Preparation of PLLA/PEG Nanofibers by Electrospinning and Potential Applications

Preparation of PLLA/PEGNanofibers by Electrospinning and

Potential Applications

M. SPASOVA, O. STOILOVA, N. MANOLOVA AND I. RASHKOV*Laboratory of Bioactive Polymers, Institute of Polymers, Bulgarian Academy of

Sciences, 1113 Sofia, Bulgaria

G. ALTANKOV

Institute of Biophysics, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria

ABSTRACT: Poly(L-lactide) (PLLA)/polyethylene glycol (PEG) mixed solu-tions were successfully electrospun into micro- or nanofibrous polymer mats.The fiber diameter was in the range 100nm–6�m. The effect of the concentra-tion of the spinning solutions and the ratio of PLLA/PEG on the fiber diameterand morphology was investigated. The hydrophilicity was tuned by varying thePLLA/PEG ratio. The tissue compatibility of the electrospun nanofibrous scaf-folds was screened using two different cell models of human dermal fibroblastsand the osteoblast-like cell line MG-63. Both types of cells attached uniformlyand approximately equally to all PLLA/PEG nanofibers. In long-term culturesosteoblast-like cells tend to spatially organize in tissue-like structure, particu-larly within the scaffold with the highest PEG content (PLLA/PEG at weightratio 70/30). These results indicate that PLLA mixed with hydrophilic PEGproduces a promising new biocompatible material for engineering scaffolds.

KEY WORDS: electrospinning, nanofibers, poly(L-lactide), poly(ethyleneglycol), fibroblasts, osteoblasts, nanoscale fibers, tissue engineering, cellingrowth.

INTRODUCTION

In the last few years, increasing attention has been paid to electro-spinning as an attractive and simple method for preparation of

*Author to whom correspondence should be addressed.E-mail: [email protected]

Journal of BIOACTIVE AND COMPATIBLE POLYMERS, Vol. 22—January 2007 62

0883-9115/07/01 62–76 $10.00/0 DOI: 10.1177/0883911506073570© 2007 SAGE Publications

Electrospun PLLA/PEG Nanofibers 63

nanofibrous materials [1]. Fabrication of micro- and nanosized porousscaffolds from biodegradable polymers, either natural or synthetic byelectrospinning, is a great challenge because of their possible applica-tions, including tissue engineering, tissue repair, wound healing, anddrug delivery [2–7]. The feasibility of generating very small fibers, thatmimic the size scales of fibers composing an extracellular matrix(ECM) of native tissues and organs, is of particular interest. Nanofi-brous scaffolds from aliphatic biodegradable polyesters, such as, poly-lactide (PLA), polyglycolide (PGA), poly(�-caprolactone) (PCL),poly(lactide-co-glycolide) (PLAGA), poly(L-lactide-co-caprolactone)have been successfully electrospun [8–12]. It has been shown that theobtained scaffolds possess a number of advantages, such as, morpho-logical resemblance to the ECM of the native tissues, good cell adhe-sion and proliferation, as well as the possibility to be used as scaffoldsfor bone tissue engineering.

Nevertheless, the high hydrophobicity of these materials restrictcertain applications in the field of tissue engineering. To augment thehydrophilicity of the electrospun fibers, a copolymer with a hydrophilicblock has been added to the spinning solutions. Using this approach,PLAGA fibers with enhanced hydrophilicity have been obtained in thepresence of triblock or diblock copolymers with PLA and polyoxyethyl-ene blocks [13–16]. It has been shown that drugs may be incorporatedin these fibers and that they may also be used as scaffolds in tissueengineering and for postoperative adhesion prevention.

An alternative, and easily achieved approach to modulating thehydrophilicity of the scaffold, is the incorporation of a hydrophilichomopolymer into the spinning solution. PEGs of molecular weightlower than 6,000 are particularly suitable for this purpose. ThesePEGs are widely used in the biomedical field because of their uniqueproperties, including lack of toxicity and good biocompatibility; in addi-tion they are easily eliminated from the human body [17]. To the bestof our knowledge, PEGs have not yet been used in electrospun scaf-folds of PLA polymers and copolymers. The reason may be due to thedifficulty to electrospin nanofibers from polymers of chain lengths thatare to short for the formation of chain entanglements.

