Electrospinning of Polymeric Nanofibers for Tissue ... spinning process, ... bead-free fibers.35...

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    INTRODUCTION

    ELECTROSPINNING HAS GAINED POPULARITY in the last10 years due in large part to an increased interest innanoscale properties and technologies. This technique al-lows for the production of polymer fibers with diametersvarying from 3 nm to greater than 5 m.1 Potential ap-plications of electrospinning include filtration mem-branes, catalytic nanofibers, fiber-based sensors, and tis-sue engineering scaffolds.13

    One attractive feature of electrospinning is the sim-plicity and inexpensive nature of the setup; the typicalelectrospinning setup consists of a syringe pump, a highvoltage source, and a collector (Fig. 1). During the elec-tro spinning process, a polymer solution is held at a nee-dle tip by surface tension. The application of an electricfield using the high-voltage source causes charge to be in-duced within the polymer, resulting in charge repulsionwithin the solution. This electrostatic force opposes the sur-face tension; eventually, the charge repulsion overcomesthe surface tension, causing the initiation of a jet. As thisjet travels, the solvent evaporates and an appropriate col-lector can be used to capture the polymer fiber. Figure 2Ashows a scanning electron microscopy image of an elec-trospun polymer mesh.4,5 This approach has been used suc-cessfully to spin a number of synthetic and natural610 poly-mers into fibers many kilometers in length.3,5

    Recently, electrospinning has gained popularity withthe tissue engineering community as a potential meansof producing scaffolds. The objective of this review is todescribe briefly the theory behind the technique, exam-ine the effect of changing the process parameters on fibermorphology, and discuss the application and impact ofelectrospinning on the field of tissue engineering.

    THEORY OF ELECTROSPINNING

    The stable electrospinning jet was described in detailby Reneker and Chun as being composed of four regions:the base, the jet, the splay, and the collection.5 In the baseregion, the jet emerges from the needle to form a coneknown as the Taylor cone. The shape of the base dependsupon the surface tension of the liquid and the force of theelectric field; jets can be ejected from surfaces that areessentially flat if the electric field is strong enough.Charging of the jet occurs at the base, with solutions ofhigher conductivity being more conducive to jet forma-tion.5 Electric forces then accelerate and stretch the poly-mer jet, causing the diameter to decrease as its length in-creases. Additionally, solvents with high vapor pressuresmay begin to evaporate, causing a decrease in jet diam-eter and velocity.5 In the next region, Reneker and Chunhypothesized that radial charge repulsions cause the jet

    TISSUE ENGINEERINGVolume 12, Number 5, 2006 Mary Ann Liebert, Inc.

    Electrospinning of Polymeric Nanofibers for Tissue Engineering Applications: A Review

    QUYNH P. PHAM,* UPMA SHARMA, Ph.D.,* and ANTONIOS G. MIKOS, Ph.D.

    ABSTRACT

    Interest in electrospinning has recently escalated due to the ability to produce materials withnanoscale properties. Electrospun fibers have been investigated as promising tissue engineering scaf-folds since they mimic the nanoscale properties of native extracellular matrix. In this review, we ex-amine electrospinning by providing a brief description of the theory behind the process, examiningthe effect of changing the process parameters on fiber morphology, and discussing the potential ap-plications and impacts of electrospinning on the field of tissue engineering.

    Department of Bioengineering, Rice University, Houston, Texas.*These two authors contributed equally to this work.

  • to splay into many small fibers of approximately equaldiameter and charge per unit length.5 The final diameterof the electrospun fibers upon collection is dependentupon how many splays are created.5

    Rutledge and co-workers have recently used high-speed photography with exposure times as low as 18 nsto demonstrate that the jet that appears to splay is actu-ally a single, rapidly whipping jet.11,12 At high electricfields after traveling a short distance, the jet becomes un-stable, begins to whip with a high frequency, and under-goes bending and stretching.11 The group modeled thebehavior of the jet in terms of three instabilities: the clas-sical Rayleigh instability and two conducting modes.The axisymmetric Rayleigh instability is dominated bysurface tension and is suppressed at high electric fieldsor charge densities.11 The conducting modes are inde-pendent of surface tension and are dominated by electricforces; one conducting mode is axisymmetric and theother is nonaxisymmetric (whipping instability).11,13,14

    Rutledge and co-workers examined the competition be-tween these instabilities for various applied electric fieldsand the flow rate and determined the dominant mode.11

    They constructed operating diagrams that outlined theconditions at which whipping could be expected; theirpredictions agreed well with experimental results.11

