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1 s2.0 S0169409X16301296 Main
1 s2.0 S0169409X16301296 Main
a r t i c l e i n f o a b s t r a c t
Article history: Poly(lactic acid) (PLA) is a synthetic polyester that has shown extensive utility in tissue engineering. Synthesized
Received 31 December 2015 either by ring opening polymerization or polycondensation, PLA hydrolytically degrades into lactic acid, a meta-
Received in revised form 29 February 2016 bolic byproduct, making it suitable for medical applications. Specifically, PLA nanofibers have widened the pos-
Accepted 18 April 2016
sible uses of PLA scaffolds for regenerative medicine and drug delivery applications. The use of nanofibrous
Available online 26 April 2016
scaffolds imparts a host of desirable properties, including high surface area, biomimicry of native extracellular
Keywords:
matrix architecture, and tuning of mechanical properties, all of which are important facets of designing scaffolds
PLA for a particular organ system. Additionally, nanofibrous PLA scaffolds hold great promise as drug delivery carriers,
Scaffolds where fabrication parameters and drug-PLA compatibility greatly affect the drug release kinetics. In this review,
Nanofibers we present the latest advances in the use of PLA nanofibrous scaffolds for musculoskeletal, nervous, cardiovascu-
Tissue engineering lar, and cutaneous tissue engineering and offer perspectives on their future use.
Drug delivery © 2016 Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
2. PLA scaffolds for musculoskeletal tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
3. PLA scaffolds for nervous tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
4. PLA scaffolds for cardiovascular tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
5. PLA scaffolds for cutaneous tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
http://dx.doi.org/10.1016/j.addr.2016.04.019
0169-409X/© 2016 Elsevier B.V. All rights reserved.
M. Santoro et al. / Advanced Drug Delivery Reviews 107 (2016) 206–212 207
properties and degradation characteristics [9]. These aspects are critical nanofibers (e.g. polyethylenimine or poly(L-lysine)) to tune the
in many tissue engineering strategies, as scaffolds that can be engineered wettability of the overall scaffold, resulting in increased penetration of
to match the mechanical properties of the native tissue are likely to be water into the mat and increasing the release of drug [25]. Another less
successful. Consequently, PLA has been widely used in tissue engineering common method of drug loading includes immobilization of drug onto
applications, both as scaffolds and as drug delivery systems [4,9,10]. the polymer surface through methods such as layer-by-layer deposition.
Electrospinning and thermally induced phase separation (TIPS) are This strategy is particularly useful for charged entities such as negatively
the most common techniques used in the recent literature for the fabri- changed DNA for gene delivery applications, where a positively charged
cation of fibrous scaffolds. Electrospinning is an established technique macromolecule such as polyethylenimine can be used as a counter-
used to fabricate fibrous scaffolds whose properties (such as porosity, charge [16,26].
pore size, fiber size) can be easily tuned [11]. Fabrication parameters Release kinetics are an important consideration when designing
such as polymer solvent, polymer concentration, voltage, and collector drug-loaded scaffolds, and choice of polymer, loading method, and
distance can be varied to modify fiber and scaffold properties. However, scaffold parameters largely determine the final mechanisms of release.
varying these fabrication parameters globally influences the resulting In general, there are three major mechanisms of release from electrospun
scaffold, and individual properties cannot be independently tuned. A nanofiber PLA membranes: desorption, diffusion, and degradation. PLA
typical example is the increasing pore size with the increasing fiber nanofibers loaded by mixing typically exhibit an initial burst release
size [11,12]. Another less common technology used to fabricate PLA followed by a reservoir-type release [27]. The initial burst release is due
scaffolds is TIPS [13]. TIPS has been used for fabricating nanofibrous to desorption of drug from the outermost surface fibers, usually followed
poly(L-lactic acid) (PLLA) scaffolds that mimic the structure of fibrillar by diffusion-mediated release. Using ibuprofen as a model drug, it has
collagen while maintaining macropores that can facilitate nutrient ex- been shown that altering scaffold parameters such as spinning time can
change and cell migration [13]. TIPS is based on the phase separation affect the fiber density within the membrane, consequently affecting
of a homogeneous polymer solution into a polymer-rich and a the penetration of water into the membrane as well as the porosity of
solvent-rich phase, typically induced by either cooling the solution or the membrane [27]. Membranes with lower fiber density have high
adding an immiscible solvent [13,14]. Although the detailed physical porosity and allow free penetration of water and release of drug, while
mechanism of TIPS is still not fully understood, during this process the higher fiber densities have lower porosity and pack drug molecules closer
polymer crystallizes into nanofiber bundles that mimic the structure together, restraining drug delivery. In general, drug-loaded electrospun
of native ECM [14]. PLA nanofiber mats demonstrate solution-diffusion kinetics, and time-
Nanofibrous PLA materials find wide applicability not only as scaf- scale can be tuned through a variety of processing parameters, such a fab-
folds for tissue regeneration but also as drug delivery vehicles, especially rication method, drug choice and ionization state, and uniaxial/coaxial
when fabricated via electrospinning. The simplest method for drug electrospinning [28].
loading is direct adsorption of drug to the surface of nanofibers, which Coaxial electrospinning can remove desorption from the PLA surface
leverages the intrinsic large surface area of nanoscale materials [15]. Di- as a major release mechanism, as the drug is encapsulated within the
rect adsorption relies on non-covalent chemical interactions, such as core. Entrapment of drug in a core within a porous PLA sheath can result
electrostatic and van der Waals interactions, between the drug and in diffusion-dominated release kinetics [29], while entrapment within a
the polymer to facilitate binding of the drug to the scaffold. Drug diffu- solid PLA sheath can promote degradation as the driving mechanism for
sion from the polymer surface is facilitated due to the high porosity and release [30]. However, it is important to note that the kinetics for coaxial
surface area offered by the use of nanofibers, often times leading to a spun fibers can be highly dependent on processing parameters and may
high initial release of drug upon contact with release medium, referred still show desorption-diffusion release kinetics [31]. Scaffolds produced
to as “burst release.” This method is particularly desirable for drugs and by electrostatic layer-by-layer deposition or adsorption utilize compet-
gene constructs that may be sensitive to the organic solvents or high itive binding of serum proteins to drive release of the charged
voltage used in electrospinning [16]. complexes from the scaffold [26,32].
