Download - Functional Electrospun Nanofibrous Scaffolds for Biomedical Applications

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  • modifications of electrospun membranes also provide effective means to render the electrospun scaffolds with controlled anisotropy and porosity.

    2.2. Synthetic copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1395

    3.4. Two-phase electrospinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1404

    Available online at www.sciencedirect.com

    Advanced Drug Delivery Reviews 59 (2007) 13921412www.elsevier.com/locate/addr2.3. Polymer mixtures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13972.3.1. Blends of natural polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13972.3.2. Blends of natural and synthetic polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13972.3.3. Synthetic polymer blends based on PLGA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13982.3.4. Synthetic polymer blends containing PEO/PEG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14002.3.5. Other multi-component polymer systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1400

    3. New innovations in electrospinning for biomedical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14013.1. Scaffolds with oriented fiber alignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14023.2. Multilayer electrospinning and mixing electrospinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14033.3. Fabrication of dual-porosity scaffolds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1403Keywords: Electrospinning; Nanofiber; Scaffold; Biomedical applications; Copolymers; Mixtures; Modifications

    Contents

    1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13932. Rational design of polymeric materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1394

    2.1. Homopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13942.1.1. Natural polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13942.1.2. Synthetic polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1395In this article, we review the materials, techniques and post modification methods to functionalize electrospun nanofibrous scaffolds suitable forbiomedical applications. 2007 Elsevier B.V. All rights reserved.Functional electrospun nanofibrous scaffolds for biomedical applications

    Dehai Liang 1, Benjamin S. Hsiao , Benjamin Chu

    Departments of Chemistry and of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794-3400, USA

    Received 3 January 2007; accepted 15 April 2007Available online 25 August 2007

    Abstract

    Functional nanofibrous scaffolds produced by electrospinning have great potential in many biomedical applications, such as tissue engineering,wound dressing, enzyme immobilization and drug (gene) delivery. For a specific successful application, the chemical, physical and biologicalproperties of electrospun scaffolds should be adjusted to match the environment by using a combination of multi-component compositions andfabrication techniques where electrospinning has often become a pivotal tool. The property of the nanofibrous scaffold can be further improvedwith innovative development in electrospinning processes, such as two-component electrospinning and in-situ mixing electrospinning. Post Corresponding authors. Hsiao is to be contacted at Tel.: +1 631 632 7793; fax: +1 631 632 6518. Chu, Tel.: +1 631 632 7928; fax: +1 631 632 6518.E-mail addresses: [email protected] (B.S. Hsiao), [email protected] (B. Chu).

    1 Current address: College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.

    0169-409X/$ - see front matter 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.addr.2007.04.021

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    distance between the spinneret and the collecting plate, of success.

    elivtemperature and humidity. These parameters have been wellstudied and summarized in a recent review [28]. With verysmall fiber diameters, the yield per spinneret of the electro-spinning process is extremely low. Recently, multi-jet electro-spinning [29,30] and blowing-assisted electrospinningtechnology [3032] have been developed, demonstrating theproduction capability for fabricating nanofibrous articles on anindustrially relevant scale.

    Besides taking advantage of the materials compositions, thefabrication process, through which the fiber diameter, morphol-ogy and scaffold porosity can be manipulated, also plays animportant role on the scaffold property and functionality. Forexample, the two-phase electrospinning process provides a newpathway to incorporate drugs or biopolymers inside the fibercore that will be suitable for the controlled release over aprolonged period of time [51]. Physical and chemical modifica-3.5. Fabrication of core-shelled nanofibers . . . . . . . . .3.6. Blowing-assisted electrospinning technique . . . . . . .

    4. Modifications of post-electrospun scaffolds . . . . . . . . . .5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . .Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    1. Introduction

    Electrospinning is a unique technology that can producenon-woven fibrous articles with fiber diameters ranging fromtens of nanometers to microns, a size range that is otherwisedifficult to access by conventional non-woven fiber fabricationtechniques [1,2]. Electrospun nanofibrous scaffolds possess anextremely high surface-to-volume ratio, tunable porosity, andmalleability to conform over a wide variety of sizes and shapes.In addition, the scaffold composition can be controlled toachieve desired properties and functionality. Due to theseadvantages, electrospun nanofibrous scaffolds have beenwidely investigated in the past several years with materials ofdifferent compositions [310] for applications of varying end-uses, such as filtration [1113], optical and chemical sensors[1419], electrode materials [2023], and biological scaffolds[2427].

    For small-scale productions (i.e., on a laboratory scale),electrospinning is a simple method to generate nanoscale fibers.A basic electrospinning system usually consists of three majorcomponents: a high voltage power supply, a spinneret (e.g. apipette tip) and a grounded collecting plate (usually a metalscreen, plate, or rotating mandrel). When a charged polymersolution is fed through the spinneret under an external electricfield, a suspended conical droplet is formed, whereby thesurface tension of the droplet is in equilibrium with the electricfield. When the applied electric field is strong enough toovercome the surface tension, a tiny jet is ejected from thesurface of the droplet and drawn toward the collecting plate.During the jet propagation toward the collecting plate, thesolvent in the jet stream gradually evaporates. The resultingproduct is a non-woven fibrous scaffold with a large surfacearea-to-volume ratio and a small pore size (in microns). Thefiber thickness and morphology can be controlled by manyparameters, such as solution properties (viscosity, elasticity,conductivity and surface tension), electric field strength,

    D. Liang et al. / Advanced Drug DThe usage of electrospun nanofibrous scaffolds for biomedicalapplications has attracted a great deal of attention in the pastseveral years. For examples, nanofibrous scaffolds have been. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1404

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    demonstrated as suitable substrates for tissue engineering [2427],immobilized enzymes and catalyst [3336], wound dressing[37,38] and artificial blood vessels [39,40]. They have also beenused as barriers for the prevention of post-operative inducedadhesion [41,42] and vehicles for controlled drug (gene) delivery[4347]. For a successful application to a specific target, thenanofibrous scaffold must exhibit suitable physical and biologicalproperties closely matching the desired requirements. Forexample, in tissue engineering, the electrospun scaffold shouldphysically resemble the nanofibrous features of extracellularmatrix (ECM) with suitable mechanical properties. It should alsobe able to promote cell adhesion, spreading and proliferation. Forwound dressing, the nanofibrous scaffold should not only serve asa substrate for tissue regeneration, but also may deliver suitablebioactive agents, including drugs (e.g. antibiotic agent), within acontrolled manner during healing. The fabrication of suchfunctional nanofibrous scaffolds for biomedical applicationsoften requires an interdisciplinary approach combining physics,chemistry, biology and engineering.

    For electrospun nanofibrous scaffolds in biomedical applica-tions, its physical and biological properties, such as hydro-philicity, mechanical modulus and strength, biodegradability,biocompatibility, and specific cell interactions, are largelydetermined by the materials' chemical compositions. Based onpolymer physics, copolymerization and polymer blending aretwo effective means to combine different polymers to yield newmaterials properties. Thus, by selecting a combination of propercomponents and by adjusting the component ratio, properties ofelectrospun scaffolds can be tailored with desired newfunctions. For example, many kinds of copolymers and polymermixtures, such as poly(lactide-co-glycolide) [41], poly(ethyl-ene-co-vinyl alcohol) [48], mixtures of collagen with elastin[49], and mixtures of chitosan with poly(ethylene oxide) (PEOor PEG when the molecular weight is small, say less than5000 Da) [50], have been electrospun to fabricate nanofibrousscaffolds for biomedical applications, but with varying degrees

    1393ery Reviews 59 (2007) 13921412tions of the scaffolds after electrospinning are also able to renderthe scaffolds with enhanced properties and suitable functionalityfor specific applications. For example, the grafting of gelatin

  • onto the surface of a polyethylene terephthalate (PET) scaffoldafter electrospinning could increase the biocompatibility andmake the scaffold more suitable for cell adhesion andproliferation [40].

