ADR-12976; No of Pages 7

Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

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

1Q1 Poly(lactic acid) nanofibrous scaffolds for tissue engineering☆

2Q2 Marco Santoro a,1, Sarita R. Shah b,1, Jennifer L. Walker b, Antonios G. Mikos a,b,⁎

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3Q3 a
Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005, United States
4Q4 b
Department of Bioengineering, Rice University, Houston, TX 77030, United States

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6 a r t i c l e i n f o a b s t r a c t

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7 Article history: Poly(lactic acid) (PLA) is a synthetic polyester that has shown extensive utility in tissue engineering. Synthesized 17
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Received 31 December 2015 either by ring opening polymerization or polycondensation, PLA hydrolytically degrades into lactic acid, a meta- 18
9 Received in revised form 29 February 2016 bolic byproduct, making it suitable for medical applications. Specifically, PLA nanofibers have widened the pos- 19
10 Accepted 18 April 2016
sible uses of PLA scaffolds for regenerative medicine and drug delivery applications. The use of nanofibrous 20
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Available online xxxx
scaffolds imparts a host of desirable properties, including high surface area, biomimicry of native extracellular 21
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28 Keywords:
matrix architecture, and tuning of mechanical properties, all of which are important facets of designing scaffolds 22
29 PLA for a particular organ system. Additionally, nanofibrous PLA scaffolds hold great promise as drug delivery carriers, 23
30 where fabrication parameters and drug-PLA compatibility greatly affect the drug release kinetics. In this review, 24
31
Scaffolds
Nanofibers
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we present the latest advances in the use of PLA nanofibrous scaffolds for musculoskeletal, nervous, cardiovascu- 25
32 Tissue engineering lar, and cutaneous tissue engineering and offer perspectives on their future use. 26
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Drug delivery © 2016 Published by Elsevier B.V. 27
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38 Contents
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40 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
41 2. PLA scaffolds for musculoskeletal tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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42 3. PLA scaffolds for nervous tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

43 4. PLA scaffolds for cardiovascular tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
44 5. PLA scaffolds for cutaneous tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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45 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
46 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
47 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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49 1. Introduction other polyesters, PLA degrades by non-enzymatic hydrolysis, and its 54

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byproducts are eliminated through normal cell metabolism [5]. 55

50 Poly(lactic acid) (PLA) is one of the most widely used synthetic The cytocompatibility and biodegradability of PLA make it an ideal 56
51 polymers in the biomedical field [1,2]. First synthesized by Carothers candidate for implantable devices [5,6]. (See Tables 1–4.) 57
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52 in 1932, PLA is produced from polycondensation of lactic acid or by The regulation of PLA-based devices by the Food and Drug Adminis- 58
53 ring opening polymerization of the cyclic dimer lactide [3,4]. Like tration has raised further interest in the use of PLA in the field of tissue 59
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engineering. Tissue engineering aims to restore, sustain, or improve tis- 60

Abbreviations: ACL, anterior cruciate ligament; β-TCP, β-tricalcium phosphate; BMP-2, sue function through the combination of three components: scaffolds, 61
bone morphogenetic protein-2; HA, hydroxyapatite; PLA, poly(lactic acid) (if the stereo- bioactive molecules, and/or cells [7]. Although not all tissue engineering 62
regularity is not specified); PDLA, poly(D-lactic acid); PLLA, poly(L-lactic acid); PDLLA,
approaches involve the use of all three components, the presence of a 63
poly(D,L-lactic acid); PLDLA, poly(L-co-D,L-lactic acid); TIPS, thermally induced phase sep-
aration; PEO, poly(ethylene oxide). biocompatible scaffold is essential to provide the architectural cues 64
☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “PLA biode- crucial for the regeneration of large defects [8]. PLA has been widely 65
gradable polymers”. employed to fulfill this requirement, not only for its intrinsic 66
⁎ Corresponding author at: Department of Bioengineering, MS-142, BioScience cytocompatibility and biodegradability, but also because the chirality of 67
Research Collaborative, Rice University, 6500 Main Street, Houston, TX 77030, United
lactic acid (L- and D-lactic acid) can be leveraged to synthesize PLA 68
States. Tel.: +713 348 5355; fax: +713 348 4244.
E-mail address: mikos@rice.edu (A.G. Mikos). with different stereoregularities. Stereoregularity influences the physico- 69
1
These authors contributed equally to this work. chemical properties of the material, such as mechanical and thermal 70

http://dx.doi.org/10.1016/j.addr.2016.04.019
0169-409X/© 2016 Published by Elsevier B.V.

