Electrospinning is a commonly used technology to obtain polymer nanofibers with diameters in the range of several nanometers to micrometers [1, 2, 3, 4]. During the electrospinning process electrostatic repulsion is used to overcome the surface tension of a solution droplet at the needle tip, thus stretching the droplet to form a jet, which dries while flying toward a collector, to produce nanofibers . The accumulation of electrospun nanofibers forms a membrane with high porosity and specific surface area. This membrane is suitable for use in tissue engineering, drug release and separation process . Coaxial electrospinning is a modified electrospinning method which uses a blunt-tip coaxial needle to extrude core and shell solutions without mixing during electrospinning, thus producing nanofibers with a core/shell structure [7, 8, 9, 10]. There are several advantages associated with the core/shell structure. For example, by using a material easy to be electrospun as core layer, another material, which cannot be electrospun alone, may have a chance to be spun successfully as shell layer. On the other hand, if the core layer contains drugs, the outer shell layer can act as a barrier to give a slow and sustained drug release. Furthermore, the mechanical properties of the coaxial nanofibers can be improved by choosing a material with good strength as the core layer. Therefore, in the application of tissue engineering, natural materials with good biocompatibility can be used as shell layer material to wrap the core material with low biocompatibility but good mechanical strength, thus generating biocompatible coaxial nanofibers that also possess suitable strength.
In the present study, polyvinyl alcohol (PVA) and chitosan were selected as major core and shell materials, respectively. PVA is a water-soluble polymer that can be used as an excipient for drug delivery. PVA is also a material easy to be electrospun and thus can be used as core material for coaxial electrospinning [11, 12]. Chitosan is a natural basic polysaccharide composed of glucosamine and N-acetyl glucosamine . It has been used in drug delivery, tissue engineering, and other biomedical applications because it is biocompatible, biodegradable and antimicrobial. Chitosan is soluble in acidic solution but the chitosan solution becomes highly viscous when its concentration goes high, making the preparation of chitosan nanofibers by electrospinning quite problematic. To overcome this difficulty, chitosan has to dissolve in high concentration of acetic acid or organic solvents such as trifluotoacetic acid (TFA) and hexafluoroisopropanol (HFIP) [14, 15, 16]. However, TFA and HFIP are highly corrosive and expensive. To prevent the use of TFA and HFIP, we employed our newly developed method (i.e., the addition of gum arabic) to prepare a solution with a high chitosan content but a much lower viscosity, thus making the electrospinning process feasible [17, 18]. Gum arabic is a branched biopolymer. In our previous research, we found that gum arabic can interact with chitosan to form globe-like microstructures and thus remarkably decrease the viscosity of the resulting chitosan solution .
Similarly, this research demonstrated that the addition of a small amount of gum arabic significantly decreased the viscosity of chitosan solutions even though chitosan was dissolved in a mild (5 wt%) aqueous acetic acid solution. The chitosan solution thus prepared was then used as the shell solution in the coaxial electrospinning while the PVA solution was selected as the core solution. The parameters affecting the electrospinning process such as the flow rates and compositions of core and shell solutions were optimized. The mechanical properties and the application of the coaxial PVA/chitosan nanofiber membranes were also investigated.
2 Materials and methods
Chitosan (molecular weight: about 300 kDa; degree of deacetylation: about 90%) was purchased from Kiotek Co. (Taipei, Taiwan). Polyvinyl alcohol (PVA) (degree of hydrolysis: 98.5-99.2%) was supplied by Chang Chun Petrochemical Co. Ltd (Taiwan). Gum arabic, acetic acid and other chemicals of reagent grade were purchased from Sigma-Aldrich (St. Louis, MO, USA).