    This review is concerned with the recent progress on the useof electrospun scaffolds for biomedical applications, withemphasis on materials, technology, and post treatment of thescaffolds: (1) rational polymer material design, includingcopolymers and polymer mixtures, (2) new innovative electro-spinning techniques, and (3) post-electrospinning modifica-tions. In practice, the three considerations can be combined

    together to generate new functional nanofibrous scaffolds withenhanced physical and biological properties.

    2. Rational design of polymeric materials

    2.1. Homopolymers

    2.1.1. Natural polymersCompared with synthetic polymers, naturally occurring

    polymers normally exhibit better biocompatibility and lowimmunogenicity, when used in biomedical applications. All

    1394 D. Liang et al. / Advanced Drug Delivery Reviews 59 (2007) 13921412Fig. 1. Field-emission scanning electron microscopic images of lecithin fibers prconcentration for entanglement). (From Ref. [77] with permission).epared at different solution concentrations (from below to above the critical

  • the performance of electrospun scaffolds based on copolymerscan be significantly improved when compared to that ofhomopolymers. For example, biodegradable hydrophobicpolyesters generally have good mechanical properties but lackcell affinity for tissue engineering. The incorporation of a properhydrophilic polymer segment can increase the cell affinity.Besides the cell affinity, the mechanical properties, morphology,structure, pore size and distribution, biodegradability and otherphysical properties can also be tailored by using copolymers.Moreover, with amphiphilic copolymers as protecting mole-cules to encapsulate drug molecules, electrospun scaffolds canbe used for drug release in a controlled manner.

    PLGA, the random copolymer of glycolide (G) and lactide(L), is a popular and well-studied system that has been broadlyused as electrospun scaffolds for biomedical applications. Aslisted in Table 1, the mechanical properties and the degradationrate of PLGA, being dependent on the L/G ratio, are quitedifferent from PGA and PLA homopolymers. The in vitro

    elivfour major classes of biopolymers: proteins, polysaccharides,DNAs and lipids, have been fabricated into electrospunscaffolds. Protein fibers, mainly from collagen, gelatin, elastinand silk fibroin, have been well studied in recent years [5255].For example, collagen is the principal structural element of theextracellular matrix (ECM) in tissues, where three types ofcollagen, types I, II and III, have been fabricated intonanofibrous scaffolds for studies of cell growth and penetration[5658]. Wnek et al. have electrospun human or bovinefibrinogen fraction I, dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFP) with minimal essential medium (Earle's salts),and used the resulting scaffolds for tissue-engineering applica-tions [59]. Min et al. have prepared silk fibroin (SF) electrospunscaffolds with fiber diameters of around 80 nm [60]. They foundthat normal human keratinocytes and fibroblasts seeded on theSF nanofibers were able to attach and grow, indicating that theSF nanofibers may be a good candidate for wound dressing andtissue engineering [60,61]. The treatment of the scaffold bywater vapor induced a conformational transition of SF fromrandom coil to beta-sheet structures, thereby the mechanicalstrength and the cellular compatibility were improved [62,63].In addition, Huang et al. have electrospun gelatin intonanofibers with diameters ranging from 100 to 340 nm using2,2,2-trifluoroethanol as the solvent [64].

    Recently, our group has demonstrated the successfulelectrospinning of hyaluronic acid (HA) in aqueous solutions[65]. HA is essentially an associating polymer in aqueoussolution, often exhibiting very high solution viscosity. Conse-quently, typical electrospinning processes could not be usedsuccessfully to develop a steady jet stream. The sample has to bespun with the assistance of air flow at elevated temperatures,thereby broadening the processing window. This process istermed blowing-assisted electrospinning, which has beendescribed elsewhere [32,65] and will not be elaborated on in thisreview. The electrospun HA nanofibrous scaffolds with asuitable degree of post-crosslinking will be suitable for cartilagerepair, since hyaluronan is an abundant polysaccharide foundalmost exclusively in articular joints, allowing the cells to attachfor cartilage regeneration. Other polysaccharides, such asdextran [66], chitosan (chitin) [6770] and cellulose acetate[7175], have also been fabricated to form nanofibers byelectrospinning. Besides proteins and polysaccharides, calfthymus Na-DNA in an aqueous solution was electrospun toform nanofibers with diameters of around 5080 nm [76].However, no specific biomedical applications of such DNAnanofibers have been reported. Recently, McKee M. et al.reported the non-woven membranes from electrospinninglecithin solutions in a single processing step [77]. Atconcentrations above the critical concentration for entangle-ment, Ce, electrospun fibers with diameters ranging from 1 to5 m were fabricated (Fig. 1). Such scaffolds offered manypotential applications, such as tissue growth and engineeringvehicles, as well as drug-delivery platforms.

    D. Liang et al. / Advanced Drug D2.1.2. Synthetic polymersSynthetic polymers often offer many advantages over natural

    polymers in that they can be tailored to give a wider range ofproperties and predictable lot-to-lot uniformity. Moreover,synthetic polymers are cheaper and represent a more reliablesource of raw materials. Typical synthetic polymers used inbiomedical applications are hydrophobic biodegradable polye-sters, such as polyglycolide (PGA)[76,78,79], polylactide (PLA)[10,8083] and poly(-caprolactone) (PCL) [8487], whichhave all been electrospun into nanofibrous scaffolds. Table 1 liststhe physical properties of some popular biodegradable polyestersand their copolymers [88]. Other hydrophilic biodegradablepolymers, such as polyurethane [89,90], poly(vinyl alcohol)[91,92], PEO [93], polydioxanone [94] and polyphosphazenederivatives [95,96] have also been electrospun into nanofibrousscaffolds for biomedical applications.

    2.2. Synthetic copolymers

    The use of copolymers is a viable scheme to generate newmaterials of desirable properties. When properly implemented,

    Table 1Biodegradable polymers for biomedical applications

    Polymer name Melting point(C)

    Glass transitiontemperature(C)

    Modulus(Gpa)a

    Degradation time(Month)b

    PGA 225230 3540 7.0 6 to 12L-PLA 173178 6065 2.7 N24D,L-PLA Amorphous 5560 1.9 12 to 16PCL 5863 (65) (60) 0.4 N24PDO N/A (10) 0 1.5 6 to 1285/15 PLGA Amorphous 5055 2.4 5 to 675/25 PLGA Amorphous 5055 2.0 4 to 565/35 PLGA Amorphous 4550 2.0 3 to 450/50 PLGA Amorphous 4550 2.0 1 to 2

    aTensile or flexural modulus.bTime to complete mass loss. Rate also depends on geometry.PGA: poly(glycolide); PLA: poly(lactide); PCL: poly(-caprolactone); PDO:poly(dioxanone); PLGA: copolymer of PGA and DL-PLA, ratio is PLA/PGA.

    1395ery Reviews 59 (2007) 13921412degradation rate of electrospun PLGA scaffold at different L/Gcomposition has been investigated by our group. Thenanofibrous PLGA scaffolds generally degrade faster than the

  • regular casting film with the same dimensions and composi-tion, mainly due to the high surface area-to-volume ratio andthe high water adsorption ability (both decrease the inductiontime during hydrolysis) [41]. Recently, Laurencin et al. havestudied the potential use of PLGA nanofibrous scaffolds as anantibiotic delivery vehicle for the treatment of wounds [44].They demonstrated that PLGA nanofibers could be tailored todesired diameters through modifications in processing para-meters, such as orifice diameter (needle gauge), polymersolution concentration and voltage per unit length, where theantibiotic drugs, such as cefazolin, could be incorporated intothe nanofibers.

