ng C 27 (2007) 504–509www.elsevier.com/locate/msec

Materials Science and Engineeri

Electrospinning for tissue engineering scaffolds

J. Lannutti a,⁎, D. Reneker b, T. Ma c, D. Tomasko d, D. Farson e

a Department of Materials Science and Engineering, Ohio State University, Columbus, OH 43210, USAb Maurice Morton Institute of Polymer Science, University of Akron, Akron, OH 44325, USA

c Department of Chemical Engineering, FAMU-FSU College of Engineering, Tallahassee, FL 32310, USAd Department of Chemical and Biomolecular Engineering, Ohio State University, Columbus, OH 43210, USA

e Department of Industrial, Welding & Systems Engineering, Ohio State University, Columbus, OH 43210, USA

Available online 27 June 2006

Abstract

Tissue engineering involves fabrication of three-dimensional scaffolds to support cellular in-growth and proliferation. The goal: generation of‘neotissues’ that the body can adapt to carry out physiological function. To achieve this generation of scaffolds having tailored, biomimetic (acrossmultiple scales) geometries has become important. The functional complexity of electrospun scaffolds provides significant advantages over othertechniques; however, improvements are required before optimal utilization in vivo becomes routine. Cells on such surfaces are sensitive totopography. Electrospinning can be altered to influence either (1) the surface topography of the fibers themselves or (2) the larger topography ofthe ‘web’ of spun fibers. Improved deposition efficiencies are a necessary advance needed to maintain the attractiveness of this technique. Whilethe role of residual solvent in the electrospun polymer remains unclear, high pressure CO2 can be used to enhance chemical functionality whilemaintaining polymer morphology. Electrospun pore sizes, as spun, are typically too small for cells to pass through. Post-processing of thesescaffolds to improve internal proliferation is expected to yield considerable benefits as tissue engineering matures as a subdiscipline and the limitsof the basic electrospinning process are more widely realized.© 2006 Elsevier B.V. All rights reserved.

Keywords: Scaffolds; Electrospin; Topography; Tissue engineering; Nanofibers; Biomaterials

1. Introduction

The National Institute of Biomedical Imaging and Bioengi-neering (NIBIB) (http://www.nibib1.nih.gov/) defines tissueengineering as “a rapidly growing area that seeks to create,repair and/or replace tissues and organs by using combinationsof cells, biomaterials, and/or biologically active molecules”. Ingeneral, tissue engineering involves the fabrication of three-dimensional scaffolds that can support cell in-growth andproliferation. In this context, the generation of scaffolds withtailored, biomimetic geometries (across multiple scales) hasbecome an increasingly active area of research [1–10]. At thispoint in history tissue engineering is largely an Edisonianexercise in which the scaffold provides mechanical supportwhile host-appropriate cells populate the structure and depositextracellular matrix (ECM) components specific to the organtargeted for replacement. The current goal is a ‘neotissue’ that

⁎ Corresponding author. Tel.: +1 614 292 3926; fax: +1 614 292 1537.E-mail address: lannutti.1@osu.edu (J. Lannutti).

0928-4931/$ - see front matter © 2006 Elsevier B.V. All rights reserved.doi:10.1016/j.msec.2006.05.019

the body can “work with” and eventually adapt to carry out thefull range of expected biological activities.

The primary constituent of the various ECM's involved istypically collagen; the ratios of collagen type and hierarchicalorganization define the mechanical properties and organizationof the evolving neotissue. In addition, the ECM provides cellswith a broad range of chemical signals that regulate cellfunction. Ideal scaffolds probably approximate the structuralmorphology of the natural collagen found in the target organ.

The ideal scaffold must satisfy a number of often conflictingdemands: (1) appropriate levels and sizes of porosity allowingfor cell migration; (2) sufficient surface area and a variety ofsurface chemistries that encourage cell adhesion, growth,migration, and differentiation and (3) a degradation rate thatclosely matches regeneration rate of the desired natural tissue.While a broad range of tissue engineering matrices have beenfabricated, a few types of synthetic scaffolding show specialpromise. Structures composed of the thin fibers generated byelectrospinning fall into this category as demonstrated by thewidespread use of the process.