2.2 Preparation of solutions
The abbreviations and compositions of various PVA and chitosan solutions prepared in this study are shown in Table 1. PVA solutions were prepared by dissolving PVA in 90 °C water. 8, 10 and 12 wt% PVA solutions were prepared and designated as P8, P10 and P12, respectively. The preparation of chitosan solutions suitable for electrospinning was carried out by using our newly developed method [17, 18, 19]. Our method included the addition of a small amount of gum arabic (10 wt% of chitosan) that significantly decreased the viscosity of chitosan solutions when using a mild aqueous acetic acid solution as a solvent. To prepare various chitosan solutions, chitosan powder was dissolved in acetic acid solution, and then gum arabic (10 wt% of chitosan) was added into the solution to greatly decrease the viscosity of chitosan solution. 4, 6, 8, 10 and 12 wt% chitosan solutions (containing gum arabic) were prepared using 5, 10 or 20 wt% aqueous acetic acid solution as a solvent. These chitosan solutions were designated as Cm-n (m representing the concentration of chitosan and n representing the concentration of acetic acid). For example, C4-5 represents a chitosan solution containing 4wt% chitosan, 0.4wt% gum arabic and 5 wt% acetic acid.
2.3 Characterization of solutions
A pH meter (model 420A, Orion, USA) was used to determine the pH of various solutions. The viscosity of various solutions was measured by a viscometer (model DV-II+, Brookfield, USA), and the rotation speed of spindle was fixed at 2 rpm. The conductivity and surface tension of various solutions were also measured by using a conductivity meter (model COND6 plus, Eutech, Singapore) and a tesiometer (model 514-B, Itoh Seisakusho, Japan), respectively.
2.4 Coaxial electrospinning of solutions
Coaxial electrospun nanofibers with core/shell structures were fabricated by using an electrospinning unit (Jyi-Goang Enterprise, Taipei, Taiwan). The blunt-tip coaxial needle was composed of a 23G (i.d. 0.33 mm, o.d. 0.63 mm) inner needle concentrically mounted on an 18G (i.d. 0.96 mm, o.d. 1.26 mm) outer needle. PVA and chitosan solutions were loaded in two individual syringes and fed by two separate syringe pumps. The applied voltage and working distance between needle tip and collector were 25 KV and 15 cm, respectively. The environmental temperature and relative humidity were controlled at 32 °C and 40-50%.
2.5 Analysis of coaxial nanofibers
A scanning electron microscope (SEM, JSM-5310, Jeol, Japan) and a transmission electron microscope (TEM, JEM-1230, Jeol, Japan) were used to observe the morphology of coaxial nanofibers. Fourier transform infrared spectroscopy (FT-IR) analysis was carried out using an FT-IR spectrometer (Spectrum One, Perkin-Elmer, USA).
Thermal behavior of various samples was investigated by a thermogravimetric analysis meter (TGA, model Pyris 1, Perkin-Elmer, USA). For TGA analysis, about 5 mg sample was hold at 50 °C for 20 min to remove residual water in the sample, and then was heated from 50 °C to 600 °C at a rate of 10 °C/min. The process of TGA analysis was under continuous nitrogen purge at a rate of 20 ml/min.
2.6 Mechanical properties of coaxial nanofiber membranes
To analyze mechanical properties of nanofiber membranes, the membranes were cut into a dumbbell shape, and the thicknesses of membranes were measured with a micrometer. The mechanical properties including tensile strength (stress at maximum load) and elongation (strain at maximum load) were measured with a tensile strength instrument (model LRX, Lloyd, Hampshire, UK). The stretching rate of the measurement was 10 mm/min.
2.7 Drug release experiments
The application potential of the PVA/chitosan coaxial nanofiber membranes was tested in drug release experiments when the core (PVA) was loaded with theophylline (5 mg/ml) as a model drug. For comparison purposes, conventional (non-coaxial) PVA nanofiber membranes were also fabricated and used as controls. The theophylline containing nanofiber membranes were crosslinked with glutaraldehyde vapor for 8 hours, followed by drying in a vacuum oven for 12 hours. The drug release experiments were carried out by immersing the nanofiber membranes in phosphate-buffered saline (PBS). PBS samples (1 ml) were withdrawn periodically at predetermined time intervals and the theophylline concentrations in the PBS samples were determined using a spectrophotometer (model U-2001, Hitachi, Japan) at 274 nm. The “percentage of drug released” was calculated using the following formula:
Since theophylline was initially present in the core (PVA), the shell (chitosan) acted as a barrier to the release of theophylline. It was expected that the use of drug-loaded coaxial nanofiber membranes would give a gradual and sustained drug release. However, several phenomena such as nanofiber swelling, disintegration, and drug diffusion were involved in the release of theophylline. To investigate these anomalous transport phenomena, a semi-empirical model called “Korsmeyer-Peppas model” was utilized to correlate the theophylline release from the coaxial nanofiber membranes because the above-mentioned anomalous phenomena were considered in this model, as shown below [20, 21, 22]:
where Mt is the cumulative amount of drug at any time t, M∞ is the cumulative amount of drug at the last time of the measurement, k is the release rate constant, and n is the release exponent. To obtain the parameters of release kinetics (k and n), data obtained from drug release experiments were plotted as log percentage of drug released vs. log time [21, 23].