    The lactide component can also be copolymerized with-caprolactone. The degradation rate of the copolymer, P(LA-CL),is between those of the two homopolymers (PLA and PCL), whichare significantly longer than that of PGA. Its degradation ratecan also be controlled by the composition ratio. The potentialuse of electrospun P(LA-CL) scaffolds in tissue engineeringhas been investigated by several groups [97100]. For example,Kwon et al. [97] electrospun P(LA-CL) scaffolds using differentL/CL molar ratios (70/30, 50/50, 30/70) and systematcallyinvestigated the scaffold structure, mechanical properties andcell adhesion ability. They found that the human umbilical veinendothelial cells (HUVECs) could adhere and proliferate on

    1396 D. Liang et al. / Advanced Drug Delivery Reviews 59 (2007) 13921412Fig. 2. Electrospun scaffolds from 5 wt.% total concentration of mixtures with PEO to10% concentration. (From Ref. [108] with permission).casein ratio at (a) 100:0, (b) 80:20, (c) 50:50, (d) 20:80, (e) 5:95, and (f) 20:80 at

  • elivthe P(LA-CL) nanofibers with the average diameter rangingfrom 300 nm to 1.2 m. Mo et al. [99] studied the interactionsof smooth muscle cells and endothelial cells with P(LA-CL)nanofibrous scaffolds. They found that both cell adhesion andproliferation took place after 7 days on the electrospun P(LA-CL) scaffold with a LA/CL ratio of 75/25. Their resultsindicated that P(LA-CL) nanofibrous scaffolds have excellentbiocompatibility and they are potentially very useful in tissueengineering applications.

    Electrospun scaffolds based on DegraPol, a degradableblock polyester-urethane, containing crystalline blocks of poly((R)-3-hydroxybutyric acid)-diol and blocks of poly(-capro-lactone-co-glycolide)-diol linked with a diisocyanate, wasstudied as a potential scaffold for skeletal muscle tissueengineering [26]. As a block copolymer, DegraPol combinedthe characteristics of traditional polyesters with good process-ibility and distinct elasticity of polyurethanes; it also exhibitedgood affinity with tissue cells. Electrospun DegraPol nanofi-brous scaffolds showed satisfactory mechanical properties andpromising cellular response in preliminary cell adhesion anddifferentiation experiments. It has now been considered as oneof the most promising scaffolds for skeletal muscle tissueengineering [26].

    Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) is abiodegradable and biocompatible copolymer derived frommicrobial polyesters; it has also been fabricated into nanofi-brous scaffolds recently. By controlling the electrospinningparameters, nanofibers with an average diameter of around185 nm were fabricated. Compared with the PHBV cast films,electrospun PHBV nanofibrous scaffolds provided a much moresuitable environment for the attachment and growth ofchondrocytes derived from rabbit ears [101]. Choi et al. foundthat the fiber diameter of PHBV was decreased by addition of asmall amount of benzyl trialkylammonium chlorides in thesolution before electrospinning, and the degradation rate ofPHBV fiber was also accelerated, probably due to a significantincrease in the surface area of PHBV nanofibers [102].

    Bhattarai et al. [103,104] developed a novel block copolymerbased on poly(p-dioxanone-co-L-lactide)-block-poly(ethyleneglycol) (PPDO/PLLA-b-PEG) that could be electrospun intoscaffolds for applications of tissue engineering and drug-release. The random disposition of the PPDO and PLLAsegments, as well as the incorporation of PEG oligomers,significantly improved the biodegradability and hydrophilicityof the electrospun scaffolds. For example, NIH 3T3 fibroblastcells were found to grow and proliferate on the scaffold after10 days, which showed a six-fold increase in the cell populationafter incubation when compared with the same environmentwithout the scaffold [104]. Kenawy et al. [48] combined thehydrophilicity of the vinyl-alcohol repeating unit with thehydrophobicity of the ethylene repeating unit in electrospunpoly(ethylene-co-vinyl alcohol) nanofibrous scaffolds, alsoresulting in improved biocompatibility. The hydroxyl group inthe vinyl-alcohol repeating unit could offer opportunities for

    D. Liang et al. / Advanced Drug Dchemical modifications either before or after electrospinning.Without modification, the electrospun poly(ethylene-co-vinylalcohol) scaffold was found to be readily able to support theculturing of smooth muscle cells and fibroblasts. In addition, thederivatives of poly(ethylene-co-vinyl alcohol), poly(ethylene-co-vinylacetate) [105], as well as poly(L-lactic acid-co-succinicacid-co-1,4-butane diol) [106] have also been fabricated intoelectrospun nanofibers that appeared to be suitable for varyingtissue engineering applications.

    2.3. Polymer mixtures

    2.3.1. Blends of natural polymersPolymer mixtures (or blends) have an advantage over

    copolymers in that they are not limited by suitable syntheticschemes. Therefore, nanofibrous scaffolds formed by mixingdifferent polymers become an appealing option, which isespecially true for natural polymers, as their chemical mono-mers are often more difficult to modify. Blending of naturalpolymers may provide a straightforward pathway to combinedifferent bioactivities for biomedical applications. For example,Boland et al. [49] demonstrated the electrospinning of micro-and nano-fibrous scaffolds based on collagen and elastinmixtures in order to develop viable vascular tissue engineeredconstructs. Collagen/elastin scaffolds could replicate thecomplex architecture of a blood vessel wall and withstandhigh pressures under the pulsatile environment induced by thebloodstream. Therefore, such scaffolds could have the potentialto create a suitable environment for in vitro generation ofvascular replacements [49]. The thermal stability of thecollagen/elastin scaffolds was able to be improved by cross-linking of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimidehydrochloride and N-hydroxysuccinimide (NHS) [107].

    2.3.2. Blends of natural and synthetic polymersAs regenerated natural polymers usually possess weak

    mechanical properties, blends of natural and synthetic polymerscan overcome this problem and combine two desired character-istics, i.e., the strength and durability of a synthetic polymer,and the specific cell affinity of a natural polymer. Electrospunscaffolds based on blends of natural and synthetic polymers canenhance both physical properties and biological functionality.One example was the electrospinning of casein or lipasesuspensions, mixed with synthetic PEO or PVA [108]. Thestand-alone suspensions of casein and lipase were not suitablefor electrospinning. However, their mixtures with PEO or PVAcould significantly facilitate the electro-spinning process. Fig. 2shows the scanning electron microscopic (SEM) images ofelectrospun scaffolds from PEO/casein mixtures. With the PEO(Mv, 600 KDa) concentration below 5%, a non-fibrous scaffoldwas obtained (Fig. 2e). However, this situation could besignificantly improved by increasing the PEO content to 80%,as illustrated in Fig. 2b [108]. To maintain casein concentrationas high as 80%, an increase in the total mixture concentration to10% appeared to be capable of producing fine fibers byelectrospinning (Fig. 2f). Their study also showed that lipasecould be electrospun together with PEO or PVA, and the

    1397ery Reviews 59 (2007) 13921412catalytic activity on the hydrolysis of olive oil in lipase/PVAelectrospun scaffolds was 6 times higher than that in cast filmwith similar compositions [108]. Furthermore, the crosslinking

  • elivof polymer/lipase scaffolds using a dialdehyde could signifi-cantly improve the water stability. The pH level of the reactionmedia during crosslinking was found to play an important rolein the activity of the immobilized lipase [34].