Hydrophobic drugs that are soluble in organic solvents can be direct- Despite its many desirable properties, the main concern with the use
ly mixed into solution of PLA for electrospinning with homogeneous of PLA lies in its degradation products. PLA degrades into lactic acid, a
distribution in the fibers. Hydrophilic water-soluble drugs can be incor- relatively strong acid that can elicit an inflammatory response [1]. This
porated into PLA through water/oil emulsification, allowing for a simple effect is further exacerbated by the fact that PLA-based devices com-
and cost-effective method to electrospin drug-loaded nanofibrous scaf- monly undergo bulk erosion. As a result, the accumulation of acidic
folds with drug loading and encapsulation efficiency higher than other products within the bulk of the material accelerates its degradation,
delivery carriers, such as hydrogels and liposomes [17,18]. This method leading eventually to a sudden loss of its mechanical integrity and a
entraps drug within the polymer matrix as well as retaining some drug delayed inflammatory response [1,10]. However, PLA is still a preferred
at the polymer surface, taking advantage of the degradability of PLA and material for scaffold fabrication because of the reduced concentration of
leading in general to sustained release kinetics with an early burst. The degradation products with increased porosity. Consequently, several
release profile depends on the drug distribution within the fiber section, approaches have been proposed to mitigate the shortcomings of this
which is partly dictated by interactions between PLA and the drug of synthetic polymer including preparation of lactic acid copolymers and
choice. In particular, hydrophilic drugs may undergo phase separation PLA-based composites [33–36].
when mixed with hydrophobic polymers like PLA, resulting in a burst In this review, we discuss advances with PLA scaffolds for tissue
release of drug due to a high fraction of drug at the fiber surface [19]. engineering applications during the last 5 years. Specifically, we focus
To address this issue, coaxial electrospinning has emerged as a way to on the use of lactic acid homopolymers for the fabrication of scaffolds
spin fibers with a core-shell morphology, where the drug is dissolved in a and drug delivery systems for tissue engineering.
compatible material in the core while the outer PLA layer determines the
release kinetics and protects the drug from the surrounding environ- 2. PLA scaffolds for musculoskeletal tissue engineering
ment [20,21]. This approach, together with the more recently developed
emulsion electrospinning [18], is now pursued to encapsulate sensitive Musculoskeletal defects are common and can result from a variety of
growth factors and plasmids and to minimize the interaction between etiologies, including trauma, infection, or underlying pathology. Failure
the drug and the PLA solvent that may denature the biomolecule/genetic to adequately address defects in bone, muscle, or tendon may lead to
material [22–24]. In the case of drugs that demonstrate slow release rates significant loss of function and lower quality of life for those affected.
due to the low wettability of PLA, such as the model protein cytochrome In light of the significant role of PLA in the orthopedic field, it is not sur-
C, the hydrophobic PLA nanofibers can be blended with hydrophilic prising that PLA continues to play a central role in many
208 M. Santoro et al. / Advanced Drug Delivery Reviews 107 (2016) 206–212
ume ratio geometries, usually cylinders, which provide mechanical sta- Scaffold type Application Reference
bility and an environment conducive to bone regeneration [33,38]. To Cylindrical composite of In vitro culture with mesenchymal [13]
this end, mechanical properties and degradation kinetics of PLA-based PLLA/chitosan nanofibers via TIPS stem cells for bone repair
scaffolds can be tuned by varying the racemic mixture of lactic acids PLLA/β-TCP nanocomposite disk Scaffold with hierarchical porosity [41]
composing the polymer chains [10]. via TIPS and salt leaching for bone ingrowth
PLLA/silanized HA nanocomposite Scaffold with improved [42]
Among the techniques used to process PLA, TIPS has been leveraged
via TIPS ceramic/polymer interactions
to fabricate PLLA scaffolds with nanoscale features [14]. Cylindrical PLLA PLLA nanofibrous sheet via phase In vitro culture with mouse [43]
nanofibrous scaffolds fabricated using with TIPS have demonstrated sig- separation micromolding progenitor myoblasts
nificantly greater surface area than raw PLLA material, which conse- Thermally stressed electrospun In vitro testing of scaffold with [44]
quently leads to higher protein adsorption but also faster degradation. PLDLA nanofibrous sheet bovine fibroblasts for anterior
cruciate ligament repair
This shortcoming can be mitigated by using a dual TIPS process to
form a chitosan network within a PLLA network. The addition of
chitosan slows the PLLA degradation kinetics and makes the resulting
scaffold more biomimetic, as shown by in vitro cell viability tests with engineering involves the development of mechanically strong scaffolds
mesenchymal stem cells [13]. that are highly porous enabling vascularization [37]. Future research
In an attempt to design scaffolds suitable for load-bearing applica- with PLA will likely focus on the design of L/D-lactic acid copolymers
tions, a common strategy to improve PLA mechanical properties for to develop new materials suitable for load-bearing applications. Addi-
bone applications involves the use of ceramics, rather than the more tionally, the incorporation of ceramics will continue being a valuable
common metal implants [39,40]. For example, TIPS and salt leaching strategy to improve the mechanical properties of PLA [36].
have been used together to produce nanocomposite scaffolds made of
PLLA and β-tricalcium phosphate (β-TCP) [41]. While the PLLA provides
macropores to facilitate in vivo neovascularization and nutrient 3. PLA scaffolds for nervous tissue engineering
exchange, β-TCP nanoparticles mimic native bone microarchitecture
and strengthen the resulting composite. Compressive modulus and The destruction of peripheral nerves due to injury, pathology, or sur-
cell viability increased in a β-TCP-dependent fashion, with little effect gical intervention can cause severe functional and esthetic deficits. The
on scaffold overall porosity [41]. Similar results were found when current gold standard for nerve repair is autologous nerve grafting.
using hydroxyapatite (HA) modified with silane groups to improve However, this process has several drawbacks, including donor site
the ceramic/PLLA interactions [42]. By increasing HA hydrophobicity, morbidity, limited donor tissue, need for a second surgical site, and
the ceramic was better dispersed in the PLLA phase, further improving mismatch between donor and recipient nerves [48]. Scaffolds for
the mechanical properties of the resulting scaffold [42]. nerve tissue engineering are typically either hollow or filled tubes
While PLA found the greatest applicability in bone repair and regen- designed to be biocompatible, degradable, and mechanically matched
eration, it has been recently used to engineer other musculoskeletal to nerves to support cells, growth factor release, or a combination of
tissues. Several investigations attempted to fabricate 2-dimensional both [48]. In addition, variations in topography, conduit design, and
scaffolds, usually sheets or films, with nano- and micro-features that functionalization have become increasingly popular modes of optimiz-
resemble the properties of collagen fibers, a key component of connec- ing scaffold design [49]. Because of these design criteria, PLA and its
tive tissues like bone, but also cartilage, ligaments, and tendons [13,38, composites have been utilized in the development of degradable
43,44]. Phase separation micromolding has been used to fabricate nerve guidance conduits.