3 Results and discussion
3.1 Properties of PVA and chitosan solutions
To search for polymer solutions suitable for electrospinning, the pH, surface tension and conductivity of various PVA and chitosan solutions were determined, as shown in Table 2. The pH of PVA solutions slightly decreased as the concentration of PVA increased, probably due to the residual acetyl groups in PVA that might be hydrolyzed to yield acetic acid. On the other hand, since chitosan is a basic polysaccharide, increasing the concentration of chitosan elevated the pH of chitosan solutions (containing chitosan, gum Arabic, and acetic acid) (Table 2).
During the electrospinning process electrostatic repulsion is used to overcome the surface tension of a solution droplet at the needle tip , suggesting that both surface tension and conductivity may influence the morphology of nanofibers. As shown in Table 2, surface tension of various PVA and chitosan solutions decreased while the concentrations of PVA and chitosan increased. The use of acetic acid solution at higher concentrations also decreased the surface tension of chitosan solutions, since the surface tension of pure acetic acid (27.08 mN/m)  is lower than that of pure water (71.97 mN/m). As for theconductivity of solutions, increasing the concentrations of PVA and chitosan improved the conductivity of solutions, especially for chitosan (Table 2). Since PVA is a relatively neutral polymer, however, chitosan is a basic polysaccharide which contains positive charge in an acidic solution, thus enhancing the conductivity of solutions.
The viscosity of polymer solutions plays an important role in electrospinning. A low-viscosity polymer solution implies less entanglement of polymer chains in the solution which may lead to poor electrospinning, resulting in the formation of beads or spindle-like structures. However, if solution viscosity is too high, the solution will become too sticky to be electrospun. Figure 1 shows the influence of concentration on the viscosity of PVA and chitosan solutions. As shown in Figure 1(a), the viscosity of PVA solutions increased as the concentration of PVA increased, possibly due to more entanglement of polymer chains. Figure 1(b) shows a similar trend for chitosan solutions. It should be noted that without the addition of gum arabic in chitosan solution, the viscosity of chitosan solution dramatically increased when the concentration of chitosan solution increased to 8 wt% (hollow symbols in Figure 1(b)). Therefore, the preparation of high-content (10-12 wt%) chitosan solutions would be impossible unless using our newly developed method, i.e., the addition of a small amount of gum arabic (10 wt% of chitosan) to greatly decrease the viscosity of chitosan solutions (solid symbols in Figure 1(b)) [17, 18]. Gum arabic is a branched biopolymer. In our previous research, we found that gum arabic can interact with chitosan to form globe-like microstructures and thus remarkably decrease the viscosity of the resulting chitosan solution . As a result, the use of our newly developed method (i.e., the addition of gum arabic) to prepare a chitosan solution with a high chitosan content (up to 12 wt%) but a much lower viscosity made the following electrospinning process feasible. Figure 1(b) also shows that the viscosity of chitosan solutions can be further lowered by decreasing the concentration of acetic acid from 20 to 5 wt%.
3.2 Influence of process parameters
Process parameters affecting the coaxial electrospinning such as the flow rates and compositions of core and shell solutions were investigated and optimized.