    Zhang et al. [109] mixed 10% w/v gelatin with 10%w/v PCLin 2,2,2-trifluoroethanol (TFE) at a ratio of 50:50 to produce agelatin/PCL nanofibrous scaffold by electrospinning. Thescaffold showed enhanced mechanical properties and morefavorable wetability than those obtained from either PCL orgelatin scaffolds alone. Bone-marrow stromal cells (BMSC)were found to attach and grow well on the surface of the blendnanofibrous scaffold. In addition, BMSCs were found to be ableto migrate inside the scaffold up to a depth of 114 m within1 week of culture, suggesting the potential use of compositegelatin/PCL fibrous scaffolds for preparation of the three-dimensional tissue construct.

    The mixture of heparin and PEG was also electrospun toprepare nanofibrous scaffolds [110]. The presence of PEG in theelectrospun scaffolds prolonged the release of heparin, whichcould closely match the time scale needed for use in wounddressings. The composition of the scaffold is also suitable fordrug delivery. It is evident that the mixtures of type I collagenand PEO can provide a convenient, non-toxic and non-denaturing way to generate collagen-containing nanofibrousscaffolds that may have good potential in biomedical applica-tions [111]. A blend of wool keratin and PEO in aqueoussolutions was also fabricated into nanofibers in a similar fashion[112].

    Electrospinning of synthetic polymers followed by thecoating of natural material has also been demonstrated as apractical approach to yield desired functional features. Forexample, He et al fabricated the collagen-coated poly(L-lacticacid)-co-poly(-caprolactone) (P(LLA-CL) 70:30) scaffoldwith a porosity of 64-67% and a fiber diameter of 470 nm byelectrospinning followed by plasma treatment and collagencoating [113]. The coating of collagen was found to improve thebiocompatibility of the scaffold, thus enhancing the spreading,viability and attachment of the human coronary arteryendothelial cells and preserving the cells' phenotype [113] inthe scaffold. The properties of the electrospun collagen-coatedpoly(L-lactic acid)-co-poly(-caprolactone) scaffold are quitesuitable for engineered vascular graft.

    2.3.3. Synthetic polymer blends based on PLGABlends of synthetic polymers have been routinely used in

    electrospinning to produce new scaffolding materials. As PLGAhas been widely used in biomedical applications from sutures,medical devices to tissue regeneration, its mixtures with othersynthetic polymers are reviewed here. By mixing PLGA withanother polymer material, the physical properties of PLGA,such as hydrophobicity, degradation rate, shrinkage behavior inbody fluids and mechanical modulus, can be altered to specificbiomedical applications, such as carriers for drugs or DNAwithcontrolled-release capability.

    1398 D. Liang et al. / Advanced Drug D2.3.3.1. PLGA with dextran. PLGA is a hydrophobic polymerwhile dextran is a hydrophilic polymer that is highly soluble inan aqueous medium. By mixing PLGA and dextran together at a1 to 1 ratio, Jiang et al. [66] produced a hydrophobic/hydrophilicelectrospun composite scaffold. With a portion of dextranmethacrylated in advance, they could also photo-crosslink thedextran phase in the solid state to fabricate water-resistantnanofibrous scaffolds with improved hydrophilicity. The cross-linked PLGA/dextran scaffolds may be used as substrates fortissue engineering. However, no further information on thestructure control and cell growth has been reported on thissystem yet.

    2.3.3.2. PLGA with PEG-g-CHN. It is difficult to incorporatehydrophilic drugs into the hydrophobic scaffolds (e.g. PLGA)by electrospinning. Jiang et al. [43] synthesized a graftcopolymer, poly(ethylene glycol)-g-chitosan (PEG-g-CHN)that could encapsulate most hydrophilic drugs, such asibuprofen (an anti-inflammatory agent), and was also compat-ible with the PLGA matrix. The unique structure of PEG-g-CHN also showed the controlled release capability ofhydrophilic drugs from electrospun PLGA scaffolds. In theirstudy [43], mixtures of PEG-g-CHN and PLGA with varyingratios were used to fabricate medicated electrospun scaffolds. Itwas found that the addition of PEG-g-CHN decreased the glasstransition temperature of PLGA, resulting in a decrease in thetensile strength at break and an increase in the tensile strain ofthe scaffold. The shrinkage behavior of the electrospun com-posite scaffold at 37 C in the body fluid was also improvedwhen compared with that of the pure PLGA scaffold (e.g. whenthe content of PEG-g-CHN reached 30 wt.%, only a 3% de-crease in the area of the composite scaffold was detected, whilethe shrinkage change of the pure PLGA electrospun scaffoldcould be more than 50% in some cases [43]). More importantly,the presence of PEG-g-CHN significantly slowed down theinitial release rate of ibuprofen from the scaffold and prolongedthe release of ibuprofen for over two weeks. Specifically, at5 wt.% loading of ibuprofen to scaffold, the initial amount ofdrug release reached 45% after day 4, and continuedgradually up to 70% over the next two weeks. This datawas in contrast with the same weight percentage of ibuprofen inPLGA alone, which rapidly reached85% after day 4. Becauseof its desired sustained release rate, Jiang et al. concluded thatthese polymer scaffolds, being mechanically strong andcompliant, could be suitable candidates for the prevention ofpost-surgery induced atrial fibrillation when applied to thesurface of the heart [43].

    Co-electrospinning of PLGA/1,1,1,3,3,3-hexafluoro-2-pro-panol (HFP) solution and chitin/formic acid solution at a weightratio of 80/20, Min et al. [114] generated a compositenanofibrous scaffold with chitin nanoparticles evenly distribut-ed and strongly adhered to the PLGA nanofibers. Both normalhuman keratinocytes and fibroblasts were used to test theefficacy of this unique scaffold for tissue engineering. ThePLGA/chitin composite scaffolds showed better results thanpure PLGA scaffolds on normal human keratinocytes. Howev-

    ery Reviews 59 (2007) 13921412er, on fibroblasts, PLGA/chitin and PLGA showed similarperformance, with no improvement observed on the PLGA/chitin electrospun scaffold [114].

  • 2.3.3.3. PLGA with PEG-PLA copolymers. Amphiphilicblock copolymers, containing hydrophobic PLA blocks andhydrophilic poly(ethylene glycol) (PEG) blocks, have showngreat promise in the applications of drug delivery. Thesecopolymers (e.g. diblock PEG-PLA, triblock PEG-PLA-PEG orPLA-drug PEG-PLA) are suitable to encapsulate and protectdrug or DNA molecules, whereby the encapsulated drug (gene)/polymer aggregates can be incorporated into the nanofibrousPLGA scaffolds by electrospinning. Since PLGA and PEG-PLA are compatible with each other, the addition of even asmall amount of PLA-PEG block copolymer can significantlychange the hydrophobicity and the degradation rate ofelectrospun PLGA-based scaffolds [115]. Blending PEG-PLAcopolymers is, thus, an effective way to fine-tune the propertiesof PLGA-based scaffolds for different biomedical applications.

    For drug delivery, our group has recently demonstrated thatthe release of cefoxitin sodium (Mefoxin), a hydrophilicantibiotic drug, could be modulated by the addition of a diblockPEG-b-PLA copolymer (Mw of PEG and PLA are 5 K and 4.6 K,respectively) in an electrospun PLGA scaffold [45]. Fig. 3 showsthe effect of PEG-b-PLA on the cefoxitin sodium release profile.