PLLA sheets for muscle applications, in which a PLLA solution was casted The fabrication of nerve conduits from PLA fibers has advanced sig-
on a patterned substrate and then exposed to a non-solvent to induce nificantly beyond simple tubes, and in recent years, many researchers
phase separation, producing a nanofibrous scaffold [43]. By optimizing have focused on variations in the alignment, topography, and mechan-
parameters such as PLLA molecular weight and weight fraction, and ical properties of PLA fibrous scaffolds to assist in the support of nerve
pattern design, it was possible to produce highly porous fibrous regeneration. For instance, the mechanical strength of PLA sutures can
scaffolds with interconnected porosity that increased cell–cell contact be enhanced by rotor-twisting into filaments and microbraiding into
in progenitor myoblasts [43]. single or multilayer tubes [50]. When evaluated by subcutaneous im-
Poly(L-co-D,L-lactic acid) (PLDLA) has also been employed to plantation in rats, it was demonstrated that these conduits maintained
engineer the anterior cruciate ligament (ACL), with the objective of lumen and wall integrity, which can be of concern with polymers that
producing a scaffold that matches native collagen fibrous architecture swell significantly or degrade too quickly [50]. Furthermore, implanta-
and mechanical properties [44]. Specifically, electrospun PLDLA fibers tion of the conduits into a 10 mm defect in rat sciatic nerve resulted in
were exposed to a water solution at a temperature higher than the nerve regeneration in all animals, with histologically visible axon-
PLDLA glass transition temperature. The thermally induced stress with- Schwann cell regeneration units and minimal inflammation [50]. Recent
in the polymer network was exploited to produce crimp-like fibers and investigations have also sought to combine microscale and nanoscale
to alter the mechanical properties of the scaffold. Scaffolds fabricated via features by fabricating nanofibrous conduit scaffolds with single or mul-
this method exhibited a compressive modulus close to that of native tiple microchannels [51,52]. In vitro results have shown that PLA
ACL. Additionally, the crimp-like pattern promoted ECM deposition by nanofibrous conduits fabricated by injection molding/TIPS had more
fibroblasts and the formation of fascicles, a distinctive architectural fea- than three orders of magnitude greater surface area than solid wall
ture of the ECM of native ACL [44]. tubes, thus impacting protein adsorption and cell adhesion [51]. Results
Musculoskeletal tissue engineering has harnessed the chemical and from this study showed increased adhesion of rat PC12 cells and rabbit
mechanical properties of PLA to engineer both hard and soft tissues (see patellar fibroblasts to PLA nanofibrous scaffolds compared to solid wall
Table 1) [2,39,45,46]. The combination of L- and D-lactic acid offers the scaffolds [51]. This strategy has been widely applied in tissue engineer-
possibility to tune polymer crystallinity, mechanical properties, and ing to several biomaterials, including PLA and PCL, to modify the surface
degradation kinetics [1,2,10,47]. Additionally, PLLA has been blended topography of the scaffold and ultimately influence cell phenotype and
with poly(D-lactic acid) (PDLA), resulting in a fibrous scaffold with long-term differentiation [52]. The dominant effects on cellular growth
higher compressive and tensile strength than scaffolds made of pure are likely due to the orientation of fibers. However, synthetic biomate-
PLLA or PDLA [47]. Nevertheless, a major challenge in bone tissue rials can vary greatly in terms of mechanical properties and degradation
M. Santoro et al. / Advanced Drug Delivery Reviews 107 (2016) 206–212 209
time, two parameters that affect further development of these scaffolds this improvement is currently unclear, and focus has shifted toward the
as gene or drug delivery vehicles [53,54]. use of nanofibrous scaffolds to promote nerve regeneration. Recent
While many studies have evaluated the adhesion of differentiated research has also demonstrated that the increase in surface area from
cells to PLA scaffolds, other researchers have explored these scaffolds utilizing nanofibers and the fabrication of highly aligned fiber geometry
as substrates to support the differentiation of stem cells. Nanofibrous scaffolds, mimicking the fiber alignment of nerves, improves the
mats of PLLA functionalized with the peptide sequence YIGSR through suitability of scaffolds for cell growth [55,57].
click-chemistry significantly impacted the differentiation of mouse em-
bryonic stem cells [55]. Electrospun mats of aligned or random PLLA 4. PLA scaffolds for cardiovascular tissue engineering
nanofibers were fabricated and were either functionalized or left un-
treated. Evaluation of neuron-specific class III β-tubulin, neurite exten- Cardiovascular disease is the leading cause of death worldwide,
sion, and gene expression for neural markers showed that aligned and warranting a serious look at tissue engineering strategies to replace
functionalized PLLA nanofibrous scaffolds increased the proportion of cardiovascular tissues [59]. There is large-scale need for scaffolds that
embryonic stem cells that demonstrated markers of neural differentia- support the regeneration of heart and blood vessels, leading to the use
tion compared to mats of either random or untreated fibers [55]. Simi- of PLA nanofibrous scaffolds for these applications. More in-depth
larly, coaxial electrospinning was used to fabricate PLLA/gelatin reviews of the physiology behind the need for tissue engineering strat-
composites for neuronal stem cell differentiation [56]. These composite egies to address cardiovascular problems are available elsewhere in the
scaffolds incorporated controlled release of retinoic acid and literature [59–61]. In recent years, PLA nanofibrous scaffolds have been
purmorphamine from the gelatin fibers [56]. Contrary to most coaxially most commonly used for the purpose of vascular tissue engineering,
spun composites of PLLA, drug-loaded cross-linked gelatin comprised although there are instances where PLA nanofibrous patches are fabri-
the outer sheath with an interior core of PLLA. This configuration allows cated for cardiac muscle repair [62]. Similar to nerve conduit scaffolds,
for early quick release of drug while using PLLA nanofibers to comprise the design of PLA fibrous vascular scaffolds requires a tube with hollow
the structural integrity of the scaffold. Drug release demonstrated an at- lumen that is biocompatible, degradable, and mechanically compliant
tenuated burst release at higher gelatin cross-linking, as expected [56]. with the graft site.