Fig. 1. Fibers containing high concentrations of solvent can form mechanicalconnections with other fibers at their crossing points. This creates a three-dimensional (i.e., conglutinate) network.

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Electrospinning produces non-woven meshes containingfibers ranging in diameter from tens of microns to tens ofnanometers. Synthetic or natural materials can be used thateliminate concerns regarding unfavorable immune responses ordisease transmission. Synthetic polymers typically allow agreater ability to tailor mechanical properties and degradationrate. Clearly, the electrospinning process can eventually bedeveloped to achieve successful utilization in vivo on a routinebasis. Advances in processing techniques, morphologicalcharacteristics and interesting, biologically relevant modifica-tions are underway.

The objective of this work is to examine components of theelectrospinning process that can improve the ‘downstream’suitability of electrospun fibers and structures for biologicalimplementation. Specific opportunities for improvement thatare not immediately obvious in this particular context are noted.

2. Background

Polymer fibers ranging from 10 to 100 μm can be producedby conventional melt, dry, or wet spinning processes. Mostcommonly, a polymer melt is extruded and subsequently drawn.For the generation of finer fibers, ranging from 15 nm to 10 μmor greater, electrospinning is a broadly useful technology.Electrospinning relies on the application of an electrostatic forceto drive fiber formation. The fibers are often collected in a non-woven mesh characterized by high surface area/unit mass. Alarge fraction of the volume of such non-woven meshes is in theform of interconnected porosity.

Interest in the electrospinning technology was recentlyrevived when Reneker et al. first demonstrated that a multitudeof polymers could be electrospun [11] and refined the associatedtheory [12]. Hundreds of different natural and syntheticcompositions have been electrospun into thin fibers since 1990.

3. The electrospinning process

The elements required for electrospinning include a polymersource, a high voltage supply, and a collector [13]. When anelectric potential is applied between the polymer source andcollector, charge accumulates and is forced to the surface of anemerging polymeric droplet at the end of a metal needle. Inelectrospinning, the force of the electric field overcomes thecohesive force of the solution, often dominated by surfacetension, and an electrically charged jet of polymer-containingsolution erupts. As the jet moves toward the collector plate, it iselongated by electrostatic interactions between charges onnearby segments of the same jet. Meanwhile, the solventevaporates and finally the jet solidifies into a fiber. Typicalelectrospinning processes create very long fibers that can varyin diameter along the length from one half to as much as twicethe average diameter. The diameter of these fibers may beconsiderably larger than the nanometer scale.

While the electrospinning process itself is over 70 years old,the concept of electrospun scaffolding for biomedical applica-tions appears to have first emerged in 1978. “An ElastomericVascular Prosthesis” was reportedly produced from polyure-

thane elastomer utilizing “electrostatic spinning” by Annis et al.[14]. In another first, the authors produced tubes by the nowcommon expedient of deposition onto a rotating mandrel. Thesetubes were used to replace lengths of the thoracic aorta in 42mini-pigs. Even without prior cell seeding, these graftsapparently demonstrated full patency over a period of manymonths in vivo even though the maximum burst pressure wasonly ∼800 mm Hg [14].

4. Surface morphology

It is well known that cells are sensitive to the topography ofthe supporting surface although the exact reasons for this areunclear. In electrospinning, there are techniques that can be usedto influence the nanoscale surface morphology of the fibersthemselves [15]. A great variety of such nanoscale surfaces canbe made to support cells. The search for surfaces having strong,well-defined beneficial influences on cell growth is an activesubject of contemporary research. At a slightly larger scale (1 to10 μm), the electrospinning process has an additional role indetermining topography. Spindle-shaped beads or nearlyspherical beads on the nanofibers may be produced. Solventvolatility is a factor: if the fluid jet is collected prior to completesolvent evaporation, the deformable fibers may either flattenupon impact with the surface of a collector or adhere to otherfibers. If the arriving jet or fiber lands on previously collectedfibers the still fluid material can merge and coalesce at crossingpoint to create a conglutinated network (Fig. 1). Conglutinatednetworks appear to be useful in some situations where a well-established network is desirable.