    D. Liang et al. / Advanced Drug DelivFig. 3. Drug (cefoxitin sodium) release profiles (cumulative curve-top anddifferential curve-bottom) from medicated electrospun scaffolds. The data

    represents the meanS.D. (n=5 scaffolds): (a) medicated PLGA with 1 wt.%drug, (b) medicated PLGA/PLA/PEG-b-PLA blend with 5 wt.% drug, and(c) medicated PLGA with 5 wt.% drug. (From Ref. [45] with permission).Without the block copolymer, about 75% of cefoxitin sodiumwas released in one day; while with 15 wt.% of PEG-b-PLA,only about 60% of cefoxitin sodiumwas released in one day. Therapid initial burst release was designed to prevent bacteriainfection immediately after surgery, but the prolonged secondarydelivery profile was also desirable in order to minimize potentialbacteria growth. The efficacy of released cefoxitin sodium waschecked by an inhibition study using S. aureus bacteria culture.The results showed that the process of electrospinning did notcompromise the efficacy of this drug. In other words, thestructure and bioactivity of cefoxitin sodiumwas retained duringthe processes of drug incorporation and electrospinning [45].

    Using a triblock PLA-PEG-PLA copolymer (Mw of PEG andPLA are 3.4 K and 0.6 K, respectively), our group also reportedthatDNAmolecules could be incorporated and then released fromelectrospun scaffolds in a controlled manner [47]. With additionof 1015 wt.% PLA-PEG-PLA, the release of -galactosidaseencoding plasmid DNA from the gene-containing electrospunPLGA scaffold was sustained over 20 days, with the maximumamount of release occurring within about 2 h. The cumulativerelease profiles indicated that the amount of DNA released wasapproximately 6880% of the initial load. Fig. 4 shows thetransfection activity of the released DNA from the electrospunscaffold. Results indicated that DNA released directly from thePLGA scaffolds was indeed intact, capable of cellular transfectionand successfully encoding the protein -galactosidase [47].

    Our group also evaluated the potential use of a compositescaffold containing PLGA, PEG-PLA diblock copolymer andcefoxitin sodium to prevent surgery-induced adhesion [42].Acting as a physical barrier but with drug delivery capability,this electrospun medicated PLGA-based scaffold was able tocompletely prevent any adhesion formation after 28 days usingan objective rat model. The combined advantages of thecomposition adjustment, drug-loading capability, and easyplacement handling ability in the body (the material is relativelyhydrophobic) have made these scaffolds potential candidates forfurther clinical evaluations [42].

    A composite scaffold formed by electrospinning of a multi-component mixture containing PLA, PLGA, triblock copoly-mer of PLA-b-PEG-b-PLA and lactide was fabricated by ourgroup [115]. The objective of choosing multi-components wasto precisely control the physical and biological properties of thescaffold, with each component providing a different function.For example, PLA of high molecular weight provided theoverall mechanical strength, PLA-PEG-PLA affected thehydrophilicity, PLGA coarse-tuned and lactide fine-tuned thedegradation rate[115]. We found that a scaffold containing40 wt.% high molecular weight PLA, 25 wt.% low molecularweight PLGA, 20 wt.% PLA-PEG-PLA and 15 wt.% lactideshowed a suitable degradation profile, good hydrophilicity, andstable mechanical properties in aqueous solution (and bodyfluids) for the prevention of post-operative adhesion [115].

    2.3.3.4. PLGA with other polymers. Many other biocompat-

    1399ery Reviews 59 (2007) 13921412ible and biodegradable polymers have been mixed together withPLGA based polymers to form nanofibrous scaffolds byelectrospinning. For example, mixtures of PLA with poly

  • eliv1400 D. Liang et al. / Advanced Drug D(vinylpyrrolidone) [116], and of PLA with poly(ethylene-co-vinylacetate) [117] were fabricated into nanofibrous scaffoldsby electrospinning for biomedical applications.

    2.3.4. Synthetic polymer blends containing PEO/PEGPoly(ethylene oxide) (PEO) or poly(ethylene glycol) (PEG,

    when the molecular weight is small, say less than 5000 Da) is aunique polyether diol, which is amphiphilic and can bedissolved in both organic solvents and aqueous solutions,including pure water. PEO/PEG is non-toxic and can beeliminated by renal and hepatic pathways, making it suitable formany biomedical applications. Thus far, PEO/PEG has beenused as the electrospun scaffold mainly for two reasons: (1) toimprove the fiber property and functions (e.g. hydrophilicity),and (2) to facilitate electrospinning of other more difficult toprocess biomaterials as a processing aid. For example, in firstapplications, PEG has been incorporated in the electrospunscaffolds in the form of copolymers, such as PEG-g-CHN [43]and PEG-PLA [45,118] described earlier. Duan et al. [50]fabricated nanofibrous scaffolds by co-electrospinning mixturesof chitosan and PEO in aqueous solutions containing 2 wt.%acetic acid. With the PEO/chitosan mass ratio of 2:1 or 1:1, finefibers with two diameter distributions (the diameter ranged from80 nm to 180 nm) were obtained from solutions of 46 wt.%chitosan/PEO concentrations. They found that thick and thinfibers were formed mainly by PEO and chitosan, respectively[50]. Spasova et al. [119] applied electrospun chitosan/PEOscaffolds for delivery of potassium 5-nitro-8-quinolinolate

    Fig. 4. Bioactivity of released DNA in the transfection of MC3T3 cells. (a) Naked DN(Fugene 6), (c) DNA containing scaffold incubated with cell for 4 h, then removed,(From Ref. [47] with permission).ery Reviews 59 (2007) 13921412(K5N8Q), an antimicrobial and antimycotic drug. They showedthat the drug had an effect on the production of fiber diameterand fiber morphology. With 1 wt.% K5N8Q loading in thescaffold based on the chitosan/PEO ratio of 1:1, the resultingnanofibrous mat showed antibacterial and antimycotic activityagainst E. coli, S. aureus and C. albicans [119]. The molecularweight of PEG as a processing aid for electrospinning wasrelatively high, usually larger than 5000 Da. This is because thelower molecular weight PEG has the form of a liquid. Forexample, Xie et al. used oligomeric PEG to facilitate theelectrospinning of two natural proteins: casein and lipaseenzyme [108]. Jin et al. also showed that the addition of a smallamount of oligomeric PEG was able to improve the process-ibility of silkworm fibroin solutions [120].

    2.3.5. Other multi-component polymer systemsOther mixtures of biocompatible and biodegradable poly-

    mers have also been electrospun into nanofibrous scaffolds,such as polyether imide/poly(3-hydroxybutyrate-co-3-hydroxyvalerate) [6]. In addition to polymer blends, blends of syntheticpolymers and inorganic particles, such as silver particles[74,121], calcium carbonate [122], calcium phosphate [123],and hydroxy-apatite [124,125] were also used to preparenanofibrous scaffolds, which were found to be useful inbiomedical applications. Since elemental silver and silver saltshave been used for decades as antimicrobial agents in curativeand preventive health care, Son et al. [74] electrospun celluloseacetate fibers containing AgNO3, which was further reduced to

    A added directly to cell medium, (b) cells transfected with control DNA complex(d) released DNA from scaffold complexed with Fugene 6. Scale bar 100 m.

  • the porosity through the electrospinning processing technology.In this section, we describe several innovative electrospinningtechniques to enhance the functions and properties of electro-spun nanofibers. The new development includes multilayeredelectrospinning, core-shelled electrospinning, two-phase elec-trospinning, blowing-assisted electrospinning and post-align-ment methods. Furthermore, some of these techniques are

    1401elivery Reviews 59 (2007) 13921412silver nanoparticles by a photo-reduction technique using UVirradiation. Silver nanoparticles in cellulose acetate fibers werestabilized by interactions with carbonyl oxygen groups oncellulose acetate and showed very strong antimicrobial activity.Recently, Melaiye et al. [121] prepared Tecophilic nanofibers (afamily of hydrophilic polyether-based thermoplastic aliphaticpolyurethanes), containing up to 75 wt.% silver-imidazolecyclophane gem-diol complex by electrospinning. The nanofi-brous mat encapsulated the silver particles and released them ina sustained profile over a long period of time. Therefore, the rateof bactericidal activity of the silver particles was greatly im-proved and the amount of silver used was much reduced. Suchelectrospun organic/inorganic hybrid scaffolds were found to bevery effective againstE. coli, P. aeruginosa, S. aureus, C. albicans,A. niger and S. cerevisiae [121].

