when
bio-relatedmaterials are employed to form nanofibrous scaffolds.
Forexample, Jiang et al. electrospun a fiber with
poly(-caprolactone)as the shell and BSA together with dextran as
the core [140].Withthe help of dextran and the protection of the
shell, BSAwas nearlyintact during the electrospinning process. A
release of BSA in acontrolled manner was achieved by the formation
of the core-Fig. 9. Visualization of fluorescently labeled protein
encapsulated in polymerfibers using visible (a) and ultraviolet (b)
light. (From Ref. [51] withpermission).
-
shelled fiber [140]. Besides proteins, the shell has the ability
toprotect even living cells. Recently, Townsend-Nicholson
andJayasinghe [141] demonstrated that, with poly(dimethylsilox-ane)
(PDMS) forming the shell, the cell suspension inside the
3.6. Blowing-assisted electrospinning technique
To date, it is believed that nearly one hundred
differentpolymers have been successfully electro-spun [28].
However,
Fig. 10. A setup used to generate core-shelled structure by
electrospinning. (From Ref. [138] with permission).
1405D. Liang et al. / Advanced Drug Delivery Reviews 59 (2007)
13921412core suffered almost no cellular damage during the
fabricationprocess. Fig. 11 shows the fluorescent micrographs of
core-shelled fibers obtained at two different flow rates.
Obviously,the Rhodamine 6G labeled cells, which are red in color
underthe microscope, were safely encapsulated by PDMS
afterelectrospinning [141].Fig. 11. Characteristic fluorescent
micrographs showing the variation in fiber diamet1012 m3/s, polymer
solution, 1011 m3/s; (b) cell suspension, 108 m3/s, polymer sthere
are many more polymers that could not be electro-spunsuccessfully.
One of them is hyaluronic acid (HA), a naturallyoccurring
polysaccharide, commonly found in connectivetissues in the body,
such as vitreous, umbilical cord, and jointfluid, due to its very
high solution viscosity and high surfacetension, even at fairly low
solution concentrations.er that results from cell encapsulation.
Flow rate conditions: (a) cell suspension,olution 107 m3/s. (From
Ref. [141] with permission).
-
ma
1406 D. Liang et al. / Advanced Drug Delivery Reviews 59 (2007)
13921412Our research group has successfully demonstrated
thefabrication of high molecular weight HA nanofibers using
theblowing-assisted electro-spinning technique, which combinedthe
process of electro-spinningwith air blowing capability aroundthe
spinneret (a schematic diagram of the setup is shown inFig. 12)
[32,65]. In this study, the effects of various experimental
Fig. 12. A setup of blowing-assisted electrospinning device that
can processparameters, such as air-blowing rate, HA concentration,
feedingrate of HA solution, applied electric field, and type of
collector onthe performance of blowing-assisted electro-spinning of
HAsolution were investigated.With the assistance of air-blowing,
theHA solution feeding rate could be increased to 40
l/min/spinneret and the applied electric field could be decreased
to2.5 kV/cm. The optimum conditions for consistent fabrication
of
Fig. 13. Surface modification scheme for galactose conjugation
to PCLPEEPHA (with a molecular weight about 3.5 million)
nanofibersinvolved the use of an air blowing rate of around 70
ft3/h and aconcentration range between 2.5 to 2.7 wt.% in aqueous
solution.
We demonstrated that there were at least four advantages inthe
electro-blowing process [32]. (1) The combination of airblowing
force and the applied electric field is capable of over-
terials usually difficult to be electrospun. (From Ref. [32]
with permission).coming the high viscosity, as well as the high
surface tension, ofthe polymer solution. (2) The use of elevated
temperature of theblown air can further decrease the HA solution
viscosity at thespinneret, facilitating the jet formation of the HA
solution at thespinneret. (3) The blowing air can accelerate the
solvent evap-oration process, a necessary condition for the fiber
formationbefore the solution jet stream reaches the ground
collector during
nanofiber mesh and spin-cast film. (From Ref. [142] with
permission).