Please cite this article as: M. Santoro, et al., Poly(lactic acid) nanofibrous scaffolds for tissue engineering, Adv. Drug Deliv. Rev. (2016), http://
dx.doi.org/10.1016/j.addr.2016.04.019
 2 M. Santoro et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

t1:1 Table 1 Table 3 t3:1

t1:2 PLA scaffolds for musculoskeletal tissue engineering. PLA scaffolds for cardiovascular tissue engineering. t3:2

t1:3 Scaffold type Application Reference Scaffold type Application Reference t3:3

t1:4 Cylindrical composite of In vitro culture with mesenchymal [13] Nanofibrous PLA patch via rotary Seeding with neonatal rat [62] t3:4
t1:5 PLLA/chitosan nanofibers via TIPS stem cells for bone repair jet-spinning ventricular cardiomyocytes as
t1:6 PLLA/β-TCP nanocomposite disk Scaffold with hierarchical porosity [41] cardiac patch precursor
t1:7 via TIPS and salt leaching for bone ingrowth Nanofibrous and microfibrous In vitro culture of fibroblasts and [63] t3:5
t1:8 PLLA/silanized HA nanocomposite Scaffold with improved [42] bilayered electrospun PLA/silk endothelial cells; in vivo testing in a t3:6
t1:9 via TIPS ceramic/polymer interactions fibroin/gelatin scaffold rat subcutaneous model t3:7
t1:10 PLLA nanofibrous sheet via phase In vitro culture with mouse [43] Nanofibrous tubular scaffold via In vitro culture with human aortic [64] t3:8
t1:11 separation micromolding progenitor myoblasts phase separation in sugar smooth muscle cells; subsequent t3:9
t1:12 Thermally stressed electrospun In vitro testing of scaffold with [44] template in vivo subcutaneous implantation
t1:13 PLDLA nanofibrous sheet bovine fibroblasts for anterior in nude mice
cruciate ligament repair Nanofibrous tubular scaffold of In vitro culture with human [65] t3:10
PLLA/gelatin aligned fibers umbilical cord-derived endothelial t3:11
cells and smooth muscle cells

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Nanofibrous PLA conduit Infrarenal aortic graft [66] t3:12
71 properties and degradation characteristics [9]. These aspects are critical implantation in nude mice

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72 in many tissue engineering strategies, as scaffolds that can be engineered
73 to match the mechanical properties of the native tissue are likely to be
74 successful. Consequently, PLA has been widely used in tissue engineering Direct adsorption relies on non-covalent chemical interactions, such as 102

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75 applications, both as scaffolds and as drug delivery systems [4,9,10]. electrostatic and van der Waals interactions, between the drug and 103
76 Electrospinning and thermally induced phase separation (TIPS) are the polymer to facilitate binding of the drug to the scaffold. Drug diffu- 104
77 the most common techniques used in the recent literature for the fabri- sion from the polymer surface is facilitated due to the high porosity and 105

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78 cation of fibrous scaffolds. Electrospinning is an established technique surface area offered by the use of nanofibers, often times leading to a 106
79 used to fabricate fibrous scaffolds whose properties (such as porosity, high initial release of drug upon contact with release medium, referred 107

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80 pore size, fiber size) can be easily tuned [11]. Fabrication parameters to as “burst release.” This method is particularly desirable for drugs and 108
81 such as polymer solvent, polymer concentration, voltage, and collector gene constructs that may be sensitive to the organic solvents or high 109
82 distance can be varied to modify fiber and scaffold properties. However, voltage used in electrospinning [16].
D 110
83 varying these fabrication parameters globally influences the resulting Hydrophobic drugs that are soluble in organic solvents can be direct- 111
84 scaffold, and individual properties cannot be independently tuned. A ly mixed into solution of PLA for electrospinning with homogeneous 112
85 typical example is the increasing pore size with the increasing fiber
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86 size [11,12]. Another less common technology used to fabricate PLA
87 scaffolds is TIPS [13]. TIPS has been used for fabricating nanofibrous Table 4 t4:1
t4:2
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PLA scaffolds for cutaneous tissue engineering.

88 poly(L-lactic acid) (PLLA) scaffolds that mimic the structure of fibrillar
89 collagen while maintaining macropores that can facilitate nutrient ex- Scaffold type Application Reference t4:3
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90 change and cell migration [13]. TIPS is based on the phase separation Drug-loaded electrospun In vitro drug delivery of wound- [68] t4:4
91 of a homogeneous polymer solution into a polymer-rich and a nanofibrous PLLA mesh healing agents alkannin and t4:5
92 solvent-rich phase, typically induced by either cooling the solution or shikonin
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Drug-loaded electrospun In vitro cytotoxicity of [69] t4:6

93 adding an immiscible solvent [13,14]. Although the detailed physical
nanofibrous PLA patch wound-healing agent curcumin on t4:7
94 mechanism of TIPS is still not fully understood, during this process the mouse myoblasts; in vivo
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95 polymer crystallizes into nanofiber bundles that mimic the structure implantation in a full-thickness
96 of native ECM [14]. skin defect in mice
97 Nanofibrous PLA materials find wide applicability not only as scaf- Drug-loaded electrospun In vitro cytotoxicity test of ibuprofen [70] t4:8
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nanofibrous PLA scaffold on human dermal keratinocytes t4:9