    Fujihara et al. demonstrated that the incorporation of calciumcarbonate (CaCO3) in the electrospun PCL scaffold was able toassist the bone cell regeneration [122]. To achieve the desiredmechanical stability, two layered structures, one formed by neatPCL and one formed by the mixture of PCL and CaCO3 atdifferent compositions, were employed. Good cell attachmentand proliferation was observed in such composite scaffolds. Fanet al. incorporated b-tertiary calcium phosphate (b-TCP) intoelectrospun PLA scaffolds [123]. Compared with pure PLAscaffold, the incorporation of b-TCP increased the hydrophili-city of the scaffold and improved cell adhesion and prolifer-ation, greatly improving its potential for use in tissue engineering.

    Bioceramic hydroxy-apatite and PLA were fabricated intonanocomposite nanofibers by electrospinning [124]. A surfac-tant, hydroxysteric acid (HSA), was added in the system toeffectively disperse hydrophilic hydroxy-apatite powders in thePLA solutions in chloroform. As a result, continuous and uni-form nanofibers with diameters about 12 m were generated.Cellular assay experiments indicated that this scaffold hadexcellent cell attachment and proliferation properties as well asenhanced expression of alkaline phosphatase at 7 days ofculturing. Tomimic the human bonematrix, Kim et al. fabricateda nanocomposite nanofibrous scaffold by electrospinningmixtures of gelation and hydroxy-apatite nanocrystals [125].The hydroxy-apatite/gelatin mixture was lyophilized anddissolved in the organic solvent HFP and then electrospununder controlled conditions. With this method, the hydroxy-apatite nanocrystals were well distributed within the gelatinfibers. Compared to pure gelatin, the nanocomposite nanofiberssignificantly improved the bone-derived cellular activity, thushaving good potential in the application of guided tissue (bone)regeneration [125].

    3. New innovations in electrospinning forbiomedical applications

    Using the schemes of copolymerization and polymermixtures, desirable physical and biological properties ofelectrospun nanofibrous scaffolds can be obtained. However,

    D. Liang et al. / Advanced Drug Dthe performance of the electrospun scaffold can be furthercontrolled by adjusting the diameter and morphology of thenanofibers, desirable 3D patterns (e.g., layered structures) andFig. 5. Confocal micrographs of immunostained myosin filaments in SMCs after

    1 day of culture; (a) on aligned nanofibrous scaffold, (b) on aligned nanofibrousscaffold, overlay image on the aligned fiber, and (c) on tissue culture polystyreneas control. (From Ref. [100] with permission).

  • highly complementary in nature and can be combined togenerate new hybrid materials in the platform of nanofibrousscaffolds with specific and desired properties. The selectedexamples represent only a snapshot of current activities reportedin the community of electrospinning. Without a doubt, there willbe many more innovative developments on the fabricationmethods based on electrospinning technology in the future.

    3.1. Scaffolds with oriented fiber alignment

    During electrospinning, as the velocity of the fiber jet near thecollector is very high (e.g. near a fraction of the speed of sound),the resulting nanofiber is usually collected in a random fashionwithout preferred orientation (i.e., non-woven structure). Forcertain applications in tissue engineering, scaffolds with alignedfibers are often more desirable to guide the cell growth with

    desired anisotropy [27,53,100,126,127]. Several fiber collectionmethods, including (1) auxiliary electrode/electrical field [128130], (2) thin wheel with sharp edge collector [131], and (3)frame collector [28], have been developed to align the fibers onthe collector. The most practical method to align the electrospunscaffold is perhaps by mechanical drawing (e.g. uniaxialdrawing or sequential biaxial drawing) [132]. However, it hasbeen found that with the increase in the stretching extensionratio, the porosity of the scaffold would decrease correspond-ingly. If this is a concern, the sequential biaxial stretchingprocess with asymmetric draw ratios can be effectively used tocontrol both orientation and porosity of the electrospun scaffold.

    The use of oriented electrospun scaffolds has beendemonstrated in several studies. For example, Xu et al. [100]investigated the P(LA-CL) nanofibrous scaffold with alignedfibrous structure and found that human coronary artery smooth

    1402 D. Liang et al. / Advanced Drug Delivery Reviews 59 (2007) 13921412Fig. 6. (a) SEM images of cardiac myocytes cultured on uniaxially stretched align(c) electrical response of cardiac myocytes on electrospun scaffolds (action potentialoptical recording system). (From Ref. [133] with permission).ed PLLA electrospun scaffolds, (b) corresponding confocal micrograph of (a);s were measured using a voltage-sensitive dye di-8-ANEPPS and a micro scale

  • muscle cells (SMCs) attached and migrated along the axis of thealigned nanofibers and expressed a spindle-like contractilephenotype. Fig. 5 illustrates that the distribution and organiza-tion of smooth muscle cytoskeleton proteins inside SMCs wereparallel to the direction of nanofibers. They also found that theadhesion and proliferation rate of SMCs on the alignednanofibrous scaffold was significantly improved when com-pared with those on solid polymer films [100].

    Our group has investigated the structural and functionaleffects of oriented electrospun scaffolds on the growth ofcardiac myocytes (CM) [133]. The orientation was achieved byusing a post-drawing process after electrospinning. Scanningelectron microscopy (SEM) revealed that the fine fiberarchitecture of the non-woven matrix allowed the cardiomyo-cytes to make extensive use of provided external cues forisotropic or anisotropic (oriented) growth, and to some extent tocrawl inside and pull on fibers (Fig. 6a). Structural analysis byconfocal microscopy indicated that CM had a preference forrelatively hydrophobic surfaces (Fig. 6b). Cardiac myocytes on

    Fig. 7a, such a process could produce a multilayered non-wovennanofibrous mesh, in which a hierarchically ordered structurecomposed of different polymer meshes could be obtained. Inmixing electrospinning, two different polymer solutions weresimultaneously electrospun from different syringes under differentprocessing conditions. The spun polymer fibers were mixed on thesame target collector, resulting in the formation of mixed fibermesh (Fig. 7b). Three layered scaffolds, containing segmentedpolyurethane, styrenated gelatin and type I collagen, fabricated byusing the multilayered electrospinning technique, and co-minglednanofibrous scaffold, containing segmented polyurethane and poly(ethylene oxide), fabricated by using the mixing electrospinningtechnique, have been demonstrated [134]. The multilayer electro-spun scaffolds have been further used for guided bone regeneration[122] and biohemostat [135] studies.

    3.3. Fabrication of dual-porosity scaffolds

    The presence of clay nanoparticles is capable of enhancing the

    1403D. Liang et al. / Advanced Drug Delivery Reviews 59 (2007) 13921412electrospun poly(L-lactide) (PLLA) scaffolds developed maturecontractile machinery (sarcomeres). Functionality (excitability)of the engineered constructs was confirmed by optical imagingof electrical activity using voltage-sensitive dyes (Fig. 6c). Thestudy clearly indicates that engineered cardiac tissue structureand function could be modulated by the chemistry and geometryof the provided nano- and micro-textured surfaces.