Bead-on-a-string morphologies are also sometimes observed(Fig. 2). This is attributed to a complex interaction betweensolution viscosity, net charge density, and surface tension [16].Deliberate neutralization of the charge on a fluid jet allows thefluid to retract towards droplet form and this causes beadformation. In some cases, as the viscosity is decreased, fiberdiameter is decreased and the spindle-shaped beads becomemore spherical. Higher flow rates are observed to have similar

Fig. 2. Beads on electrospun fiber caused by the capillary instability of theejected jet.

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effects. The presence of beads is reportedly reduced by theaddition of a secondary solvent that increased conductionthrough the polymeric solution [17].

Is this phenomenon of concern to the end goal of tissueengineering? The possible effects of beads on biologicalactivity such as cellular proliferation, growth and adhesion arenot clearly anticipated. On the positive side, understanding ofthe development of beads provides another parameter fordesign of scaffolds. For example, beads may prove to be usefulas reservoirs of therapeutics. However, the presence of suchbeading can lead to practical difficulties associated with cellcounting by manual techniques because in either scanningelectron or transmission optical microscopy, these beadsclosely resemble cells (Fig. 3a). For reasons that are notclear, use of a length of plastic tubing between the solutionreservoir and the charged metal needle can reduce beading(Fig. 3b) even though the polymer and solvent combinationremains unchanged.

Fig. 3. Observations of electrospun fiber through a standard optimal microscope in tthickness of the scaffold, all of the beading becomes visible as opposed to just the ssimilarity to cells. In (b), indirect spinning has eliminated the presence of beading.

5. ‘Focused’ electrospinning

One of the overarching influences in electrospinninginvolves the cost of the process. Although constructing afunctional electrospinning apparatus is relatively inexpensive,the literature shows that other economies of scale can drive theresearch focus. The best example of this is that a significantportion of the work on electrospun scaffolds for tissueengineering involves polycaprolactone [18–30], an inexpensivebiodegradable polymer relative to polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA) that are more important inbiomedicine. In biologically-driven investigations, as in perhapsfew other fields, materials costs can be even more impressive.One of the complicating factors associated with electrospinningexpensive biologicals (growth factors, cytokines) in this contextis that the most widely used approaches produce a poorlycontrolled deposition zone even on a simple flat plate! Inmoving toward smaller, more complex components (such astubes formed on spinning mandrels for vascular applications)substantial fractions of the as-spun fiber may actually neverdeposit on the target. This behavior can make research usingexotic polymers and even minimally interesting biologicalsslow, inefficient and financially painful. Better-controlledspinning that utilizes small drops [31] or capillaries can producemuch more directed, efficient deposition. Use of an auxiliaryelectric field can reduce the deposition cross-section to ‘focus’the deposition as demonstrated by Deitzel et al. who constraineda charged jet of a 10 weight percent solution of PEO in a seriesof electrically charged rings [32]. The rings effectively reducedthe size of the area in which the jet was collected. Many otherstrategies for improving control are beginning to emerge.

6. Residual solvent

Electrospinning uses a solution of polymer in a solvent.Some of this solvent may be retained in the resulting polymer

ransmission (10× magnification). In (a), because light passes through the entireurface layer normally visible in SEM. The beading bears a close morphological

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fiber and could affect the biological performance of a scaffoldeither beneficially or adversely. As an example, collagen isused in a number of tissue engineering applications. Naturalcollagen is relatively non-immunogenic; however, solutionprocessing of collagen generally changes both biological andstructural properties. Type I collagen can be dissolved inhexafluoropropanol (HFP) and electrospun. We recentlydetermined that the resulting nanofiber can contain, immedi-ately after spinning, as much as 1600 ppm of residual HFP.Being the fluorinated analog of isopropanol, a commonsterilizing agent, HFP certainly has the potential to negativelyinfluence cell culture. Subsequent treatment with vacuum, andvacuum and heating to remove residual solvent) reduced HFPlevels to well below 100 ppm; whether these levels are lowenough to completely eliminate downstream biological effectsis uncertain. Fortunately, more easily removed or benignsolvents, such as acetone, are widely used. More detailedobservations of the biological effects of residual solvents, or thelack thereof, need to be made.