3.2.1 Flow rate ratio of core and shell solutions
Figure 2 shows the SEM images of coaxial PVA/chitosan (P10/C8-20 as core/shell) nanofibers prepared under different flow rate ratios of core and shell solutions. Nanofibers with better morphology were found when flow rate ratios of core:shell solutions were 0.15:0.15 and 0.15:0.3 (mL/h). Further increase in the flow rate of shell (chitosan) solution might interrupt the formation of PVA nanofibers. Repeating the experiment indicated that the best flow rate ratio of core:shell solution was 0.15:0.15 (mL/h) which was then utilized to carry out the following experiments.
3.2.2 Composition of core (PVA) solution
Figure 3(a) shows the SEM images of coaxial PVA/chitosan nanofibers prepared using different core (PVA) solutions (P8, P10, P12) but the same shell solution (C8-20). No nanofibers were found in P8/C8-20 group since the viscosity of P8 solution was too low to form nanofibers (see Figure 1(a)). Few nanofibers were found in P12/C8-20 group since the viscosity of P12 solution was slightly too high and thus not favorable for nanofiber formation. In contrast, more nanofibers were found in P10/C8-20 group and thus P10 was selected as the composition of core solution for coaxial electrospinning in this research.
3.2.3 Composition of shell (chitosan) solution
Figure 3(b) shows the SEM images of coaxial PVA/chitosan nanofibers prepared using the same core solution (P10) but different shell solutions (C4-20, C6-20, C8-20, C10-20, C12-20). Few nanofibers were found in P10/C10-20 and P10/C12-20 groups since the viscosity of C10-20 and C12-20 solutions was quite high and thus not favorable for nanofiber formation. In contrast, more nanofibers were found in P10/C4-20, P10/C6-20, and P10/C8-20 groups and thus these three groups were selected as the compositions of shell solutions for further investigation.
3.2.4 Concentration of acetic acid
One of the parameters affecting electrospinning is the solvent utilized to prepare a polymer solution . It was found that better coaxial nanofibers were obtained when the solvent of core solution was more similar to the solvent of shell solution . So far the solvents of core (PVA) and shell (chitosan) solutions were water and 20 wt% aqueous acetic acid solution, respectively. In order to make these two solvents more similar to each other, two methods were considered. The first method was to replace the solvent of core solution by 20 wt% aqueous acetic acid solution. The second method was to replace the solvent of shell solution by water, but it was unfeasible because chitosan was water-insoluble. The alternative method was to use acetic acid solution at lower concentration (5 or 10 wt%) as the solvent of shell solution.
About the first method, Figure 4(a) shows the SEM images of coaxial PVA/chitosan nanofibers obtained when the solvents of core and shell solutions were the same (20 wt% aqueous acetic acid solution). However, very few nanofibers were found in these groups (P10-20/C4-20, P10-20/C6-20 and P10-20/C8-20), indicating that acetic acid solution might not be a suitable solvent for PVA.
About the second method, Figure 4(b) shows the SEM images of coaxial PVA/chitosan nanofibers obtained when acetic acid solution at lower concentration (5 or 10 wt%) was utilized as the solvent of shell (chitosan) solution. When the concentration of acetic acid decreased to 10 wt%, nanofibers were found only in P10/C8-10 group (see the second row in Figure 4(b)). When the concentration of acetic acid decreased further to 5 wt%, nanofibers were found in P10/C8-5 and P10/C10-5 groups (see the third row in Figure 4(b)). In comparison with the results of nanofibers obtained using 20 wt% acetic acid solution as the solvent of shell solution (see the first row in Figure 4(b)), a similar amount of nanofibers but less beads and spindle-like structures were found when using 5 wt% acetic acid solution as the solvent. Hence, P10/C8-5 and P10/C10-5 groups were selected for further investigation.
3.3 Characteristics of coaxial PVA/chitosan nanofibers
Figure 5 shows the TEM images of various coaxial PVA/chitosan (as core/shell) nanofibers. The coaxial structures of electrospun nanofibers can be found in all five groups. However, among these chitosan-wrapped coaxial nanofibers better coverage of chitosan was present in P10/C8-5 group.