98 folds for tissue regeneration but also as drug delivery vehicles, especially
and fibroblasts; in vivo implantation
99 when fabricated via electrospinning. The simplest method for drug in a full-thickness mouse skin
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100 loading is direct adsorption of drug to the surface of nanofibers, which incision model
101 leverages the intrinsic large surface area of nanoscale materials [15]. Electrospun nanofibrous PLA In vitro plasmid deliver and [77] t4:10
scaffold coated with transfection of 3 T3 cells; in vivo t4:11
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plasmid/poly(ethylenimine) wound healing repair in a mouse

dorsal full thickness defect
Drug-loaded uniaxial PLA, uniaxial In vitro release of gentamicin, [31] t4:12
t2:1 Table 2
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collagen, and coaxial collagen susceptibility testing against t4:13

t2:2 PLA scaffolds for nervous tissue engineering. core/PLA sheath electrospun pathogenic bacteria, and culture t4:14
nanofiber wound dressing with MG-63 osteoblasts t4:15
t2:3 Scaffold type Application Reference
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Drug-loaded PLA/PEO blend In vitro release of antimicrobial [74] t4:16

t2:4 Multilayer microbraided PLA Subcutaneous implantation in a rat [50] nanofibrous wound dressing peptide bacteriocin and t4:17
t2:5 suture conduit susceptibility testing against
t2:6 Multichannel nanofibrous PLLA In vitro cytocompatibility of [51] pathogenic bacteria
conduit neuroblasts and fibroblasts Drug-loaded PLA/PEO blend In vitro testing of antimicrobial [75] t4:18
t2:7 Peptide-functionalized PLLA In vitro differentiation of mouse [55] nanofibrous wound dressing peptide nisin against S. aureus and t4:19
t2:8 nanofibrous scaffold embryonic stem cells in vivo evaluation of nanofibrous
t2:9 Drug-releasing coaxial In vitro neuronal stem cell [56] wound dressing in an infected
t2:10 electrospun PLLA/gelatin differentiation and controlled [24] full-thickness murine cutaneous
t2:11 composite nanofibrous scaffold release of neurogenic drugs wound
t2:12 Growth-factor-releasing coaxial In vitro release of nerve growth Electrospun nanofibrous PLA In vitro drug delivery of silver in [76] t4:20
t2:13 electrospun PLA/silk fibroin factor and PC12 neuronal stem wound dressing doped with human dermal keratinocyte culture t4:21
t2:14 composite nanofibrous scaffold cell differentiation and neurite silver nano/microparticles and antimicrobial effect on S. aureus t4:22
extension Drug-loaded electrospun PLA In vivo delivery of anti-scarring [78] t4:23
t2:15 Aligned PLLA nanofibrous scaffold In vitro culture of dorsal root [57] nano/microfiber wound dressing agent 20(R)-ginsenoside Rg3 in a t4:24
ganglion cells and Schwann cells; rabbit ear model of hypertrophic
neurite formation and extension scarring

Please cite this article as: M. Santoro, et al., Poly(lactic acid) nanofibrous scaffolds for tissue engineering, Adv. Drug Deliv. Rev. (2016), http://
dx.doi.org/10.1016/j.addr.2016.04.019
 M. Santoro et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx 3

113 distribution in the fibers. Hydrophilic water-soluble drugs can be incor- relatively strong acid that can elicit an inflammatory response [1]. This 179
114 porated into PLA through water/oil emulsification, allowing for a simple effect is further exacerbated by the fact that PLA-based devices com- 180
115 and cost-effective method to electrospin drug-loaded nanofibrous scaf- monly undergo bulk erosion. As a result, the accumulation of acidic 181
116 folds with drug loading and encapsulation efficiency higher than other products within the bulk of the material accelerates its degradation, 182
117 delivery carriers, such as hydrogels and liposomes [17,18]. This method leading eventually to a sudden loss of its mechanical integrity and a 183
118 entraps drug within the polymer matrix as well as retaining some drug delayed inflammatory response [1,10]. However, PLA is still a preferred 184
119 at the polymer surface, taking advantage of the degradability of PLA and material for scaffold fabrication because of the reduced concentration of 185
120 leading in general to sustained release kinetics with an early burst. The degradation products with increased porosity. Consequently, several 186
121 release profile depends on the drug distribution within the fiber section, approaches have been proposed to mitigate the shortcomings of this 187
122 which is partly dictated by interactions between PLA and the drug of synthetic polymer including preparation of lactic acid copolymers and 188
123 choice. In particular, hydrophilic drugs may undergo phase separation PLA-based composites [33–36]. 189
124 when mixed with hydrophobic polymers like PLA, resulting in a burst In this review, we discuss advances with PLA scaffolds for tissue 190
125 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 191
126 To address this issue, coaxial electrospinning has emerged as a way to on the use of lactic acid homopolymers for the fabrication of scaffolds 192