Engineered neural stem-like cells cultured on scaffolds loaded with PLA nanofibrous tubes have emerged as a popular scaffold type for
retinoic acid and purmorphamine were able to differentiate toward a vascular tissue engineering, and researchers have attempted to improve
neuronal lineage, and neurite length was greatest on fibers with these scaffold biomimicry by developing a bilayered electrospun scaffold
instructive cues [56]. Coaxial electrospun nanofibrous scaffolds com- comprising a nano- to microscale PLA fibrous outer layer and silk fibro-
prising a silk fibroin core with a PLA sheath have been investigated for in–gelatin nanofibrous inner layer [63]. The outer PLA fibrous layer was
the delivery of nerve growth factor to support differentiation of neuro- shown to support the growth and proliferation of 3T3 mouse fibroblasts,
nal stem cells [24]. Nerve growth factor was incorporated into the silk while the inner silk fibroin–gelatin layer supported the attachment and
fibroin core to preserve bioactivity and attenuate burst release. These growth of human umbilical vein endothelial cells [63]. Subcutaneous
scaffolds were also plasma treated in order to increase wettability and implantation of the scaffold demonstrated minimal inflammatory re-
attachment of PC12 neuronal stem cells [24]. Neurite extension was sponse, and at 3 months, the authors reported the formation of a con-
shown to be enhanced on air plasma treated coaxial nanofibrous scaf- nective vascular network coinciding with degradation of the implant
folds eluting nerve growth factor when PC12 cells were cultured in dif- [63]. Another study evaluated PLA nanofibrous scaffolds fabricated via
ferentiation medium without the growth factor [24]. Embryonic E9 phase separation and seeded with adult primary human aortic smooth
chick dorsal root ganglion cells and rat Schwann cells cultured on highly muscle cells, demonstrating that cells cultured on nanofibrous scaffolds
aligned PLA nanofibrous scaffolds promoted neurite extension parallel upregulated gene expression of smooth muscle myosin heavy chain
to fibers, as well as aligned Schwann attachment and cell growth [57]. compared to cells on flat films, though there was no difference in ex-
This investigation clearly demonstrated the importance of fiber align- pression of smoothelin or myoCD genes [64]. Subcutaneous implanta-
ment by showing that the presence of transverse fibers had the ability tion of scaffolds into nude mice 24 h after cell seeding revealed
to divert or even stop neurite extension [57]. significant deposition of collagen into the pores of the scaffold and
Recent research on PLA nanofibrous nerve conduits has focused on maintenance of human primary aortic smooth muscle cells within the
the optimization of fiber design and surface topography for cell survival, scaffold 2 weeks post-implantation [64]. The PLA nanofibrous scaffold
proliferation, and/or differentiation (see Table 2). Though some results used in this study supported the growth of contractile cells and also con-
have indicated that the incorporation of microchannels or microgrooves firmed integration into the host tissue [64]. Moreover, the use of a com-
to the surface of conduits can improve vascularity [58], the final utility of posite scaffold of PLA/gelatin with aligned fibers demonstrated that cells
on aligned fibers oriented and elongated with the direction of the fibers,
and the presence of gelatin caused an increase in human umbilical vein
Table 2 endothelial cell and smooth muscle cell attachment, likely due to the
PLA scaffolds for nervous tissue engineering.
presence of adhesion sites normally absent on PLA alone [65]. Conduits
Scaffold type Application Reference for vascular tissue engineering are often limited by the tendency for the
Multilayer microbraided PLA Subcutaneous implantation in a rat [50] lumen to clot, especially in small diameter vessels, preventing blood
suture conduit flow from occurring. However, small diameter PLA nanofibrous con-
Multichannel nanofibrous PLLA In vitro cytocompatibility of [51] duits have been shown to remain patent after 12 months of implanta-
conduit neuroblasts and fibroblasts tion in the infrarenal aorta of a mouse [66]. In addition, histological
Peptide-functionalized PLLA In vitro differentiation of mouse [55]
nanofibrous scaffold embryonic stem cells
and polymerase chain reaction analyses supported the presence of
Drug-releasing coaxial In vitro neuronal stem cell [56] smooth muscle cells, collagen I and III, matrix metalloproteinases-2
electrospun PLLA/gelatin differentiation and controlled [24] and -9, and a macrophage marker, indicating that the conduit was
composite nanofibrous scaffold release of neurogenic drugs undergoing remodeling [66].
Growth-factor-releasing coaxial In vitro release of nerve growth
Much of the recent work utilizing PLA nanofibrous scaffolds for car-
electrospun PLA/silk fibroin factor and PC12 neuronal stem
composite nanofibrous scaffold cell differentiation and neurite diovascular tissue engineering has focused on characterizing scaffolds
extension and introducing porosity to improve mass transport of nutrients, meta-
Aligned PLLA nanofibrous scaffold In vitro culture of dorsal root [57] bolic wastes, and degradation products (see Table 3). In vitro work has
ganglion cells and Schwann cells; shown that these scaffolds can support the proliferation of cells contrib-
neurite formation and extension
uting to vessel development and growth, and in vivo implantation in
210 M. Santoro et al. / Advanced Drug Delivery Reviews 107 (2016) 206–212
Table 3 between the uniaxial collagen and PLA release profiles, indicating that
PLA scaffolds for cardiovascular tissue engineering. gentamicin was not completely entrapped within the collagen core and
Scaffold type Application Reference some drug remained adsorbed to the surface of the PLA [31]. When all
Nanofibrous PLA patch via rotary Seeding with neonatal rat [62]
three gentamicin-releasing constructs were cultured with MG-63 osteo-
jet-spinning ventricular cardiomyocytes as blasts, no difference in cell viability was noted in comparison to a con-
cardiac patch precursor struct of PLA without gentamicin [31]. Other antibiotics have been
Nanofibrous and microfibrous In vitro culture of fibroblasts and [63] incorporated into PLA or PLA composite nanofibrous cutaneous wound
bilayered electrospun PLA/silk endothelial cells; in vivo testing in a
dressings, such as mupirocin [72] and tetracycline [73]. In addition to
fibroin/gelatin scaffold rat subcutaneous model
Nanofibrous tubular scaffold via In vitro culture with human aortic [64] conventional antibiotics, the antimicrobial peptide bacteriocin has been
phase separation in sugar smooth muscle cells; subsequent incorporated into blends of PDLLA and poly(ethylene oxide) (PEO) in
template in vivo subcutaneous implantation an attempt to offer an alternative solution to antibiotic-resistance [74].
in nude mice As expected, cumulative drug release increased as the ratio of PEO:PDLLA
Nanofibrous tubular scaffold of In vitro culture with human [65]
PLLA/gelatin aligned fibers umbilical cord-derived endothelial
increased, and bacteriocin maintained the majority of its antimicrobial
cells and smooth muscle cells activity [74]. The antimicrobial peptide nisin has also been electrospun
Nanofibrous PLA conduit Infrarenal aortic graft [66] into a nanofibrous PEO:PDLLA (50:50) wound dressing and tested
implantation in nude mice against a full-thickness wound infected with Staphylococcus aureus in a
mouse model [75]. Drug-eluting nanofibrous wound dressing signifi-
cantly reduced the bacterial burden present in the wound, but did not
subcutaneous pockets has demonstrated biocompatibility. However, appear to improve wound healing compared to non-loaded nanofibrous
PLA nanofibrous scaffolds will require additional functional testing in wound dressing [75]. While the ideal cutaneous wound dressing would
animal models before any clinical translation. prevent and/or treat infection in conjunction with improving healing,
resolution of infection is a minimum requirement for any further thera-
5. PLA scaffolds for cutaneous tissue engineering pies to succeed and thus this type of therapy remains useful for cutane-
ous wound healing. PLA nanofibrous wound dressings have also been
The healing of cutaneous wounds is of immense importance to every doped with silver microparticles and nanoparticles to evaluate the com-
field, especially tissue engineering. As the body's primary protection posite mesh as an antibacterial wound dressing [76]. When evaluated in
against the outside environment, failure of the skin barrier leads to a a 3-dimensional co-culture of keratinocytes and S. aureus, silver was
host of issues with infection, hydration, and thermoregulation. PLA shown to decrease both S. aureus and keratinocyte proliferation [76]. In-
nanofibrous mats are particularly well suited to address cutaneous terestingly, the cell-seeded wound dressings inhibited bacterial growth
healing. Nanofibrous meshes mimic the native topography of the der-
mal bed and assist in protecting the wound bed, preventing loss of mois-
ture and proteins, and removal of exudate [67]. The large surface area- Table 4
PLA scaffolds for cutaneous tissue engineering.