-
the process. (4) The fiber diameter, which is one of the
keyfactors to control the physical properties of
nanofibrousmembranes, can be tailored by controlling the air
temperatureand the air flow rate. With these advantages, it is
expected thatmany useful polymers, which could not be electro-spun
untilnow, can be processed by using the new electro-blowing
ap-proach. Furthermore, the electro-blowing process shall
signif-icantly increase the production rate and thus can lead to
practicalmass production schemes.
4. Modifications of post-electrospun scaffolds
Although the combined use of different polymer
preparationschemes (e.g. copolymers and mixtures) and
innovativeelectrospinning techniques can significantly improve
physicaland biological properties of nanofibrous scaffolds,
furthermodifications on the surface of electrospun nanofibers are
oftenneeded in order to refine their in vivo or clinical usage. In
otherwords, surface modifications of electrospun scaffolds
withsuitable bioactive molecules are often essential to render
thematerials with more desirable biological features for
biomedical
hydrochloride (EDC). During cell culture, hepatocyte was ableto
adhere to the surface through the
galactose-asialoglycoproteinreceptor (ASGPR). Besides the
electrospun nanofibrous scaf-folds, spin-coating films containing
the same material were alsosurface-modified using the same
procedure. The authors showedthat hepatocytes cultured on the
electrospun galactosylatedscaffolds clearly exhibited superior
biological properties, includ-ing cell attachment, albumin
synthesis and 3-methylcholanthrene-induced cytochrome P450
function, to hepatocytes cultured onunmodified electrospun
scaffolds [142]. Selected SEM images ofhepatocytes after 8 days of
culture on galactosylated spin-castfilms and electrospun scaffolds
are shown in Fig. 14.Hepatocytes,cultured onmodified electrospun
scaffolds, formed spheroids thatengulfed the galactosylated
nanofibers (Fig. 14df); the spheroidswere immobilized on the
scaffold and would not detach from thescaffold upon agitation,
which was quite different from that onmodified spin-cast films
(Fig. 14ac). Based on these results, theyconcluded that hepatocyte
spheroid immobilization and stabili-zation strategy through the use
of galactosylated nanofibrousscaffolds would be advantageous in the
design of a bioartificialliver-assist device [142].
1407D. Liang et al. / Advanced Drug Delivery Reviews 59 (2007)
13921412applications.Chua et al. [142] reported an approach to
modify the poly
(-caprolactone-co-ethyl ethane phosphate) (PCLEEP)
nanofibersurface by grafting a hepatocyte-specified galactose
ligand forhepatocyte culture. Fig. 13 schematically shows the
surfacemodification procedure. In brief, electrospun PCLEEP
nanofi-bers, having an average diameter of about 760 nm, were
firstcleaned by ethanol and grafted with poly(acrylic acid) (PAA)
byphoto-induced polymerization.
1-O-(6-aminohexyl)-D-galacto-pyranoside (AHG) and then conjugated
to PAA chains in asodium phosphate buffer containing
N-hydroxysulfosuccinimide(NHS) and
1-ethyl-3-(3-dimethylaminopropyl) carbodiimideFig. 14. SEM images
of hepatocytes after 8 days of culture: (ac) hepatocytes
cultuhepatocytes cultured on galactosylated electrospun scaffold
showed aggregates enguUsing a similar strategy, Ma et al. [40]
grafted gelatin ontothe electrospun poly(ethylene terephthalate)
(PET) nanofibrousscaffolds by using a chemical scheme to overcome
the chemicaland biological inertness of the PET surface. The scheme
is asfollows. The electrospun PET scaffold was fixed on a piece
ofglass with glue and then treated with formaldehyde to
introducehydroxyl groups. Methacrylic acid was polymerized on
thesurface with Ce(IV) as the initiator, followed by the grafting
ofgelatin with carbodiimide as the coupling agent. They tested
thebioactivity of the gelation-modified electrospun PET scaffoldby
using endothelial cells (ECs). Compared with the unmod-ified PET
scaffold, the gelatin-modified PET scaffold showed ared on
galactosylated spin-cast film formed around spheroids; (df) in
contrast,lfed the functional nanofibers. (From Ref. [142] with
permission).
-
elastomeric nonwoven media, Advances in Filtration and
Separation
elivclear improvement in cell adhesion, spreading and
proliferation.Moreover, the modified scaffold preserved the EC's
phenotype[40].