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127 spin fibers with a core-shell morphology, where the drug is dissolved in a and drug delivery systems for tissue engineering. 193
128 compatible material in the core while the outer PLA layer determines the

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129 release kinetics and protects the drug from the surrounding environ- 2. PLA scaffolds for musculoskeletal tissue engineering 194
130 ment [20,21]. This approach, together with the more recently developed
131 emulsion electrospinning [18], is now pursued to encapsulate sensitive Musculoskeletal defects are common and can result from a variety of 195

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132 growth factors and plasmids and to minimize the interaction between etiologies, including trauma, infection, or underlying pathology. Failure 196
133 the drug and the PLA solvent that may denature the biomolecule/genetic to adequately address defects in bone, muscle, or tendon may lead to 197

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134 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. 198
135 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- 199
136 C, the hydrophobic PLA nanofibers can be blended with hydrophilic prising that PLA continues to play a central role in many musculoskele- 200

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137 nanofibers (e.g. polyethylenimine or poly(L-lysine)) to tune the tal tissue engineering strategies [37]. Scaffolds for bone tissue 201
138 wettability of the overall scaffold, resulting in increased penetration of engineering are typically fabricated with low surface area to volume 202
139 water into the mat and increasing the release of drug [25]. Another less ratio geometries, usually cylinders, which provide mechanical stability
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140 common method of drug loading includes immobilization of drug onto and an environment conducive to bone regeneration [33,38]. To this 204
141 the polymer surface through methods such as layer-by-layer deposition. end, mechanical properties and degradation kinetics of PLA-based 205
142 This strategy is particularly useful for charged entities such as negatively scaffolds can be tuned by varying the racemic mixture of lactic acids 206
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143 changed DNA for gene delivery applications, where a positively charged composing the polymer chains [10]. 207
144 macromolecule such as polyethylenimine can be used as a counter- Among the techniques used to process PLA, TIPS has been leveraged 208
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145 charge [16,26]. to fabricate PLLA scaffolds with nanoscale features [14]. Cylindrical PLLA 209
146 Release kinetics are an important consideration when designing nanofibrous scaffolds fabricated using with TIPS have demonstrated sig- 210
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147 drug-loaded scaffolds, and choice of polymer, loading method, and nificantly greater surface area than raw PLLA material, which conse- 211
148 scaffold parameters largely determine the final mechanisms of release. quently leads to higher protein adsorption but also faster degradation. 212
149 In general, there are three major mechanisms of release from electrospun This shortcoming can be mitigated by using a dual TIPS process to 213
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150 nanofiber PLA membranes: desorption, diffusion, and degradation. PLA form a chitosan network within a PLLA network. The addition of 214
151 nanofibers loaded by mixing typically exhibit an initial burst release chitosan slows the PLLA degradation kinetics and makes the resulting 215
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152 followed by a reservoir-type release [27]. The initial burst release is due scaffold more biomimetic, as shown by in vitro cell viability tests with 216
153 to desorption of drug from the outermost surface fibers, usually followed mesenchymal stem cells [13]. 217
154 by diffusion-mediated release. Using ibuprofen as a model drug, it has In an attempt to design scaffolds suitable for load-bearing applica- 218
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155 been shown that altering scaffold parameters such as spinning time can tions, a common strategy to improve PLA mechanical properties for 219
156 affect the fiber density within the membrane, consequently affecting bone applications involves the use of ceramics, rather than the more 220
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157 the penetration of water into the membrane as well as the porosity of common metal implants [39,40]. For example, TIPS and salt leaching 221
158 the membrane [27]. Membranes with lower fiber density have high have been used together to produce nanocomposite scaffolds made of 222
159 porosity and allow free penetration of water and release of drug, while PLLA and β-tricalcium phosphate (β-TCP) [41]. While the PLLA provides 223
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160 higher fiber densities have lower porosity and pack drug molecules closer macropores to facilitate in vivo neovascularization and nutrient 224
161 together, restraining drug delivery. In general, drug-loaded electrospun exchange, β-TCP nanoparticles mimic native bone microarchitecture 225
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162 PLA nanofiber mats demonstrate solution-diffusion kinetics, and time- and strengthen the resulting composite. Compressive modulus and 226
163 scale can be tuned through a variety of processing parameters, such a fab- cell viability increased in a β-TCP-dependent fashion, with little effect 227
164 rication method, drug choice and ionization state, and uniaxial/coaxial on scaffold overall porosity [41]. Similar results were found when 228
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165 electrospinning [28]. using hydroxyapatite (HA) modified with silane groups to improve 229
166 Coaxial electrospinning can remove desorption from the PLA surface the ceramic/PLLA interactions [42]. By increasing HA hydrophobicity, 230
167 as a major release mechanism, as the drug is encapsulated within the the ceramic was better dispersed in the PLLA phase, further improving 231
168 core. Entrapment of drug in a core within a porous PLA sheath can result the mechanical properties of the resulting scaffold [42]. 232
169 in diffusion-dominated release kinetics [29], while entrapment within a While PLA found the greatest applicability in bone repair and regen- 233
170 solid PLA sheath can promote degradation as the driving mechanism for eration, it has been recently used to engineer other musculoskeletal 234
171 release [30]. However, it is important to note that the kinetics for coaxial tissues. Several investigations attempted to fabricate 2-dimensional 235
172 spun fibers can be highly dependent on processing parameters and may scaffolds, usually sheets or films, with nano- and micro-features that 236
173 still show desorption-diffusion release kinetics [31]. Scaffolds produced resemble the properties of collagen fibers, a key component of connec- 237
174 by electrostatic layer-by-layer deposition or adsorption utilize compet- tive tissues like bone, but also cartilage, ligaments, and tendons [13,38, 238
175 itive binding of serum proteins to drive release of the charged 43,44]. Phase separation micromolding has been used to fabricate 239
176 complexes from the scaffold [26,32]. PLLA sheets for muscle applications, in which a PLLA solution was casted 240
177 Despite its many desirable properties, the main concern with the use on a patterned substrate and then exposed to a non-solvent to induce 241
178 of PLA lies in its degradation products. PLA degrades into lactic acid, a phase separation, producing a nanofibrous scaffold [43]. By optimizing 242