to-volume ratio of nanofibrous meshes also encourages the attachment
and proliferation of cells, promoting the closure of large wounds. Infor- Scaffold type Application Reference
mative reviews of skin anatomy and the use of scaffolds for skin tissue Drug-loaded electrospun In vitro drug delivery of wound- [68]
engineering can be found in the literature [67]. nanofibrous PLLA mesh healing agents alkannin and
In the area of skin regeneration, PLA is particularly useful because shikonin
nanofibrous mats can be leveraged as drug delivery vehicles as well as Drug-loaded electrospun In vitro cytotoxicity of [69]
nanofibrous PLA patch wound-healing agent curcumin on
providing a hydrophobic barrier against water loss and the environ- mouse myoblasts; in vivo
ment. Electrospun PLA has been used to entrap and deliver drugs that implantation in a full-thickness
promote wound healing, especially anti-inflammatory and anti- skin defect in mice
oxidant molecules, and to facilitate non-viral nucleic acid delivery. Drug-loaded electrospun In vitro cytotoxicity test of ibuprofen [70]
nanofibrous PLA scaffold on human dermal keratinocytes
Drugs such as alkannin, shikonin, curcumin, and ibuprofen have been
and fibroblasts; in vivo implantation
loaded into electrospun PLA scaffolds to promote cutaneous wound in a full-thickness mouse skin
healing [68–70]. It has been shown that curcumin, a plant extract with incision model
anti-inflammatory, anti-oxidant, and wound healing properties, loaded Electrospun nanofibrous PLA In vitro plasmid deliver and [77]
into PLA nanofibrous meshes increased the rate of healing of a cutaneous scaffold coated with transfection of 3 T3 cells; in vivo
plasmid/poly(ethylenimine) wound healing repair in a mouse
wound in mice compared to either PLA meshes alone or no treatment dorsal full thickness defect
[69]. Similarly, ibuprofen-loaded PLA nanofibrous scaffolds support the Drug-loaded uniaxial PLA, uniaxial In vitro release of gentamicin, [31]
attachment and proliferation of human epidermal keratinocytes and collagen, and coaxial collagen susceptibility testing against
human dermal fibroblasts [70]. It was also demonstrated in an in vivo core/PLA sheath electrospun pathogenic bacteria, and culture
nanofiber wound dressing with MG-63 osteoblasts
full-thickness mouse skin incision model that cell-seeded ibuprofen-
Drug-loaded PLA/PEO blend In vitro release of antimicrobial [74]
loaded PLA bandages rescued wound contracture and increased blood nanofibrous wound dressing peptide bacteriocin and
vessel formation compared to acellular ibuprofen-loaded PLA bandages susceptibility testing against
[70]. pathogenic bacteria
PLA nanofibrous scaffolds are ideally suited for local drug delivery to Drug-loaded PLA/PEO blend In vitro testing of antimicrobial [75]
nanofibrous wound dressing peptide nisin against S. aureus and
infected cutaneous wounds due to their ability to load a variety of anti- in vivo evaluation of nanofibrous
bacterial drugs [71]. Although uniaxial loading of antibiotics was popular wound dressing in an infected
in the past, this strategy has been replaced by more sophisticated full-thickness murine cutaneous
methods to gain increased control over release kinetics [71]. For exam- wound
Electrospun nanofibrous PLA In vitro drug delivery of silver in [76]
ple, in a study comparing the release of gentamicin from uniaxial PLA
wound dressing doped with human dermal keratinocyte culture
nanofibers, uniaxial collagen nanofibers, or coaxial nanofibers with a col- silver nano/microparticles and antimicrobial effect on S. aureus
lagen core and a PLA sheath, it was found that collagen fibers release all Drug-loaded electrospun PLA In vivo delivery of anti-scarring [78]
drug in a burst fashion, while PLA fibers released surface adsorbed drug nano/microfiber wound dressing agent 20(R)-ginsenoside Rg3 in a
as a burst but then retained drug within the polymer matrix [31]. The co- rabbit ear model of hypertrophic
scarring
axial spun nanofibrous scaffolds showed an intermediate release profile
M. Santoro et al. / Advanced Drug Delivery Reviews 107 (2016) 206–212 211
as much as the presence of silver particles, indicating that a scaffold that [4] M.S. Lopes, A.L. Jardini, R.M. Filho, Poly (lactic acid) production for tissue engineer-
ing applications, Procedia Eng. 42 (2012) 1402–1413.
is more conducive to cell growth will be more resistant to S. aureus infec- [5] A.J. Lasprilla, G.A. Martinez, B.H. Lunelli, A.L. Jardini, R.M. Filho, Poly-lactic acid
tion [76]. synthesis for application in biomedical devices—a review, Biotechnol. Adv. 30
In addition to traditional drug delivery, non-viral delivery of (2012) 321–328.
[6] S.T. Lovald, T. Khraishi, J. Wagner, B. Baack, Mechanical design optimization of
plasmids encoding for keratinocyte growth factor via PLA nanofibrous bioabsorbable fixation devices for bone fractures, J. Craniofac. Surg. 20 (2009)
scaffolds has been shown to improve the healing of full-thickness 389–398.
cutaneous wounds in mice [77]. Furthermore, higher levels of plasmid- [7] R. Langer, J.P. Vacanti, Tissue engineering, Science 260 (1993) 920–926.
[8] P.X. Ma, Scaffolds for tissue fabrication, Mater. Today 7 (2004) 30–40.
derived keratinocyte growth factor in the wound area correlated to
[9] D.M. Bigg, Polylactide copolymers: effect of copolymer ratio and end capping on
more mature skin tissue with less inflammation and decreased unhealed their properties, Adv. Polym. Technol. 24 (2005) 69–82.
epithelial wound size [77]. [10] B.D. Ratner, Biomaterials Science: An Introduction to Materials in Medicine, third ed.
Elsevier/Academic Press, Amsterdam; Boston, 2013.