7. Degradation versus time

A clear example of technical need for the successfuldevelopment of scaffolds made from electrospun fibers is howtheir mechanical behavior is altered during in vitro and in vivoexposures. Increased understanding of the basic principlesgoverning tissue formation requires an improved picture of howthe structure and mechanical properties of the underlyingscaffold change with time. Whether or not the cell plus scaffoldconstruct will have the appropriate overall mechanical proper-ties in the application (which will vary widely depending uponthe target) also depends to an extent upon the degradation of themechanical properties versus time. Transport and retention ofsignaling molecules in the vicinity of the fibers is also anunexamined issue.

We have carried out exposures of electrospun PCL to showthat as much as 70% degradation in tensile strength occursfollowing 28 days in simple biological fluids such as plasma,urine or milk. Equally long exposures to saline, deionizedwater and sodium bicarbonate solution produced a strengthdegradations of only 40%. Parallel measurements of weightversus time showed that plasma and milk exposures caused anet gain in the weight of these fiber networks while all othersolutions resulted in as much as a 20% loss over the same timeperiod. The weight gain in the former is attributed to adsorbedproteins observed to be present in the electrospun fiber evenafter extensive rinsing. A complete understanding of thepotentially competitive effects of fiber degradation, proteindeposition and adherent mammalian cells on neotissueproperties is a worthwhile long-term goal.

8. Adding bioactive function

While electrospun materials have morphological resem-blance to the natural tissues the chemical similarities arepresently less than ideal as practical synthetic polymers cantypically provide morphological not biochemical biomimesis.

There have been efforts to label polymer surfaces with specificchemical signaling factors [33–35] as well as direct electro-spinning of polymer plus biomolecule combinations. Theseefforts seem unlikely to produce a long-term solution but manyother synthesis methods are available. If conformationally-sensitive biomolecules are present, questions and concernsregarding stability or activity in the resulting electrospunpolymer fiber are inevitable [36,37]. In addition, the majority ofthe biomolecule embedded in a fiber may never be exposed atthe external surface of a scaffold during critical portions ofcellular growth and proliferation. Chemically attached biomo-lecules [33–35] benefit from the high innate surface area ofelectrospun materials.

In this context, we recently extended the use of subcriticallevels (i.e., pressures and temperatures below the triple point) ofcarbon dioxide previously demonstrated to cause embedding inbulk biopolymer implants [38] toward adding bioactivity toelectrospun scaffolds after their formation. Carboxytetrameth-lyrhodamine, a fluorescent molecule, was used to test theconcept of impregnation into electrospun PCL utilizingsubcritical CO2. This is necessary as our objective is tophysically entrap molecules in this relatively low Tg polymerwithout deforming the geometric dimensions of the scaffolditself. Since subcritical CO2 is of lower density thansupercritical CO2, foaming during pressure release [39] is nota concern.

Experiments were performed using a view cell similar to thatused in previous work [40]. Five-and-6-carboxytetramethlyrho-damine (Mw=466.92, Molecular Probes®, Eugene, OR) wasdissolved (0.1 mg/ml) in water. A small glass beaker was filledwith 3 ml of carboxytetramethlyrhodamine solution; theelectrospun PCL disks were then placed into solution. A sightgauge (Jerguson Model RW-20) was used to monitor theimpregnation process. The beaker was placed in the view cell,which was then filled with CO2 at 500 psi and 25 °C. Totalcontact time was 2.5 h and the CO2 release rate at the end of theimpregnation was approximately 1.0 ml/min.

Even under these relatively benign conditions we observedsignificant, uniform impregnation of the electrospun fibers. Thesample exposed only to carboxytetramethlyrhodamine solution(in the absence of CO2) for 10 h at 25 °C exhibited littleimpregnation either before or after rinsing. These particularfibers were white in color following rinsing and were thusidentical in appearance to the starting material. In contrast,samples retained a distinctive pinkish color following thecombined CO2 and carboxytetramethlyrhodamine exposure.This pink color was apparent even after a month of release intodeionized water at 37 °C.