In the present study, electrospun poly(L-lactide)-based fibers wereprepared and characterized. The possibility to modulate thehydrophilicity of the nanofibers by adding PEG to the spinning solu-tions was investigated. The PLLA/PEG nanofibrous mats obtainedwere tested with respect to their response to fibroblast and osteoblastcells with a view to potential tissue engineering applications.

64 M. SPASOVA ET AL.

MATERIALS AND METHODS

Poly(L-lactic acid) (PLLA) (M—

w �152,000g/mol, PDI 1.54) and poly-ethylene glycol (M

—r �1,900–2,200g/mol) were purchased from Fluka.

All other reagents were of analytical grade and were used withoutfurther purification.

Preparation and Characterization of PLLA/PEG Nanofibersand Films

The nonwoven nanofibrous mats were obtained by electrospinningof PLLA/PEG solutions in chloroform, at weight ratios 90/10, 80/20,and 70/30, respectively. The total polymer concentration was 5, 7 and9wt%.

The electrospinning technique has been described in our previouswork [18,19]. In a typical run, PLLA/PEG solutions were placed in asyringe with a conical nozzle in which the electrode was immersed.The electrode was connected to a high voltage power supply generat-ing positive DC voltage up to 30 kV. Electrospinning was carried outat a constant value of the applied voltage (11 kV) and at a varying dis-tance from the conical nozzle to the collector (8, 12 and 20 cm). Elec-trospun samples were placed under vacuum to remove any solventresidues.

PLLA and PLLA/PEG films (90/10, 80/20, and 70/30wt ratios) wereobtained by the casting of polymer solutions in chloroform on Petridishes, dried on air and stored under vacuum.

The morphology of the nanofiber mats was observed using scanningelectron microscopy (SEM). The collected nanofibers were vacuum-covered with carbon and/or gold and examined by SEM Philips 515.The average fiber diameters, standard deviation, as well as theminimal and maximal value of the fiber diameters were evaluatedusing Image J software by measuring 20 fibers from each SEM image.In the case of fibers with “bead” defects, the average fiber diameter inthe defect free part, average defect length along the fiber axis (L

–)

and average defect width perpendicular to the fiber axis (W–

) weremeasured.

Static contact angles of distilled water on the surface of the electro-spun mats and films were measured with a DG drops GBX Instru-ments apparatus at 25°C. The experimental procedure was as follows:(a) the electrospun materials were attached to a glass slide, (b) about3�L of distilled water was dropped onto the samples, (c) temporalimages of the droplet were taken, (d) the contact angles were calcu-


lated by computer analysis of the acquired images. The data areaverage values from 10 measurements.

Differential scanning calorimetry (DSC) was determined on a TAInstruments Q10 apparatus at a heating/cooling rate of 10°C/min inargon atmosphere. The samples were heated from 20 to 250°C. Therheological measurements of the PLLA/PEG mixed solutions at 25°Cwere performed on a “Brookfield LUT” viscometer, supplied with anadaptor for small samples, a spindle and a camera SC4-18/13R.

Cells

Two types of cells – human fibroblasts and osteoblasts, were used forthe biological characterization of the obtained mats. Human dermalfibroblasts obtained from fresh skin biopsy were purchased from CellLining GmbH (Berlin, Germany) and used up to twelfth passage.Human osteoblasts-like MG-63 cells were kindly donated by the Labora-tory of Nanobioengineering at the Technical University of Catalonia,Barcelona, Spain. The cells were maintained in Dulbecco’s MEMenriched with 10% foetal bovine serum (FBS), sodium pyruvate andantibiotics (Sigma Chemicals Co., St. Louis, MO) in a humidified incuba-tor with 5% CO2. For these experiments, cells from pre-confluent cultureflasks were harvested with 0.05% trypsin/0.6mM EDTA (Sigma) and re-suspended in DMEM. Trypsin was neutralized with FBS.

Cell Adhesion and Morphology

Interaction of cells with the nanofiber mats was studied in 24 wellTC plates (Falcon Becton Dickinson, USA) containing the samples:mats of nanofibers with different PLLA/PEG ratios directly electro-spun onto standard 15mm round-shaped glass slides. 6�104 cells perwell were seeded on each sample and cultured for 2h in 1mL serum-free medium (fibroblasts and osteoblasts) or 5 days (osteoblasts only)in the presence of 10% serum. All samples were pre-coated with20g/mL fibronectin (FN) for 30min in PBS and washed with PBS. Inorder to prevent the mats from floating, thin Teflon rings adapted tothe inner diameter of the wells were used.