While most applications of cutaneous scaffolds are concerned with
[11] Q.P. Pham, U. Sharma, A.G. Mikos, Electrospinning of polymeric nanofibers for tissue
the attachment and growth of cells, their use in hypertrophic scarring engineering applications: a review, Tissue Eng. 12 (2006) 1197–1211.
is more nuanced, requiring modulation of the appropriate balance of [12] Q.P. Pham, U. Sharma, A.G. Mikos, Electrospun poly(epsilon-caprolactone) microfi-
cells, inflammation, and extracellular matrix since hypertrophic ber and multilayer nanofiber/microfiber scaffolds: characterization of scaffolds and
measurement of cellular infiltration, Biomacromolecules 7 (2006) 2796–2805.
scarring is a disorder of dermal fibroproliferation [78]. PLA fibrous [13] J.H. Zhao, W.Q. Han, M. Tu, S.W. Huan, R. Zeng, H. Wu, Z.G. Cha, C.R. Zhou, Prepara-
mats with nano- and micro-fibers can be leveraged to deliver the drug tion and properties of biomimetic porous nanofibrous poly(l-lactide) scaffold
ginsenoside-Rg3 over 3 months and have been shown to reduce the with chitosan nanofiber network by a dual thermally induced phase separation
technique, Mater. Sci. Eng., C Mater. 32 (2012) 1496–1502.
formation of hypertrophic scars in rabbits [78]. [14] J.D. Shao, C. Chen, Y.J. Wang, X.F. Chen, C. Du, Early stage evolution of structure and
PLA nanofibrous mats serve many roles in the healing of cutaneous nanoscale property of nanofibers in thermally induced phase separation process,
wounds, including occlusive dressings, mechanical scaffolds, anti- React. Funct. Polym. 72 (2012) 765–772.
[15] H.S. Yoo, T.G. Kim, T.G. Park, Surface-functionalized electrospun nanofibers for tissue
infective devices, and drug delivery vehicles (see Table 4). Research in engineering and drug delivery, Adv. Drug Deliv. Rev. 61 (2009) 1033–1042.
this area has focused primarily on drug delivery, with results indicating [16] S. Lee, G. Jin, J.H. Jang, Electrospun nanofibers as versatile interfaces for efficient gene
that PLA nanofibrous scaffolds promote cell attachment and skin regen- delivery, J. Biol. Eng. 8 (2014).
[17] S.F. Chou, D. Carson, K.A. Woodrow, Current strategies for sustaining drug release
eration without significant inflammation. In addition, cutaneous appli- from electrospun nanofibers, J. Control. Release 220 (2015) 584–591.
cations offer additional opportunities to address disorders beyond the [18] M. Zamani, M.P. Prabhakaran, S. Ramakrishna, Advances in drug delivery via
classic “critical size defect,” including infection and disorders of normal electrospun and electrosprayed nanomaterials, Int. J. Nanomedicine 8 (2013)
2997–3017.
healing such as hypertrophic scarring.
[19] J. Zeng, L. Yang, Q. Liang, X. Zhang, H. Guan, X. Xu, X. Chen, X. Jing, Influence of the
drug compatibility with polymer solution on the release kinetics of electrospun fiber
6. Conclusions formulation, J. Control. Release 105 (2005) 43–51.
[20] I.C. Liao, S. Chen, J.B. Liu, K.W. Leong, Sustained viral gene delivery through core-
shell fibers, J. Control. Release 139 (2009) 48–55.
PLA nanofibrous scaffolds have shown themselves to be a versatile [21] A. Saraf, G. Lozier, A. Haesslein, F.K. Kasper, R.M. Raphael, L.S. Baggett, A.G. Mikos,
tool for tissue engineering, as a 3-dimensional topographical surface Fabrication of nonwoven coaxial fiber meshes by electrospinning, Tissue Eng. Part
C Methods 15 (2009) 333–344.
for cell attachment, a depot for drug delivery, and a substrate for [22] T.T.T. Nguyen, O.H. Chung, J.S. Park, Coaxial electrospun poly(lactic acid)/chitosan
bio-functionalization. Electrospinning and thermally induced phase (core/shell) composite nanofibers and their antibacterial activity, Carbohydr.
separation are widely used techniques for the production of Polym. 86 (2011) 1799–1806.
[23] T.T. Nguyen, C. Ghosh, S.G. Hwang, N. Chanunpanich, J.S. Park, Porous core/sheath
nanofibrous scaffolds, and recent refinements upon these processes composite nanofibers fabricated by coaxial electrospinning as a potential mat for
have enabled the creation of designer scaffolds addressing the needs drug release system, Int. J. Pharm. 439 (2012) 296–306.
of specific tissues, such as having fiber alignment and incorporating of [24] L.L. Tian, M.P. Prabhakaran, J. Hu, M.L. Chen, F. Besenbacher, S. Ramakrishna, Coaxial
electrospun poly(lactic acid)/silk fibroin nanofibers incorporated with nerve growth
bioactive molecules. While many PLA nanofibrous scaffolds have been
factor support the differentiation of neuronal stem cells, RSC Adv. 5 (2015)
characterized and evaluated in vitro, translation of these scaffolds into 49838–49848.
human use will require more testing in appropriate animal models. [25] S. Maretschek, A. Greiner, T. Kissel, Electrospun biodegradable nanofiber nonwovens
for controlled release of proteins, J. Control. Release 127 (2008) 180–187.
The future of PLA likely lies in its combination with other biomaterials
[26] S. Sakai, Y. Yamada, T. Yamaguchi, T. Ciach, K. Kawakami, Surface immobilization of
in order to leverage its strengths and mitigate its weaknesses, a potent poly(ethyleneimine) and plasmid DNA on electrospun poly(L-lactic acid) fibrous
strategy for the engineering of complex tissues. mats using a layer-by-layer approach for gene delivery, J. Biomed. Mater. Res. A
88a (2009) 281–287.
[27] A.P.S. Immich, M.L. Arias, N. Carreras, R.L. Boemo, J.A. Tornero, Drug delivery
Acknowledgments systems using sandwich configurations of electrospun poly(lactic acid) nano-
fiber membranes and ibuprofen, Mater. Sci. Eng., C Mater. 33 (2013)
4002–4008.
We acknowledge support by the National Institutes of Health (R01 [28] V. Pillay, C. Dott, Y.E. Choonara, C. Tyagi, L. Tomar, P. Kumar, L.C. du Toit, V.M.K.
CA180279) and the Army, Navy, NIH, Air Force, VA and Health Affairs Ndesendo, A review of the effect of processing variables on the fabrication of
for the support of the AFIRM II effort, under Award No. W81XWH-14- electrospun nanofibers for drug delivery applications, J. Nanomater. (2013).
[29] T.T.N. Thuy, C. Ghosh, S.G. Hwang, N. Chanunpanich, J.S. Park, Porous core/sheath
2-0004. Opinions, interpretations, conclusions and recommendations composite nanofibers fabricated by coaxial electrospinning as a potential mat for
are those of the author and are not necessarily endorsed by the drug release system, Int. J. Pharm. 439 (2012) 296–306.