    3.2. Multilayer electrospinning and mixing electrospinning

    Recently, Kidoaki et al. [134] demonstrated two novel electro-spinning techniques: (1) multilayer electrospinning and (2) mixingelectrospinning (Fig. 7), to fabricate composite scaffolds contain-ing different polymers. In multilayer electrospinning, eachpolymer was electrospun to form its individual layer and wassequentially collected on the same target collector. As shown inFig. 7. Schematic diagram of (a) multilayer electrospinning and (bstrength, stiffness, resistance to heat, andmechanical and physicalproperties of the polymer matrix. Lee et al. [136] used thecombination of electrospinning, based on suspensions containingPLA, solvent and clay nanoparticles, and salt addition, to fabricatea nanofibrous composite. After the salt leaching/gas formingprocess, a unique dual-porosity nanofibrous scaffold based onPLA/clay nanocomposites was generated. As shown in Fig. 8, thescaffold exhibited a 3-D structure with nano-sized pores at theinterstices of the entangled fibers (Fig. 8a) and micro-sized (50300 m) pores formed by the salt particles and gas bubbles(Fig. 8b). Such morphology is desired for scaffolding in tissueregeneration, as the large holes will enable the transportation oftypical cells (in tens of microns) and the small holes will enablethe perfusion of smaller size molecules (e.g. nutrients, growthfactors). The biological activity of the dual-porosity scaffold,however, has not been reported.) mixing electrospinning. (From Ref. [134] with permission).

  • could be immobilized for a long time and then released in acontrolled manner. Therefore, the techniques may offerpotentially useful advantages over other electrospinning techni-ques in the applications of drug delivery and tissue engineering.

    3.5. Fabrication of core-shelled nanofibers

    The fabrication of core-shelled nanofibers by electrospinningwas first reported by Sun et al. [137]. Using this technology,some difficult-to-process polymer solutions could be co-electrospun to form an ultra-fine core within the shell of otherpolymer materials [138]. Fig. 10 shows a typical setup used togenerate the core-shelled structures by electrospinning. Basi-cally, two polymer solutions were co-electrospun without directmixing. Zhang et al. [139] reported the fabrication of a

    elivery Reviews 59 (2007) 139214121404 D. Liang et al. / Advanced Drug D3.4. Two-phase electrospinning

    Immiscible polymer solutions, such as poly(ethylene-co-vinyl acetate) in dichloromethane and bovine serum albumin(BSA) in phosphate-buffered saline (PBS) at a 40:1 ratio, havebeen electrospun to form a fibrousmat, containing a distinct two-phase structure in the resulting fibers [51]. The morphology ofsuch fibers is illustrated in Fig. 9 (left). The incompatible waterphase (BSA in PBS) was encapsulated in the matrix of poly(ethylene-co-vinyl acetate). In Fig. 9 (right), the florescent-labeled protein in PBS could be visualized directly by bothvisible and ultraviolet light, exhibiting different spectroscopicproperties from the polymer matrix [51]. The two-phaseelectrospinning process, using a single spinneret, provides aviable means to incorporate small molecules and/or macro-molecules, including drugs and proteins in the nanofibrousscaffolds, provided that the molecules could withstand theelectrospinning process. The encapsulated bioactive molecules

    biodegradable core-shelled structure with PCL being the shelland gelatin being the core. Transmission electron microscopy(TEM) images and X-ray photoelectron spectroscopy (XPS)analysis confirmed the encapsulation of the gelatin within thePCL phase. This technique can be particularly useful inproducing surface-modified nanofibers, functional nanocompo-sites, and even continuous hollow fibers.

    Another advantage of the core-shelled fiber is that the shell

    Fig. 8. SEM image of PLA/clay nanocomposite scaffold by electrospinning andsalt leaching/gas foaming methods. (From Ref. [136] with permission).protects the material in the core during the electrospinningprocess. This feature is even more attractive when bio-relatedmaterials are employed to form nanofibrous scaffolds. Forexample, Jiang et al. electrospun a fiber with poly(-caprolactone)as the shell and BSA together with dextran as the core [140].Withthe help of dextran and the protection of the shell, BSAwas nearlyintact during the electrospinning process. A release of BSA in acontrolled manner was achieved by the formation of the core-Fig. 9. Visualization of fluorescently labeled protein encapsulated in polymerfibers using visible (a) and ultraviolet (b) light. (From Ref. [51] withpermission).

  • shelled fiber [140]. Besides proteins, the shell has the ability toprotect even living cells. Recently, Townsend-Nicholson andJayasinghe [141] demonstrated that, with poly(dimethylsilox-ane) (PDMS) forming the shell, the cell suspension inside the

    3.6. Blowing-assisted electrospinning technique

    To date, it is believed that nearly one hundred differentpolymers have been successfully electro-spun [28]. However,

    Fig. 10. A setup used to generate core-shelled structure by electrospinning. (From Ref. [138] with permission).

    1405D. Liang et al. / Advanced Drug Delivery Reviews 59 (2007) 13921412core suffered almost no cellular damage during the fabricationprocess. Fig. 11 shows the fluorescent micrographs of core-shelled fibers obtained at two different flow rates. Obviously,the Rhodamine 6G labeled cells, which are red in color underthe microscope, were safely encapsulated by PDMS afterelectrospinning [141].Fig. 11. Characteristic fluorescent micrographs showing the variation in fiber diamet1012 m3/s, polymer solution, 1011 m3/s; (b) cell suspension, 108 m3/s, polymer sthere are many more polymers that could not be electro-spunsuccessfully. One of them is hyaluronic acid (HA), a naturallyoccurring polysaccharide, commonly found in connectivetissues in the body, such as vitreous, umbilical cord, and jointfluid, due to its very high solution viscosity and high surfacetension, even at fairly low solution concentrations.er that results from cell encapsulation. Flow rate conditions: (a) cell suspension,olution 107 m3/s. (From Ref. [141] with permission).

  • ma

    1406 D. Liang et al. / Advanced Drug Delivery Reviews 59 (2007) 13921412Our research group has successfully demonstrated thefabrication of high molecular weight HA nanofibers using theblowing-assisted electro-spinning technique, which combinedthe process of electro-spinningwith air blowing capability aroundthe spinneret (a schematic diagram of the setup is shown inFig. 12) [32,65]. In this study, the effects of various experimental

    Fig. 12. A setup of blowing-assisted electrospinning device that can processparameters, such as air-blowing rate, HA concentration, feedingrate of HA solution, applied electric field, and type of collector onthe performance of blowing-assisted electro-spinning of HAsolution were investigated.With the assistance of air-blowing, theHA solution feeding rate could be increased to 40 l/min/spinneret and the applied electric field could be decreased to2.5 kV/cm. The optimum conditions for consistent fabrication of

    Fig. 13. Surface modification scheme for galactose conjugation to PCLPEEPHA (with a molecular weight about 3.5 million) nanofibersinvolved the use of an air blowing rate of around 70 ft3/h and aconcentration range between 2.5 to 2.7 wt.% in aqueous solution.

    We demonstrated that there were at least four advantages inthe electro-blowing process [32]. (1) The combination of airblowing force and the applied electric field is capable of over-

    terials usually difficult to be electrospun. (From Ref. [32] with permission).coming the high viscosity, as well as the high surface tension, ofthe polymer solution. (2) The use of elevated temperature of theblown air can further decrease the HA solution viscosity at thespinneret, facilitating the jet formation of the HA solution at thespinneret. (3) The blowing air can accelerate the solvent evap-oration process, a necessary condition for the fiber formationbefore the solution jet stream reaches the ground collector during

    nanofiber mesh and spin-cast film. (From Ref. [142] with permission).

  • the process. (4) The fiber diameter, which is one of the keyfactors to control the physical properties of nanofibrousmembranes, can be tailored by controlling the air temperatureand the air flow rate. With these advantages, it is expected thatmany useful polymers, which could not be electro-spun untilnow, can be processed by using the new electro-blowing ap-proach. Furthermore, the electro-blowing process shall signif-icantly increase the production rate and thus can lead to practicalmass production schemes.