The overall morphology of adhering fibroblasts was studied by SEM.The samples were fixed at the second hour of incubation with 3%paraformaldehyde in PBS for 10min, then washed in deionized water,dehydrated via freeze-drying using type Elta-90 apparatus (Spain) andcovered with gold under vacuum.

The morphology of adhering MG63 cells was determined via vital


staining with fluorescine diacetate (FDA, Sigma), which converts into afluorescent analogue (by cellular esterases) when entering the livingcells. An initial solution of FDA in acetone with a concentration of10mg/mL was prepared, from which 5�L were added to each well, fol-lowed by incubation for 3min. The fluorescent vital cells were observeddirectly from the plates on an inverted fluorescence microscopeAxiovert 100 (Zeiss, Germany).

RESULTS AND DISCUSSION

Electrospinning of PLLA solutions generally results in fibers withdiameters in the range 600–6,000nm [5,8]. Ultra-fine PLLA fibers withaverage fiber diameter 20nm have been obtained using adichloromethane/pyridine mixture as the solvent [20]. We assumedthat the addition of PEG to the PLLA solution will change consider-ably the rheological properties of the solution and, therefore, will haveinfluence on the fiber diameters and morphology obtained. For thisreason the effect of the concentration and PLLA/PEG ratio on the fibermorphology was investigated.

Effect of Total Polymer Concentration

In order to investigate the effect of the total polymer concentrationon the fiber morphology and diameters, solutions with three differentconcentrations (5, 7 and 9%) at a constant PLLA/PEG ratio (70/30)were electrospun. It was found that on increasing the total polymerconcentration of the spinning solutions, the average fiber diameterincreased (Figures 1 and 2). This increase is probably due to theincrease of the solution viscosity. Indeed, for the solutions atconcentrations of 5, 7 and 9%; the dynamic viscosity values were 71,145 and 530cP, respectively.

SEM micrographs and diameter distribution of the fibers are shownin Figure 1. At the lowest concentration of the spinning solutions, thefibers with the smallest diameters were obtained. Furthermore, theaverage diameter of fibers obtained from a spinning solution with aconcentration of 5% was 330nm, and from the solution with concentra-tion �9% was 1,850nm, respectively. However, it was found that atthe lowest solution concentration fibers with “bead” defects withaverage defect length along the fiber axis (L

–) 24±4.4�m and average

defect width perpendicular to the fiber axis (W—

) – 11±2�m, wereformed. When the total polymer concentration was increased defect-free fibers were formed (Figure 1).


It is known that in the more viscous solutions that there are agreater number of entanglements per polymer chain which is a prereq-uisite for the formation of a stable jet compensating the effect of thesurface tension which shrinks the jet. Solutions with a higher contentof the hydrophilic PEG were not studied, because this would lead tofragmentation of the fibers as a result of dissolution of PEG when themats are put in contact with an aqueous medium. In addition, increas-ing the amount of oligomers would considerably decrease the viscosityof the spinning solution which could lead to the transition from elec-trospinning to electrospraying.

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Figure 1. SEM micrographs and diameter distribution of PLLA/PEG fibers, preparedat PLLA/PEG weight ratio 70/30, AFS�1.375kV/cm and different concentrations 5%(A), 7% (B), and 9% (C).


Effect of the Polymer Weight Ratio

For the investigation of PLLA/PEG weight ratio effect, spinningsolutions with constant polymer concentration (5%) and differentPLLA/PEG weight ratios (70/30 and 90/10) were prepared. Solutionswith a higher content of the hydrophilic PEG were not studied,because this would lead to fragmentation of the fibers as a result of dis-solution of PEG. In addition, the low molecular weight of PEG willdecrease considerably the viscosity of the spinning solution whichcould lead to electrospraying.

SEM micrographs of electrospun PLLA/PEG nanofibers at thestudied weight ratios are shown in Figure 3. It was found that increas-

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)

Figure 2. Dependence of the average fiber diameter on the total PLLA/PEG concen-tration. PLLA/PEG weight ratio 70/30, AFS�1.375kV/cm.

(A) (B)

Figure 3. SEM micrographs of PLLA/PEG fibers at different weight ratios 70/30 (A)and 90/10 (B). Total polymer concentration 5%, AFS�1.375kV/cm.


ing PEG content at constant process parameters leads to the formationof fibers with smaller diameters and a greater number of defects. Forinstance the average fiber diameter at PLLA/PEG weight ratio 90/10 is400nm, while at 70/30 it is 330nm.