Wang et al. [35] demonstrated that the surface of anelectrospun
cellulose acetate scaffold was able to immobilizeenzymes after
being modified with PEG spacers. The modi-fication scheme is as
follows. The electrospun celluloseacetate nanofibrous scaffold was
hydrolyzed and followed bygrafting of PEG diacylchloride. Lipase
enzyme was thenattached to the scaffold surface through the
coupling withPEG spacers. Their result showed that the bound lipase
ex-hibited much better retention ability of catalytic activity
afterexposure to cyclohexane (81%), toluene (62%) and hexane(34%)
than the activity of the free lipase (25%). More im-pressively, the
bound lipase showed significant catalyticactivity, up to 810 more
times at 6070 C than that of thefree form [35].
Surface modifications of electrospun scaffolds can
signifi-cantly improve the biological performance while retaining
allnanostructure features and properties. The modification
schemewill be application specific and material dependent. In
general,electrospun nanofibers should first be functionalized by
areactive spacer, which can then couple with other
bioactivemolecules to modify the physical or biological properties.
Asthe electrospun nanofibrous scaffold has a very large
surfacearea-to-volume ratio, such modifications will be
extremelyuseful to generate new nanostructured materials with
novelfunctionality for biomedical applications.
5. Conclusion
Electrospun nanofibrous scaffolds showed great promise
andpotential for many biomedical applications, such as
tissueengineering, wound dressing, immobilized enzymes
andcontrolled-delivery of drugs (genes). As described in
thisreview, a successful creation of nanofibrous scaffolds must
startwith the proper selection of materials, a judicious and
realisticfabrication pathway, and possible post-modification
withfunctional reagent. The polymer material selection plays a
keyrole in the fabrication of scaffolds. Many desirable
propertiescan be achieved by polymer mixing (natural and/or
syntheticpolymers), copolymerization or a hybrid of materials
andprocessing techniques. Multi-component mixtures can bemiscible
or immiscible, containing different phases (liquid orsolid).
Several newly developed innovative electrospinningmethods have been
described, including oriented scaffolds,multilayer electrospinning,
mixing electrospinning, fabricationof dual-porosity scaffolds,
two-phase electrospinning, fabrica-tion of core-shelled nanofibers
and blowing-assisted electro-spinning. The processing schemes can
be further combinedor/and modified to generate new morphology based
on theplatform of nanofiber technology. Finally, the surface
modifi-cation of electrospun scaffolds with suitable bioactive
agents isan effective means to fine-tune the functionality of
nanofibers
1408 D. Liang et al. / Advanced Drug Dfor specific biomedical
applications. The electrospinningtechnology platform can indeed
offer the versatility and uniquenanostructure features beyond most
existing technologies.Technology 15 (2002) 525537.[13] P. Gibson,
H. Schreuder-Gibson, D. Rivin, Transport properties of porous
membranes based on electrospun nanofibers, Colloids and
Surfaces. A,Physicochemical and Engineering Aspects 187188 (2001)
469481.
[14] L. Wannatong, A. Sirivat, Electrospun fibers of
polypyrrole/polystyreneblend for gas sensing applications, PMSE
Preprints 91 (2004) 692693.
[15] X.Y. Wang, Y.G. Kim, C. Drew, B.C. Ku, J. Kumar, L.A.
Samuelson,Electrostatic assembly of conjugated polymer thin layers
on electrospunnanofibrous membranes for biosensors, Nano Letters 4
(2004) 331334.
[16] B. Ding, J. Kim, Y. Miyazaki, S. Shiratori, Electrospun
nanofibrousmembranes coated quartz crystal microbalance as gas
sensor for NH3detection, Sensors and Actuators. B, Chemical B101
(2004) 373380.Acknowledgment
Financial support of this work was provided by a
NationalInstitutes of Health-SBIR grant (GM63283-03),
administeredby Stonybrook Technology and Applied Research, Inc,
theNational Science Foundation (DMR 0454887), and ClemsonUniversity
and UC, Berkeley for subcontracts to their NIHgrants. The
assistance of Dr. Dufei Fang in the preparation ofthis review is
gratefully acknowledged.
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