Department of Defense. We would like to thank Emma Watson for her [30] C.L. He, Z.M. Huang, X.J. Han, L. Liu, H.S. Zhang, L.S. Chen, Coaxial electrospun poly(L-
lactic acid) ultrafine fibers for sustained drug delivery, J. Macromol. Sci. B 45 (2006)
assistance in editing. Sarita R. Shah acknowledges the Baylor College
515–524.
of Medicine Medical Scientist Training Program and received support [31] S. Torres-Giner, A. Martinez-Abad, J.V. Gimeno-Alcaniz, M.J. Ocio, J.M. Lagaron,
from a Ruth L. Kirschstein Fellowship from the National Institute of Controlled delivery of gentamicin antibiotic from bioactive electrospun polylactide-
Arthritis and Musculoskeletal and Skin Diseases (F30 AR067606). based ultrathin fibers, Adv. Eng. Mater. 14 (2012) B112–B122.
[32] Z. Bengali, A.K. Pannier, T. Segura, B.C. Anderson, J.H. Jang, T.A. Mustoe, L.D. Shea,
Gene delivery through cell culture substrate adsorbed DNA complexes, Biotechnol.
References Bioeng. 90 (2005) 290–302.
[33] D. Puppi, F. Chiellini, A.M. Piras, E. Chiellini, Polymeric materials for bone and
[1] R.P. Lanza, R.S. Langer, J. Vacanti, Principles of Tissue Engineering, third ed. Elsevier/ cartilage repair, Prog. Polym. Sci. 35 (2010) 403–440.
Academic Press, Amsterdam; Boston, 2007. [34] J.C. Wei, P. Guo-Wang, Q. Han, J.X. Ding, X.S. Chen, Preparation of antibacterial silver
[2] L. Lu, A.G. Mikos, Poly(lactic acid), in: J.E. Mark (Ed.), Polymer Data Handbook, nanoparticle-coated PLLA grafted hydroxyapatite/PLLA composite electrospun fiber,
second ed.Oxford University Press, New York 2009, pp. 794–800. J. Control. Release 213 (2015) E62–E63.
[3] M. Jamshidian, E.A. Tehrany, M. Imran, M. Jacquot, S. Desobry, Poly-lactic acid: [35] K.A. Athanasiou, G.G. Niederauer, C.M. Agrawal, Sterilization, toxicity, biocompatibility
production, applications, nanocomposites, and release studies, Compr. Rev. Food and clinical applications of polylactic acid polyglycolic acid copolymers, Biomaterials
Sci. Food Saf. 9 (2010) 552–571. 17 (1996) 93–102.
212 M. Santoro et al. / Advanced Drug Delivery Reviews 107 (2016) 206–212
[36] W.J.E.M. Habraken, J.G.C. Wolke, J.A. Jansen, Ceramic composites as matrices and scaf- [59] J.T. Butcher, G.J. Mahler, L.A. Hockaday, Aortic valve disease and treatment: the need
folds for drug delivery in tissue engineering, Adv. Drug Deliv. Rev. 59 (2007) 234–248. for naturally engineered solutions, Adv. Drug Deliv. Rev. 63 (2011) 242–268.
[37] A.R. Amini, C.T. Laurencin, S.P. Nukavarapu, Bone tissue engineering: recent [60] A. Hasan, A. Memic, N. Annabi, M. Hossain, A. Paul, M.R. Dokmeci, F. Dehghani, A.
advances and challenges, Crit. Rev. Biomed. Eng. 40 (2012) 363–408. Khademhosseini, Electrospun scaffolds for tissue engineering of vascular grafts,
[38] J.M. Holzwarth, P.X. Ma, Biomimetic nanofibrous scaffolds for bone tissue engineer- Acta Biomater. 10 (2014) 11–25.
ing, Biomaterials 32 (2011) 9622–9629. [61] T. Eschenhagen, A. Eder, I. Vollert, A. Hansen, Physiological aspects of cardiac tissue
[39] R.A. Pérez, J.-E. Won, J.C. Knowles, H.-W. Kim, Naturally and synthetic smart engineering, Am. J. Physiol. Heart Circ. Physiol. 303 (2012) H133–H143.
composite biomaterials for tissue regeneration, Adv. Drug Deliv. Rev. 65 (2013) [62] M.R. Badrossamay, H.A. McIlwee, J.A. Goss, K.K. Parker, Nanofiber assembly by rotary
471–496. jet-spinning, Nano Lett. 10 (2010) 2257–2261.
[40] Q.W. Zhang, V.N. Mochalin, I. Neitzel, K. Hazeli, J.J. Niu, A. Kontsos, J.G. Zhou, P.I. [63] S. Wang, Y. Zhang, H. Wang, G. Yin, Z. Dong, Fabrication and properties of
Lelkes, Y. Gogotsi, Mechanical properties and biomineralization of multifunctional the electrospun polylactide/silk fibroin–gelatin composite tubular scaffold,
nanodiamond-PLLA composites for bone tissue engineering, Biomaterials 33 Biomacromolecules 10 (2009) 2240–2244.
(2012) 5067–5075. [64] J. Hu, X. Sun, H. Ma, C. Xie, Y.E. Chen, P.X. Ma, Porous nanofibrous PLLA scaffolds for
[41] T. Lou, X.J. Wang, G.J. Song, Z. Gu, Z. Yang, Fabrication of PLLA/beta-TCP nanocom- vascular tissue engineering, Biomaterials 31 (2010) 7971–7977.
posite scaffolds with hierarchical porosity for bone tissue engineering, Int. J. Biol. [65] K.T. Shalumon, S. Deepthi, M.S. Anupama, S.V. Nair, R. Jayakumar, K.P. Chennazhi,
Macromol. 69 (2014) 464–470. Fabrication of poly (L-lactic acid)/gelatin composite tubular scaffolds for vascular
[42] Z. Fang, Q.L. Feng, Improved mechanical properties of hydroxyapatite whisker- tissue engineering, Int. J. Biol. Macromol. 72 (2015) 1048–1055.
reinforced poly(L-lactic acid) scaffold by surface modification of hydroxyapatite, [66] H. Kurobe, M.W. Maxfield, S. Tara, K.A. Rocco, P.S. Bagi, T. Yi, B. Udelsman, Z.W.
Mat. Sci. Eng. C Mater. 35 (2014) 190–194. Zhuang, M. Cleary, Y. Iwakiri, C.K. Breuer, T. Shinoka, Development of small diame-
[43] B.J. Papenburg, L.A.M. Bolhuis-Versteeg, D.W. Grijpma, J. Feijen, M. Wessling, D. ter nanofiber tissue engineered arterial grafts, PLoS One 10 (2015), e0120328.
Stamatialis, A facile method to fabricate poly(L-lactide) nano-fibrous morphologies [67] D. Sundaramurthi, U.M. Krishnan, S. Sethuraman, Electrospun nanofibers as
by phase inversion, Acta Biomater. 6 (2010) 2477–2483. scaffolds for skin tissue engineering, Polym. Rev. 54 (2014) 348–376.