The measurements of the defect sizes showed that there were nosignificant differences at these weight ratios but the number of defectsat the weight ratio 70/30 was almost twice as high as that at 90/10.This result is not unexpected, since it has been already mentioned,increasing the content of PEG leads to a decrease in the solution vis-cosity and thus an increase in the number of defects. This was alsoconfirmed by the dynamic viscosity values – 297cP for 90/10 weightratio and 71cP for 70/30 weight ratio, respectively.

Effect of the Applied Field Strength (AFS)

It is known that increasing AFS leads to an increase of the electro-static force, acting on the jet, and thus fibers with smaller diametersare formed [12,21]. The obtained results show that the diameters ofthe electrospun fibers decrease slightly on increasing the AFS at a con-stant PLLA/PEG weight ratio and constant polymer concentration(Figure 4).

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Figure 4. Dependence of the average fiber diameter on AFS. Total polymer concentra-tion 5%, PLLA/PEG weight ratio 90/10.


Contact Angle Measurements

The enhanced hydrophilicity was proved by the values of the watercontact angle of the PLLA/PEG nanofibers and solvent-cast films. Onincreasing the PEG content, the values of the contact angledecreased. Whereas the measured contact angle values were almostthe same for the mats and films of PLLA (76 ± 2.2° and 77 ± 1.7°,respectively), the values of the water contact angle of PLLA/PEGmats were lower than those of the films of the same composition. Forexample, for PLLA/PEG (70/30) mats and films the values were59 ± 5.5° and 64 ± 6.2°, respectively. The higher water contact angleof the films may be explained by the peculiarities of the dryingprocess of the solvent-cast films. The higher value of the watercontact angle of films may be explained by the tendency of thehydrophobic PLLA macromolecules to occupy the solution-air inter-face. The contact angle was determined at the surface that was incontact with air and thus enriched in PLLA, therefore, at the samecomposition, higher values of the contact angle were determined forthe films than for the electrospun mats.

From the application point of view, it is important to know thebehavior of the PLLA/PEG scaffolds in water. For this purpose,PLLA/PEG mats with the weight ratio 70/30 were soaked in water for72h. No changes in the morphology or in the size of the fibers wereobserved after this contact with water (Figure 5). These findings showthat degradation of PLLA, which can lead to dissolution and release ofPEG, had not occurred during this time period and under theseconditions.

(A) (B)

Figure 5. SEM micrographs of PLLA/PEG mats (70/30) before water contact (A) andafter 72h water contact (B). Total polymer concentration 5%, AFS�1.375kV/cm.


Thermal Behavior

Data from differential scanning calorimetry analyses of electrospunfibers and of solvent-cast films of PLLA and of mixtures PLLA/PEG(70/30) are shown in Figure 6 for the first heating runs. The endother-mal peaks of melting of the PLLA crystal phase in pure PLLA mats orfilms, and in mixed PLLA/PEG mats and films occurred at a tempera-ture Tm �177±1°C. It is interesting to note that the value of themelting enthalpy (�H) of PLLA mats is considerably higher (56.4J/g)than that for the PLLA films (41.8J/g). The incorporation of PEGdecreased the �H values to 34.5 and 32.3J/g for the PLLA/PEG matsand films, respectively. The crystallization temperature (Tc) of purePLLA in the mats was higher than the Tc in films (96 and 91°C, respec-tively). This difference in Tc, together with the difference in �H valuesfor the electrospun mats and films imply that the elongation forcesacting on the jet during electrospinning produced certain orientationof PLLA chains. Both the glass transition of PLLA amorphousdomains and the melting transition of PEG were in the temperaturerange of 50°C. When analyzing the melting behavior of the secondcomponent of the mixture, it should be pointed out that the endother-mal melting transition of PEG at 49°C with a melting enthalpy of42.4J/g in PLLA/PEG electrospun mats was much better expressed

PLLA mat

PLLA/PEG 70/30 mat

PLLA film

PLLA/PEG 70/30 film

Exo

up

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Temperature (°C)

Figure 6. DSC thermograms of PLLA and PLLA/PEG (70/30) mats and films; firstheating.


than the small melting peak at 45°C in PLLA/PEG solvent-cast films.Therefore, the DSC thermograms obtained for PLLA and PLLA/PEGelectrospun mats and solvent-cast films indicate that electrospinninghas led to increased crystallization of PLLA and PEG.