To confirm the existence of PVA and chitosan, FT-IR analysis was carried out, as shown in Figure 6. PVA shows a characteristic peak at 3248 −1 (O–H stretching) and two peaks at 2923 cm−1 (C–H stretching) and 1077 cm−1 (C–O stretching). On the other hand, chitosan shows a peak at 1647 cm−1 (C=O stretching) and another peak at 1581 cm−1 (N–H bending). Gum arabic shows a peak at 1610 cm−1 (COO-symmetric stretching) . Coaxial P10/C8-5 nanofiber membrane shows characteristic peaks of PVA at 3273 cm−1 (O–H stretching), 2925 cm−1 (C–H stretching) and 1080 cm−1 (C–O stretching), and also characteristic peaks of chitosan at 1661 cm−1 (C=O stretching) and another peak at 1584 cm−1 (N–H bending). P10/C10-5 nanofiber membrane shows similar results, thus confirming the existence of PVA and chitosan in coaxial nanofibers.
3.4 Thermal properties of coaxial PVA/chitosan nanofibers
TGA thermograms of PVA powder, chitosan powder and coaxial nanofibers (P10/C8-5 and P10/C10-5) are shown in Figure 7. According to the literature, the thermal degradation of PVA is approximately a two-step degradation , which is consistent with the PVA curve in Figure 7. The thermal degradation of chitosan is also a two-step degradation. In the first step, 50% weight loss occurs between 220°C and 320°C , which is also consistent with the chitosan curve in Figure 7. Interestingly, if comparing all four TGA curves in Figure 7, the P10/C8-5 curve is more similar to the chitosan curve while the P10/C10-5 curve is more similar to the PVA curve. The reason could be that the shell solution of P10/C8-5 was less viscous than that of P10/C10-5 andit might be easier to form coaxial P10/C8-5 nanofibers with better coverage of chitosan. Hence in comparison with P10/C10-5, the TGA thermogram of P10/C8-5 is more similar to that of chitosan. On the contrary, P10/C10-5 might have a thinner coverage of chitosan, thus making the TGA thermogram of P10/C10-5 more similar to that of PVA.
3.5 Mechanical properties of coaxial PVA/chitosan nanofiber membranes
To enhance the mechanical properties of coaxial PVA/chitosan (P10/C8-5 and P10/C10-5) nanofiber membranes, the membranes were crosslinked by glutaraldehyde for 8 hours . Figure 8 shows the mechanical properties (tensile strength and elongation) of coaxial P10/C10-5 and P10/C8-5 nanofiber membranes (uncrosslinked and crosslinked). The tensile strength (stress at maximum load) of P10/C8-5 and P10/C10-5 membranes increased from 0.77 and 0.66 MPa to 0.91 and 0.83 MPa, respectively (Figure 8(a)). The tensile strength of P10/C8-5 (uncrosslinked and crosslinked) was higher than that of P10/C10-5, possibly due to the better coverage of shell (chitosan) layer (see the second row in Figure 5) that enhanced the tensile strength of P10/C8-5 especially after crosslinking.
As shown in Figure 8(b), crosslinking also caused a slight decrease in the elongation (strain at maximum load) of P10/C8-5 and P10/C10-5 membranes, i.e., from 87% and 102% down to 77% and 92% (still ductile), respectively. Taken together, coaxial P10/C8-5 and P10/C10-5 nanofiber membranes exhibited favorable mechanical properties (good tensile strength and good ductility), but P10/C8-5 membranes were better and thus utilized in the following drug release experiments.