Please cite this article as: M. Santoro, et al., Poly(lactic acid) nanofibrous scaffolds for tissue engineering, Adv. Drug Deliv. Rev. (2016), http://
dx.doi.org/10.1016/j.addr.2016.04.019
 4 M. Santoro et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

243 parameters such as PLLA molecular weight and weight fraction, and from this study showed increased adhesion of rat PC12 cells and rabbit 307
244 pattern design, it was possible to produce highly porous fibrous patellar fibroblasts to PLA nanofibrous scaffolds compared to solid wall 308
245 scaffolds with interconnected porosity that increased cell–cell contact scaffolds [51]. This strategy has been widely applied in tissue engineer- 309
246 in progenitor myoblasts [43]. ing to several biomaterials, including PLA and PCL, to modify the surface 310
247 Poly(L-co-D,L-lactic acid) (PLDLA) has also been employed to topography of the scaffold and ultimately influence cell phenotype and 311
248 engineer the anterior cruciate ligament (ACL), with the objective of long-term differentiation [52]. The dominant effects on cellular growth 312
249 producing a scaffold that matches native collagen fibrous architecture are likely due to the orientation of fibers. However, synthetic biomate- 313
250 and mechanical properties [44]. Specifically, electrospun PLDLA fibers rials can vary greatly in terms of mechanical properties and degradation 314
251 were exposed to a water solution at a temperature higher than the time, two parameters that affect further development of these scaffolds 315
252 PLDLA glass transition temperature. The thermally induced stress with- as gene or drug delivery vehicles [53,54]. 316
253 in the polymer network was exploited to produce crimp-like fibers and While many studies have evaluated the adhesion of differentiated 317
254 to alter the mechanical properties of the scaffold. Scaffolds fabricated via cells to PLA scaffolds, other researchers have explored these scaffolds 318
255 this method exhibited a compressive modulus close to that of native as substrates to support the differentiation of stem cells. Nanofibrous 319
256 ACL. Additionally, the crimp-like pattern promoted ECM deposition by mats of PLLA functionalized with the peptide sequence YIGSR through 320

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257 fibroblasts and the formation of fascicles, a distinctive architectural fea- click-chemistry significantly impacted the differentiation of mouse em- 321
258 ture of the ECM of native ACL [44]. bryonic stem cells [55]. Electrospun mats of aligned or random PLLA 322

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259 Musculoskeletal tissue engineering has harnessed the chemical and nanofibers were fabricated and were either functionalized or left un- 323
260 mechanical properties of PLA to engineer both hard and soft tissues treated. Evaluation of neuron-specific class III β-tubulin, neurite exten- 324
261 [2,39,45,46]. The combination of L- and D-lactic acid offers the possibil- sion, and gene expression for neural markers showed that aligned and 325

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262 ity to tune polymer crystallinity, mechanical properties, and degrada- functionalized PLLA nanofibrous scaffolds increased the proportion of 326
263 tion kinetics [1,2,10,47]. Additionally, PLLA has been blended with embryonic stem cells that demonstrated markers of neural differentia- 327
264 poly(D-lactic acid) (PDLA), resulting in a fibrous scaffold with higher tion compared to mats of either random or untreated fibers [55]. Similar- 328

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265 compressive and tensile strength than scaffolds made of pure PLLA or ly, coaxial electrospinning was used to fabricate PLLA/gelatin composites 329
266 PDLA [47]. Nevertheless, a major challenge in bone tissue engineering for neuronal stem cell differentiation [56]. These composite scaffolds 330