[44] D.C. Surrao, S.D. Waldman, B.G. Amsden, Biomimetic poly(lactide) based fibrous [68] K.N. Kontogiannopoulos, A.N. Assimopoulou, I. Tsivintzelis, C. Panayiotou, V.P.
scaffolds for ligament tissue engineering, Acta Biomater. 8 (2012) 3997–4006. Papageorgiou, Electrospun fiber mats containing shikonin and derivatives with
[45] V. Mourino, J.P. Cattalini, J.A. Roether, P. Dubey, I. Roy, A.R. Boccaccini, Composite potential biomedical applications, Int. J. Pharm. 409 (2011) 216–228.
polymer-bioceramic scaffolds with drug delivery capability for bone tissue [69] T.T.T. Nguyen, C. Ghosh, S.G. Hwang, L.D. Tran, J.S. Park, Characteristics of curcumin-
engineering, Expert Opin. Drug Deliv. 10 (2013) 1353–1365. loaded poly (lactic acid) nanofibers for wound healing, J. Mater. Sci. 48 (2013)
[46] J.M. Raquez, Y. Habibi, M. Murariu, P. Dubois, Polylactide (PLA)-based nanocompos- 7125–7133.
ites, Prog. Polym. Sci. 38 (2013) 1504–1542. [70] M. Mohiti-Asli, S. Saha, S.V. Murphy, H. Gracz, B. Pourdeyhimi, A. Atala, E.G. Loboa,
[47] J. Ren, Biodegradable poly(lactic acid): synthesis, modification, processing and appli- Ibuprofen loaded PLA nanofibrous scaffolds increase proliferation of human skin
cations, Tsinghua University Press; Springer, Beijing; Heidelberg; New York, 2010. cells in vitro and promote healing of full thickness incision wounds in vivo, J.
[48] X. Gu, F. Ding, Y. Yang, J. Liu, Construction of tissue engineered nerve grafts and their Biomed. Mater. Res. B Appl. Biomater. (2015).
application in peripheral nerve regeneration, Prog. Neurobiol. 93 (2011) 204–230. [71] Y. Gao, Y.B. Truong, Y.G. Zhu, I.L. Kyratzis, Electrospun antibacterial nanofibers: pro-
[49] V. Chiono, C. Tonda-Turo, Trends in the design of nerve guidance channels in periph- duction, activity, and in vivo applications, J. Appl. Polym. Sci. 131 (2014).
eral nerve tissue engineering, Prog. Neurobiol. 131 (2015) 87–104. [72] R.A. Thakur, C.A. Florek, J. Kohn, B.B. Michniak, Electrospun nanofibrous polymeric
[50] M.C. Lu, Y.T. Huang, J.H. Lin, C.H. Yao, C.W. Lou, C.C. Tsai, Y.S. Chen, Evaluation of a scaffold with targeted drug release profiles for potential application as wound
multi-layer microbraided polylactic acid fiber-reinforced conduit for peripheral dressing, Int. J. Pharm. 364 (2008) 87–93.
nerve regeneration, J. Mater. Sci. Mater. Med. 20 (2009) 1175–1180. [73] P. Zahedi, Z. Karami, I. Rezaeian, S.H. Jafari, P. Mahdaviani, A.H. Abdolghaffari, M.
[51] C. Sun, X. Jin, J.M. Holzwarth, X. Liu, J. Hu, M.J. Gupte, Y. Zhao, P.X. Ma, Development Abdollahi, Preparation and performance evaluation of tetracycline hydrochloride
of channeled nanofibrous scaffolds for oriented tissue engineering, Macromol. loaded wound dressing mats based on electrospun nanofibrous poly(lactic acid)/
Biosci. 12 (2012) 761–769. poly(?-caprolactone) blends, J. Appl. Polym. Sci. 124 (2012) 4174–4183.
[52] C.Y. Zhao, A. Tan, G. Pastorin, H.K. Ho, Nanomaterial scaffolds for stem cell prolifer- [74] T. Heunis, O. Bshena, B. Klumperman, L. Dicks, Release of bacteriocins from nanofi-
ation and differentiation in tissue engineering, Biotechnol. Adv. 31 (2013) 654–668. bers prepared with combinations of poly(D,L-lactide) (PDLLA) and poly(ethylene
[53] W.J. Li, R.L. Mauck, R.S. Tuan, Electrospun nanofibrous scaffolds: production, charac- oxide) (PEO), Int. J. Mol. Sci. 12 (2011) 2158–2173.
terization, and applications for tissue engineering and drug delivery, J. Biomed. [75] T.D.J. Heunis, C. Smith, L.M.T. Dicks, Evaluation of a nisin-eluting nanofiber scaffold
Nanotechnol. 1 (2005) 259–275. to treat Staphylococcus aureus-induced skin infections in mice, Antimicrob. Agents
[54] R.L. Dahlin, F.K. Kasper, A.G. Mikos, Polymeric nanofibers in tissue engineering, Chemother. 57 (2013) 3928–3935.
Tissue Eng. Part B Rev. 17 (2011) 349–364. [76] M. Mohiti-Asli, B. Pourdeyhimi, E.G. Loboa, Skin tissue engineering for the infected
[55] L.A. Callahan, S. Xie, I.A. Barker, J. Zheng, D.H. Reneker, A.P. Dove, M.L. Becker, Direct- wound site: biodegradable PLA nanofibers and a novel approach for silver ion re-
ed differentiation and neurite extension of mouse embryonic stem cell on aligned lease evaluated in a 3D coculture system of keratinocytes and Staphylococcus aureus,
poly(lactide) nanofibers functionalized with YIGSR peptide, Biomaterials 34 Tissue Eng. Part C Methods 20 (2014) 790–797.
(2013) 9089–9095. [77] S. Kobsa, N.J. Kristofik, A.J. Sawyer, A.L. Bothwell, T.R. Kyriakides, W.M. Saltzman, An
[56] L. Binan, C. Tendey, G. De Crescenzo, R. El Ayoubi, A. Ajji, M. Jolicoeur, Differentiation electrospun scaffold integrating nucleic acid delivery for treatment of full-thickness
of neuronal stem cells into motor neurons using electrospun poly-L-lactic acid/ wounds, Biomaterials 34 (2013) 3891–3901.
gelatin scaffold, Biomaterials 35 (2014) 664–674. [78] L. Cheng, X. Sun, C. Hu, R. Jin, B. Sun, Y. Shi, L. Zhang, W. Cui, Y. Zhang, In vivo inhi-
[57] H.B. Wang, M.E. Mullins, J.M. Cregg, A. Hurtado, M. Oudega, M.T. Trombley, R.J. bition of hypertrophic scars by implantable ginsenoside-Rg3-loaded electrospun
Gilbert, Creation of highly aligned electrospun poly-L-lactic acid fibers for nerve fibrous membranes, Acta Biomater. 9 (2013) 9461–9473.
regeneration applications, J. Neural Eng. 6 (2009) 016001.
[58] S.H. Hsu, H.C. Ni, Fabrication of the microgrooved/microporous polylactide sub-
strates as peripheral nerve conduits and in vivo evaluation, Tissue Eng. A 15
(2009) 1381–1390.