Interaction with Fibroblasts

Preliminary studies with human dermal fibroblasts were performedin order to test the cellular interaction with nanofibrous mats. As shownin Figure 7, the fibroblasts attach relatively well to all the nanofibrousscaffolds, particularly when coated with FN. It is obvious that some ofthe cells tend to penetrate the upper layer of fibers and then attachwithin the mats (B, E, H), resulting in considerable cell spreading. Thecells acquire a specific shape following the orientation of fibers andspreading between them (C, F, I). It is important to note that regardlessof the amount of hydrophilic polymer (PEG), fibroblast adhere andspread relatively well on the three types of nanofibrous mats.

Interaction with Osteoblasts

To obtain more knowledge about the tissue compatibility of the elec-trospun nanofibrous samples with the potential application for bonetissue regeneration scaffolds, osteoblasts-like MG-63 cells were used.These cells showed a relatively high degree of differentiation andability to produce bone tissue in vitro. For this reason, in addition tothe initial cellular interaction, we studied the osteoblasts' behaviorupon longer (5 days) cultivation. The initial cellular interaction withthe different electrospun scaffolds are shown in Figure 8 where livingosteoblasts are visualized with FDA staining. The cells adhered uni-formly and approximately equally to the three types of scaffolds. In thesample with the highest PEG content, however, they become markedlyelongated and showed a tendency to orient along the fiber length.

Illustrated in Figure 9, are the interactions between the osteoblastcells and different PLLA/PEG nanofibrous scaffolds after 5-days ofculture.

As a result of active proliferation, the osteoblasts apparently reachconfluence on the PLLA/PEG (90/10) samples and grow mainly on themat surface. In contrast, in both PLLA/PEG (80/20) and PLLA/PEG(70/30) samples, the cells penetrated into the fibers and representsignificant ingrowth that is more pronounced in the latter. The abilityof cells to spatially organize in tissue-like structures (C) within thePLLA/PEG (70/30) nanofibers was a very interesting observation. In


(A) (B) (C)

(D) (E) (F)

(G) (H) (I)

Figure 7. SEM micrographs of fibers at different PLLA/PEG ratios: 90/10 (A, B, C),80/20 (D, E, F) and 70/30 (G, H, I); with (B, C, E, F, H, I) or without adhering fibroblasts(A, D, and G). Total polymer concentration 7%, AFS�1.375kV/cm.

(A) (B) (C)

Figure 8. Vital osteoblasts adhering for 2h on nanofibrous mats with differentPLLA/PEG weight ratios: 90/10 (A), 80/20 (B), and 70/30 (C). Images were captureddirectly from the wells on an inverted fluorescent microscope at magnification �10.


this matrix, the osteoblasts tended to arrange themselves in differentlyoriented cell layers, perhaps as result of the initial in vitro differentia-tion. Based on the biological screening of the outlined PLLA/PEGnanofibers, the prospect for further biological investigations and thepotential for tissue engineering application is impelling.

CONCLUSION

An original, one-step method for the preparation of electrospunPLLA nanofibrous scaffolds with enhanced hydrophilicity by addinghydrophilic PEG was accomplished. The results obtained show thatthe fiber diameters and morphology are strongly influenced by the vis-cosity of the spinning solutions and, to a smaller extent, by the appliedfield strength. The tissue compatibility of the electrospun nanofibrousscaffolds was screened using two different cell models. Both fibroblastand osteoblast-like cells were uniformly attached and were approxi-mately equal in the all PLLA/PEG nanofibers. In the long-term cul-tures, the osteoblasts tended to arrange in tissue-like structures,particularly within the scaffold with the highest PEG content. Theseresults indicate that mixing PLLA with this hydrophilic polymerprovide a promising tool for the modulation of cellular response.

ACKNOWLEDGMENT

The authors kindly acknowledge the Bulgarian National ScienceFund, Grant NANOBIOMAT, NT 4-01/04.

(A) (B) (C)

Figure 9. Pictures from inverted fluorescent microscope after 5 days culture ofosteoblasts on nanofibrous mats with different PLLA/PEG ratios: 90/10 (A), 80/20 (B),and 70/30 (C). Magnification �4.


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Preparation of PLLA/PEG Nanofibers by Electrospinning and Potential Applications

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