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267 involves the development of mechanically strong scaffolds that are incorporated controlled release of retinoic acid and purmorphamine 331
268 highly porous enabling vascularization [37]. Future research with PLA from the gelatin fibers [56]. Contrary to most coaxially spun composites 332
269 will likely focus on the design of L/D-lactic acid copolymers to develop of PLLA, drug-loaded cross-linked gelatin comprised the outer sheath
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270 new materials suitable for load-bearing applications. Additionally, the with an interior core of PLLA. This configuration allows for early quick 334
271 incorporation of ceramics will continue being a valuable strategy to release of drug while using PLLA nanofibers to comprise the structural 335
272 improve the mechanical properties of PLA [36]. integrity of the scaffold. Drug release demonstrated an attenuated 336
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burst release at higher gelatin cross-linking, as expected [56]. Engineered 337
273 3. PLA scaffolds for nervous tissue engineering neural stem-like cells cultured on scaffolds loaded with retinoic acid and 338
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purmorphamine were able to differentiate toward a neuronal lineage, 339

274 The destruction of peripheral nerves due to injury, pathology, or sur- and neurite length was greatest on fibers with these instructive cues 340
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275 gical intervention can cause severe functional and esthetic deficits. The [56]. Coaxial electrospun nanofibrous scaffolds comprising a silk fibroin 341
276 current gold standard for nerve repair is autologous nerve grafting. core with a PLA sheath have been investigated for the delivery of nerve 342
277 However, this process has several drawbacks, including donor site growth factor to support differentiation of neuronal stem cells [24]. 343
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278 morbidity, limited donor tissue, need for a second surgical site, and Nerve growth factor was incorporated into the silk fibroin core to pre- 344
279 mismatch between donor and recipient nerves [48]. Scaffolds for serve bioactivity and attenuate burst release. These scaffolds were also 345
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280 nerve tissue engineering are typically either hollow or filled tubes plasma treated in order to increase wettability and attachment of PC12 346
281 designed to be biocompatible, degradable, and mechanically matched neuronal stem cells [24]. Neurite extension was shown to be enhanced 347
282 to nerves to support cells, growth factor release, or a combination of on air plasma treated coaxial nanofibrous scaffolds eluting nerve growth 348
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283 both [48]. In addition, variations in topography, conduit design, and factor when PC12 cells were cultured in differentiation medium without 349
284 functionalization have become increasingly popular modes of optimiz- the growth factor [24]. Embryonic E9 chick dorsal root ganglion cells and 350
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285 ing scaffold design [49]. Because of these design criteria, PLA and its rat Schwann cells cultured on highly aligned PLA nanofibrous scaffolds 351
286 composites have been utilized in the development of degradable promoted neurite extension parallel to fibers, as well as aligned Schwann 352
287 nerve guidance conduits. attachment and cell growth [57]. This investigation clearly demonstrated 353
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288 The fabrication of nerve conduits from PLA fibers has advanced sig- the importance of fiber alignment by showing that the presence of trans- 354
289 nificantly beyond simple tubes, and in recent years, many researchers verse fibers had the ability to divert or even stop neurite extension [57]. 355
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290 have focused on variations in the alignment, topography, and mechan- Recent research on PLA nanofibrous nerve conduits has focused on 356
291 ical properties of PLA fibrous scaffolds to assist in the support of nerve the optimization of fiber design and surface topography for cell survival, 357
292 regeneration. For instance, the mechanical strength of PLA sutures can proliferation, and/or differentiation. Though some results have indicat- 358
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293 be enhanced by rotor-twisting into filaments and microbraiding into ed that the incorporation of microchannels or microgrooves to the 359
294 single or multilayer tubes [50]. When evaluated by subcutaneous im- surface of conduits can improve vascularity [58], the final utility of this 360
295 plantation in rats, it was demonstrated that these conduits maintained improvement is currently unclear, and focus has shifted toward the 361
296 lumen and wall integrity, which can be of concern with polymers that use of nanofibrous scaffolds to promote nerve regeneration. Recent 362
297 swell significantly or degrade too quickly [50]. Furthermore, implanta- research has also demonstrated that the increase in surface area from 363
298 tion of the conduits into a 10 mm defect in rat sciatic nerve resulted in utilizing nanofibers and the fabrication of highly aligned fiber geometry 364
299 nerve regeneration in all animals, with histologically visible axon- scaffolds, mimicking the fiber alignment of nerves, improves the 365
300 Schwann cell regeneration units and minimal inflammation [50]. Recent suitability of scaffolds for cell growth [55,57]. 366
301 investigations have also sought to combine microscale and nanoscale
302 features by fabricating nanofibrous conduit scaffolds with single or mul- 4. PLA scaffolds for cardiovascular tissue engineering 367
303 tiple microchannels [51,52]. In vitro results have shown that PLA
304 nanofibrous conduits fabricated by injection molding/TIPS had more Cardiovascular disease is the leading cause of death worldwide, 368
305 than three orders of magnitude greater surface area than solid wall warranting a serious look at tissue engineering strategies to replace 369
306 tubes, thus impacting protein adsorption and cell adhesion [51]. Results cardiovascular tissues [59]. There is large-scale need for scaffolds that 370