The release profiles showed definitive proof of the effect ofsubcritical CO2 on embedding. Carboxytetramethlyrhodaminerelease from the CO2-treated-PCL continued over a period of30 days. Even after 30 days of release into deionized water at37 °C, fluorescence microscopy still showed that carboxyte-tramethlyrhodamine was present in the CO2-treated samples.Samples exposed to carboxytetramethlyrhodamine solutionalone (without CO2) released only for a very short period.After 5 days, there was no significant release from these fibers,

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the limits of detection being 6.5 μg/ml. The amount ofcarboxytetramethlyrhodamine present in the CO2-treated sam-ples after rinsing in phosphate buffered saline was 84.2 μg/mg.The fractional amount remaining in the CO2- treated fibers after30 days of release into deionized water at 37 °C was found to be8.54 μg/mg.

Utilizing these relatively low pressures and temperatures, wedetermined that CO2 can be used to enhance the chemicalfunctionality of well-defined, three-dimensional (3D) tissueengineering scaffolds. The ability to maintain polymermorphology while embedding molecules provided samples forfollow-on studies of cell attachment, proliferation and differ-entiation as well as for potential in vivo applications involving arange of important ‘biologics,’ including growth factors,cytokines, antiproliferatives, antibiotics, analgesics and othermore traditional compounds.

9. Post-processing

A general strategy of tissue engineering is to mimic thedimensions and biological activity of the extracellular matrixcommon in all mammalian cells. This can be achieved via thedevelopment of processes that allow for the fabrication ofstructures with a pore size, porosity, and topography thatmimics in vivo conditions. Electrospinning, as presentlypracticed, typically produces constructs in which the pore sizeis too small for cells to pass. This points to the need forcontrolling the porosity during the spinning process. Theincorporation of salt crystals during the spinning processfollowed by dissolution of the salt is an example. The essentialdemands on tissue engineering scaffolds have become morecomplex and challenging. There exists a need to spatially isolatecells having distinctly different biological function from eachother. Electrospinning has many advantages for producing suchscaffolds but it is not presently used to produce cavities havingprecisely defined dimensions and repeatability. Laser machin-ing of nanofiber structures provides a means of producinguseful cavities and channels within a nanofiber structure via

Fig. 4. ES PCL scaffold textured by femtosecond laser puls

localized heating/melting while preserving essential features ofthe scaffold.

We used a Ti:sapphire pulsed femtosecond pulsed laser tolocally melt (or ‘machine’) electrospun PCL nanofiber. Code toproduce specified geometric patterns was created using textediting software. The distance between the laser source and thePCL surface was kept constant via a feedback system built intothe lasing apparatus to ensure that depth of the cut remainedconstant. The fiber mat was compressed beneath a glass coverslip and the laser focus was adjusted such that machiningoccurred in the PCL just beneath the glass cover slip. The poweroutput of the laser was kept between 8 and 12 mW; a loweroutput produced shallower cavities and a higher outputproduced deeper cavities. In addition, the plunge rate (thepercentage of the maximum speed of the lasing apparatus) wasalso adjusted with respect to the depth of the cavity. A lowerplunge rate, typically between 5 and 15% was set for deeperpenetration processes, while a plunge rate of 25–40% was usedfor significantly shallower penetration. The deeper cavitiestypically required from 3 to 10 min to complete depending onthe complexity of the geometric pattern. Due to time constraints,the plunge speeds were usually set between 12 and 15%.

As Fig. 4 shows, desirable channels were produced whileeffectively preserving the nature of the electrospun fiber withminimal effects on the nearby fibers. By controlling the motionof the beam, a wide variety of patterns could be produced. Bycontrol of sample motion specific patterns (grooves, pores andpore plus groove combinations) were easily produced inelectrospun PCL networks. This capability is expected toyield important benefits as tissue engineering matures and thecapabilities of the basic electrospinning process are more widelypracticed.

Acknowledgments

This material is based upon work supported by the NationalScience Foundation under Grant No. EEC-0425626. Anyopinions, findings, and conclusions or recommendations

es showing minimal effects on the un-processed fibers.

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expressed in this material are those of the authors and donot necessarily reflect the views of the National ScienceFoundation.

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