3.6 Drug release from coaxial PVA/chitosan nanofiber membranes
Theophylline is a small molecule drug (a bronchodilator) and can be easily released from a dense film . The use of coaxial PVA/chitosan (P10/C8-5) nanofiber membranes in drug release was carried out by loading the core (PVA) with theophylline (5 mg/ml) as a model drug. For comparison purposes, conventional (non-coaxial) PVA (P10) nanofiber membranes loaded with theophylline were also prepared. Figure 9 shows the release profiles of theophylline from coaxial P10/C8-5 nanofiber membranes and also from non-coaxial P10 nanofiber membranes. During the first 3 minutes, 95% of theophylline was released from P10 membranes (Figure 9(b)). In contrast, 95% release of theophylline from P10/C8-5 (as core/shell) membranes was prolonged to 24 hours (Figure 9(a)). In Figure 9(c), both P10/C8-5 and P10 were confirmed as nanofiber membranes, but the average diameter of P10/C8-5 nanofibers (about 620 nm) was larger than that of P10 nanofibers (about 506 nm). Since theophylline was initially present in the core (PVA), the shell (chitosan) acted as a barrier, thus slowing down the release of theophylline. Besides, due to the larger nanofiber diameter, the specific area of P10/C8-5 nanofibers should be smaller than the specific area of P10 nanofibers. The smaller specific area also caused the release of theophylline from P10/C8-5 membranes to become slower. The drug release behavior of coaxial P10/C8-5 nanofiber membranes might be divided into three stages. The first stage was the swelling of nanofibers that gave a burst release of theophylline. The second stage was the disintegration of nanofiber membranes that gave a continuous theophylline release at a rate lower than the first stage. The third stage was the gradual diffusion of theophylline from the core that permeated through the shell of nanofibers and eventually reached equilibrium . In the third stage, the chitosan shell layer was a barrier of mass transfer and thus decreased the release rate of theophylline.
As described above, several phenomena such as nanofiber swelling, disintegration, and drug diffusion were involved in the release of theophylline. To investigate these anomalous transport phenomena, a semi-empirical model called “Korsmeyer-Peppas model” was utilized to correlate the theophylline release from coaxial P10/C8-5 nanofiber membranes because the above-mentioned anomalous phenomena were considered in this model (see Section 2.7) [20, 21, 22, 23]. To obtain the parameters of release kinetics (k and n), the initial 65% of theophylline release data shown in Figure 9(b) were plotted as log drug release (%) vs. log time (min) [21, 23]. By fitting the theophylline release data with the Korsmeyer-Peppas model, the release rate constant (k) of 65.34 and release exponent (n) of 0.54 were obtained with a correlation coefficient (r2) of 0.979, as shown in Table 3. In Korsmeyer-Peppas model, for drug release from swellable cylindrical systems n ≤ 0.45 corresponds to Fickian diffusion, 0.45<n < 0.89 corresponding to anomalous (non-Fickian) transport . The release exponent (n) of 0.54 obtained in this study suggests that the release mechanisms of theophylline from coaxial P10/C8-5 nanofiber membranes may involve several anomalous transport phenomena including nanofiber swelling and disintegration as well as drug diffusion.
By adding a small amount of gum arabic to prepare much less viscous chitosan solutions, coaxial PVA/chitosan electrospun nanofiber membranes with core/shell structures were successfully fabricated in this research. The core/shell structures were confirmed by TEM. The existence of PVA and chitosan in the nanofiber membranes was established by FT-IR analysis. Among several groups of PVA/chitosan (as core/shell) nanofiber membranes prepared in this study, P10/C8-5 membranes showed a higher tensile strength than P10/C10-5 and other membranes possibly due to the better coverage of shell (chitosan) layer. The use of coaxial P10/C8-5 nanofiber membranes in drug release extended the release time of theophylline from 5 minutes to 24 hours. Further, the Korsmeyer-Peppas model was selected to fit the data of theophylline release, giving a release exponent (n) of 0.54, suggesting that the release mechanisms may involve several anomalous transport phenomena including nanofiber swelling and disintegration as well as drug diffusion. In brief, by combining the advantages of PVA and chitosan (good mechanical strength and good biocompatibility respectively), coaxial PVA/chitosan nanofiber membranes have great potential in many biomedical applications.
Ting-Yun Kuo and Cuei-Fang Jhang contributed equally to the present work. This study was financially supported in part by the Ministry of Science and Technology, Taiwan (grants: MOST 104-2221-E-002-174 & MOST 105-2221-E-002-202).
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About the article
Published Online: 2017-12-29
Citation Information: Open Physics, Volume 15, Issue 1, Pages 1004–1014, ISSN (Online) 2391-5471, DOI: https://doi.org/10.1515/phys-2017-0125.
© 2017 Ting-Yun Kuo et al.. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License. BY-NC-ND 4.0