Please cite this article as: M. Santoro, et al., Poly(lactic acid) nanofibrous scaffolds for tissue engineering, Adv. Drug Deliv. Rev. (2016), http://
dx.doi.org/10.1016/j.addr.2016.04.019
 M. Santoro et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx 5

371 support the regeneration of heart and blood vessels, leading to the use dermal bed and assist in protecting the wound bed, preventing loss of 435
372 of PLA nanofibrous scaffolds for these applications. More in-depth moisture and proteins, and removal of exudate [67]. The large surface 436
373 reviews of the physiology behind the need for tissue engineering strat- area-to-volume ratio of nanofibrous meshes also encourages the attach- 437
374 egies to address cardiovascular problems are available elsewhere in the ment and proliferation of cells, promoting the closure of large wounds. 438
375 literature [59–61]. In recent years, PLA nanofibrous scaffolds have been Informative reviews of skin anatomy and the use of scaffolds for skin 439
376 most commonly used for the purpose of vascular tissue engineering, tissue engineering can be found in the literature [67]. 440
377 although there are instances where PLA nanofibrous patches are fabri- In the area of skin regeneration, PLA is particularly useful because 441
378 cated for cardiac muscle repair [62]. Similar to nerve conduit scaffolds, nanofibrous mats can be leveraged as drug delivery vehicles as well as 442
379 the design of PLA fibrous vascular scaffolds requires a tube with hollow providing a hydrophobic barrier against water loss and the environ- 443
380 lumen that is biocompatible, degradable, and mechanically compliant ment. Electrospun PLA has been used to entrap and deliver drugs that 444
381 with the graft site. promote wound healing, especially anti-inflammatory and anti- 445
382 PLA nanofibrous tubes have emerged as a popular scaffold type for oxidant molecules, and to facilitate non-viral nucleic acid delivery. 446
383 vascular tissue engineering, and researchers have attempted to improve Drugs such as alkannin, shikonin, curcumin, and ibuprofen have been 447
384 scaffold biomimicry by developing a bilayered electrospun scaffold loaded into electrospun PLA scaffolds to promote cutaneous wound 448

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385 comprising a nano- to microscale PLA fibrous outer layer and silk fibro- healing [68–70]. It has been shown that curcumin, a plant extract with 449
386 in–gelatin nanofibrous inner layer [63]. The outer PLA fibrous layer was anti-inflammatory, anti-oxidant, and wound healing properties, loaded 450

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387 shown to support the growth and proliferation of 3T3 mouse fibroblasts, into PLA nanofibrous meshes increased the rate of healing of a cutaneous 451
388 while the inner silk fibroin–gelatin layer supported the attachment and wound in mice compared to either PLA meshes alone or no treatment 452
389 growth of human umbilical vein endothelial cells [63]. Subcutaneous [69]. Similarly, ibuprofen-loaded PLA nanofibrous scaffolds support the 453

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390 implantation of the scaffold demonstrated minimal inflammatory re- attachment and proliferation of human epidermal keratinocytes and 454
391 sponse, and at 3 months, the authors reported the formation of a con- human dermal fibroblasts [70]. It was also demonstrated in an in vivo 455

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392 nective vascular network coinciding with degradation of the implant full-thickness mouse skin incision model that cell-seeded ibuprofen- 456
393 [63]. Another study evaluated PLA nanofibrous scaffolds fabricated via loaded PLA bandages rescued wound contracture and increased blood 457
394 phase separation and seeded with adult primary human aortic smooth vessel formation compared to acellular ibuprofen-loaded PLA bandages 458