    PARAMETERS OF ELECTROSPINNING PROCESS

    From the previous description of theory, it is clear thatthe electrospinning process can be manipulated by a num-ber of variables. Doshi and Reneker classified the pa-rameters that control the process in terms of solutionproperties, controlled variables, and ambient parameters.4

    Solution properties include the viscosity, conductivity,surface tension, polymer molecular weight, dipole mo-ment, and dielectric constant. The effects of the solutionproperties can be difficult to isolate since varying one pa-rameter can generally affect other solution properties(e.g., changing the conductivity can also change the vis-cosity). Controlled variables include the flow rate, elec-tric field strength, distance between tip and collector, nee-dle tip design, and collector composition and geometry.Ambient parameters include temperature, humidity, andair velocity. In this section, studies that investigate theeffect of each parameter on electrospun fiber morpholo-gies and sizes are highlighted.

    Viscosity/concentration

    Solution viscosity (as controlled by changing the poly-mer concentration) has been found to be one of thebiggest determiners of fiber size and morphology whenspinning polymeric fibers. The relationship between the

    PHAM ET AL.

    polymer viscosity and/or concentration on fibers obtainedfrom electrospinning has been studied in a number of sys-tems,1525 including poly(DL-lactic acid) (PDLA),15

    poly(lactic-co-glycolic acid) (PLGA),16 poly(ethyleneoxide) (PEO),9,1719 poly(vinyl alcohol) (PVA),2023

    poly(methyl methacrylate) (PMMA),24 polystyrene,25

    poly(L-lactic acid) (PLLA),26 gelatin,6 dextran,8 and col-lagen type I-PEO.9 At low polymer concentrations, defects in the form of beading and droplets have beenobserved (Fig. 2B);6,8,9,15,17,19,21,22,25,2733 the processunder these conditions was characteristic of electrospray-ing rather than spinning.28 Additionally, the presence ofjunctions and bundles have been seen, indicating that thefibers were still wet when reaching the collector.17 In-creasing the solution viscosity by increasing polymer con-centration yielded uniform fibers with few beads and junc-tions.6,9,17,25 In some cases, increasing the concentration ofa polymer solution can also affect its surface tension;17

    however, for polystyrene solutions with constant surfacetension, beading still decreased with increased viscosity.25

    This result indicates that the variation in viscosity was re-sponsible for the morphological change of the fibers.25 Forsolutions that were too concentrated (and therefore too vis-cous), the droplet dried out at the tip before jets could beinitiated, preventing electrospinning.15,28,34

    Attempts have been made to quantify the minimumpolymer concentrations and viscosities required to elec-trospin fibers. Koski et al. found that it was possible tospin PVA as long as []c 5 where [] was the intrin-sic viscosity and c was the concentration.20 For PEO, itwas found that solutions with []c 10 allowed for spin-ning.18 McKee et al. found that a concentration greaterthan the entanglement concentration, ce, was required tospin linear and branched poly(ethylene terephthalate-co-ethylene isophthalate) (PET-co-PEI).35 Solutions withconcentrations 2-2.5 times the entanglement concentrationyielded uniform, bead-free fibers.35 Recently, Gupta et al.synthesized PMMA and determined the critical chain over-lap concentration, c*.24 They determined that when the so-lution concentration was less than c* there was insufficientchain overlap to form polymer fibers; at all conditions,droplet formation was observed.24 In the semi-dilute re-gion (concentrations between c* and ce), beading was oc-casionally observed. At concentrations approximately dou-ble ce, uniform, bead-free fibers were obtained.24

    The diameter of the fibers produced by electrospinninghas been found to increase with increasing solution con-centration.6,17,3537 For example, PLLA fibers with di-ameters of 100-300 nm were produced from 1 wt% so-lutions while 5 wt% solutions yielded 800-2400 nmfibers.26 Additionally, the diameter of PVA fibers in-creased from 87 14 nm to 246 50 nm by increasingthe PVA concentration from 6 to 8%.21 It was found thatan increased fiber diameter correlated directly to a de-crease in the surface area of electrospun mats.37

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  • Researchers have aimed to find a relationship betweensolution concentration and the fiber diameter. For exam-ple, it was found that increasing the concentration ofgelatin yielded fibers with an increasing diameter ac-cording to a power law relationship.6 For polyuretha-neurea, it was found that fiber diameter was proportionalto c3 for solutions of a single polymer molecular weight.28

    McKee et al. found for PET-co-PEI solutions that theconcentration could be normal