    4. Modifications of post-electrospun scaffolds

    Although the combined use of different polymer preparationschemes (e.g. copolymers and mixtures) and innovativeelectrospinning techniques can significantly improve physicaland biological properties of nanofibrous scaffolds, furthermodifications on the surface of electrospun nanofibers are oftenneeded in order to refine their in vivo or clinical usage. In otherwords, surface modifications of electrospun scaffolds withsuitable bioactive molecules are often essential to render thematerials with more desirable biological features for biomedical

    hydrochloride (EDC). During cell culture, hepatocyte was ableto adhere to the surface through the galactose-asialoglycoproteinreceptor (ASGPR). Besides the electrospun nanofibrous scaf-folds, spin-coating films containing the same material were alsosurface-modified using the same procedure. The authors showedthat hepatocytes cultured on the electrospun galactosylatedscaffolds clearly exhibited superior biological properties, includ-ing cell attachment, albumin synthesis and 3-methylcholanthrene-induced cytochrome P450 function, to hepatocytes cultured onunmodified electrospun scaffolds [142]. Selected SEM images ofhepatocytes after 8 days of culture on galactosylated spin-castfilms and electrospun scaffolds are shown in Fig. 14.Hepatocytes,cultured onmodified electrospun scaffolds, formed spheroids thatengulfed the galactosylated nanofibers (Fig. 14df); the spheroidswere immobilized on the scaffold and would not detach from thescaffold upon agitation, which was quite different from that onmodified spin-cast films (Fig. 14ac). Based on these results, theyconcluded that hepatocyte spheroid immobilization and stabili-zation strategy through the use of galactosylated nanofibrousscaffolds would be advantageous in the design of a bioartificialliver-assist device [142].

    1407D. Liang et al. / Advanced Drug Delivery Reviews 59 (2007) 13921412applications.Chua et al. [142] reported an approach to modify the poly

    (-caprolactone-co-ethyl ethane phosphate) (PCLEEP) nanofibersurface by grafting a hepatocyte-specified galactose ligand forhepatocyte culture. Fig. 13 schematically shows the surfacemodification procedure. In brief, electrospun PCLEEP nanofi-bers, having an average diameter of about 760 nm, were firstcleaned by ethanol and grafted with poly(acrylic acid) (PAA) byphoto-induced polymerization. 1-O-(6-aminohexyl)-D-galacto-pyranoside (AHG) and then conjugated to PAA chains in asodium phosphate buffer containing N-hydroxysulfosuccinimide(NHS) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimideFig. 14. SEM images of hepatocytes after 8 days of culture: (ac) hepatocytes cultuhepatocytes cultured on galactosylated electrospun scaffold showed aggregates enguUsing a similar strategy, Ma et al. [40] grafted gelatin ontothe electrospun poly(ethylene terephthalate) (PET) nanofibrousscaffolds by using a chemical scheme to overcome the chemicaland biological inertness of the PET surface. The scheme is asfollows. The electrospun PET scaffold was fixed on a piece ofglass with glue and then treated with formaldehyde to introducehydroxyl groups. Methacrylic acid was polymerized on thesurface with Ce(IV) as the initiator, followed by the grafting ofgelatin with carbodiimide as the coupling agent. They tested thebioactivity of the gelation-modified electrospun PET scaffoldby using endothelial cells (ECs). Compared with the unmod-ified PET scaffold, the gelatin-modified PET scaffold showed ared on galactosylated spin-cast film formed around spheroids; (df) in contrast,lfed the functional nanofibers. (From Ref. [142] with permission).

  • elastomeric nonwoven media, Advances in Filtration and Separation

    elivclear improvement in cell adhesion, spreading and proliferation.Moreover, the modified scaffold preserved the EC's phenotype[40].

    Wang et al. [35] demonstrated that the surface of anelectrospun cellulose acetate scaffold was able to immobilizeenzymes after being modified with PEG spacers. The modi-fication scheme is as follows. The electrospun celluloseacetate nanofibrous scaffold was hydrolyzed and followed bygrafting of PEG diacylchloride. Lipase enzyme was thenattached to the scaffold surface through the coupling withPEG spacers. Their result showed that the bound lipase ex-hibited much better retention ability of catalytic activity afterexposure to cyclohexane (81%), toluene (62%) and hexane(34%) than the activity of the free lipase (25%). More im-pressively, the bound lipase showed significant catalyticactivity, up to 810 more times at 6070 C than that of thefree form [35].

    Surface modifications of electrospun scaffolds can signifi-cantly improve the biological performance while retaining allnanostructure features and properties. The modification schemewill be application specific and material dependent. In general,electrospun nanofibers should first be functionalized by areactive spacer, which can then couple with other bioactivemolecules to modify the physical or biological properties. Asthe electrospun nanofibrous scaffold has a very large surfacearea-to-volume ratio, such modifications will be extremelyuseful to generate new nanostructured materials with novelfunctionality for biomedical applications.

    5. Conclusion

    Electrospun nanofibrous scaffolds showed great promise andpotential for many biomedical applications, such as tissueengineering, wound dressing, immobilized enzymes andcontrolled-delivery of drugs (genes). As described in thisreview, a successful creation of nanofibrous scaffolds must startwith the proper selection of materials, a judicious and realisticfabrication pathway, and possible post-modification withfunctional reagent. The polymer material selection plays a keyrole in the fabrication of scaffolds. Many desirable propertiescan be achieved by polymer mixing (natural and/or syntheticpolymers), copolymerization or a hybrid of materials andprocessing techniques. Multi-component mixtures can bemiscible or immiscible, containing different phases (liquid orsolid). Several newly developed innovative electrospinningmethods have been described, including oriented scaffolds,multilayer electrospinning, mixing electrospinning, fabricationof dual-porosity scaffolds, two-phase electrospinning, fabrica-tion of core-shelled nanofibers and blowing-assisted electro-spinning. The processing schemes can be further combinedor/and modified to generate new morphology based on theplatform of nanofiber technology. Finally, the surface modifi-cation of electrospun scaffolds with suitable bioactive agents isan effective means to fine-tune the functionality of nanofibers

    1408 D. Liang et al. / Advanced Drug Dfor specific biomedical applications. The electrospinningtechnology platform can indeed offer the versatility and uniquenanostructure features beyond most existing technologies.Technology 15 (2002) 525537.[13] P. Gibson, H. Schreuder-Gibson, D. Rivin, Transport properties of porous

    membranes based on electrospun nanofibers, Colloids and Surfaces. A,Physicochemical and Engineering Aspects 187188 (2001) 469481.

    [14] L. Wannatong, A. Sirivat, Electrospun fibers of polypyrrole/polystyreneblend for gas sensing applications, PMSE Preprints 91 (2004) 692693.

    [15] X.Y. Wang, Y.G. Kim, C. Drew, B.C. Ku, J. Kumar, L.A. Samuelson,Electrostatic assembly of conjugated polymer thin layers on electrospunnanofibrous membranes for biosensors, Nano Letters 4 (2004) 331334.

    [16] B. Ding, J. Kim, Y. Miyazaki, S. Shiratori, Electrospun nanofibrousmembranes coated quartz crystal microbalance as gas sensor for NH3detection, Sensors and Actuators. B, Chemical B101 (2004) 373380.Acknowledgment

    Financial support of this work was provided by a NationalInstitutes of Health-SBIR grant (GM63283-03), administeredby Stonybrook Technology and Applied Research, Inc, theNational Science Foundation (DMR 0454887), and ClemsonUniversity and UC, Berkeley for subcontracts to their NIHgrants. The assistance of Dr. Dufei Fang in the preparation ofthis review is gratefully acknowledged.

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