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395 muscle cells, demonstrating that cells cultured on nanofibrous scaffolds [70]. 459
396 upregulated gene expression of smooth muscle myosin heavy chain PLA nanofibrous scaffolds are ideally suited for local drug delivery to 460
397 compared to cells on flat films, though there was no difference in ex- infected cutaneous wounds due to their ability to load a variety of anti-
D 461
398 pression of smoothelin or myoCD genes [64]. Subcutaneous implanta- bacterial drugs [71]. Although uniaxial loading of antibiotics was popular 462
399 tion of scaffolds into nude mice 24 h after cell seeding revealed in the past, this strategy has been replaced by more sophisticated 463
400 significant deposition of collagen into the pores of the scaffold and methods to gain increased control over release kinetics [71]. For exam- 464
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401 maintenance of human primary aortic smooth muscle cells within the ple, in a study comparing the release of gentamicin from uniaxial PLA 465
402 scaffold 2 weeks post-implantation [64]. The PLA nanofibrous scaffold nanofibers, uniaxial collagen nanofibers, or coaxial nanofibers with a col- 466
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403 used in this study supported the growth of contractile cells and also con- lagen core and a PLA sheath, it was found that collagen fibers release all 467
404 firmed integration into the host tissue [64]. Moreover, the use of a com- drug in a burst fashion, while PLA fibers released surface adsorbed drug 468
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405 posite scaffold of PLA/gelatin with aligned fibers demonstrated that cells as a burst but then retained drug within the polymer matrix [31]. The co- 469
406 on aligned fibers oriented and elongated with the direction of the fibers, axial spun nanofibrous scaffolds showed an intermediate release profile 470
407 and the presence of gelatin caused an increase in human umbilical vein between the uniaxial collagen and PLA release profiles, indicating that 471
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408 endothelial cell and smooth muscle cell attachment, likely due to the gentamicin was not completely entrapped within the collagen core and 472
409 presence of adhesion sites normally absent on PLA alone [65]. Conduits some drug remained adsorbed to the surface of the PLA [31]. When all 473
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410 for vascular tissue engineering are often limited by the tendency for the three gentamicin-releasing constructs were cultured with MG-63 osteo- 474
411 lumen to clot, especially in small diameter vessels, preventing blood blasts, no difference in cell viability was noted in comparison to a con- 475
412 flow from occurring. However, small diameter PLA nanofibrous con- struct of PLA without gentamicin [31]. Other antibiotics have been 476
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413 duits have been shown to remain patent after 12 months of implanta- incorporated into PLA or PLA composite nanofibrous cutaneous wound 477
414 tion in the infrarenal aorta of a mouse [66]. In addition, histological dressings, such as mupirocin [72] and tetracycline [73]. In addition to 478
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415 and polymerase chain reaction analyses supported the presence of conventional antibiotics, the antimicrobial peptide bacteriocin has been 479
416 smooth muscle cells, collagen I and III, matrix metalloproteinases-2 incorporated into blends of PDLLA and poly(ethylene oxide) (PEO) in 480
417 and -9, and a macrophage marker, indicating that the conduit was an attempt to offer an alternative solution to antibiotic-resistance [74]. 481
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418 undergoing remodeling [66]. As expected, cumulative drug release increased as the ratio of PEO:PDLLA 482
419 Much of the recent work utilizing PLA nanofibrous scaffolds for car- increased, and bacteriocin maintained the majority of its antimicrobial 483
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420 diovascular tissue engineering has focused on characterizing scaffolds activity [74]. The antimicrobial peptide nisin has also been electrospun 484
421 and introducing porosity to improve mass transport of nutrients, meta- into a nanofibrous PEO:PDLLA (50:50) wound dressing and tested 485
422 bolic wastes, and degradation products. In vitro work has shown that against a full-thickness wound infected with Staphylococcus aureus in a 486
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423 these scaffolds can support the proliferation of cells contributing to ves- mouse model [75]. Drug-eluting nanofibrous wound dressing signifi- 487
424 sel development and growth, and in vivo implantation in subcutaneous cantly reduced the bacterial burden present in the wound, but did not 488
425 pockets has demonstrated biocompatibility. However, PLA nanofibrous appear to improve wound healing compared to non-loaded nanofibrous 489
426 scaffolds will require additional functional testing in animal models wound dressing [75]. While the ideal cutaneous wound dressing would 490
427 before any clinical translation. prevent and/or treat infection in conjunction with improving healing, 491
resolution of infection is a minimum requirement for any further thera- 492
428 5. PLA scaffolds for cutaneous tissue engineering pies to succeed and thus this type of therapy remains useful for cutane- 493
ous wound healing. PLA nanofibrous wound dressings have also been 494
429 The healing of cutaneous wounds is of immense importance to every doped with silver microparticles and nanoparticles to evaluate the com- 495
430 field, especially tissue engineering. As the body's primary protection posite mesh as an antibacterial wound dressing [76]. When evaluated in 496
431 against the outside environment, failure of the skin barrier leads to a a 3-dimensional co-culture of keratinocytes and S. aureus, silver was 497
432 host of issues with infection, hydration, and thermoregulation. PLA shown to decrease both S. aureus and keratinocyte proliferation [76]. In- 498
433 nanofibrous mats are particularly well suited to address cutaneous terestingly, the cell-seeded wound dressings inhibited bacterial growth 499
434 healing. Nanofibrous meshes mimic the native topography of the as much as the presence of silver particles, indicating that a scaffold 500

Please cite this article as: M. Santoro, et al., Poly(lactic acid) nanofibrous scaffolds for tissue engineering, Adv. Drug Deliv. Rev. (2016), http://
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 6 M. Santoro et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

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Please cite this article as: M. Santoro, et al., Poly(lactic acid) nanofibrous scaffolds for tissue engineering, Adv. Drug Deliv. Rev. (2016), http://
dx.doi.org/10.1016/j.addr.2016.04.019