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Fabrication and Characterization of Poly (#caprolactone)/#-Cyclodextrin Pseudorotaxane Nanofibers. Ganesh Narayanan, REMIL MARTINEZ AGUDA, Matthew Hartman, ChingChang Chung, Ramiz Boy, Bhupender S. Gupta, and Alan E Tonelli Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.5b01379 • Publication Date (Web): 02 Dec 2015 Downloaded from http://pubs.acs.org on December 8, 2015

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Fabrication and Characterization of Poly (ε-caprolactone)/α-Cyclodextrin Pseudorotaxane Nanofibers. Ganesh Narayanan 1*, Remil Aguda 2, Matthew Hartman 3, Ching-Chang Chung 4, Ramiz Boy 1, Bhupender S. Gupta 1, Alan E.Tonelli 1 ||. Affiliations: 1. Fiber and Polymer Science program, North Carolina State University, Raleigh, NC-27606, USA. 2. Department of Forest Biomaterials, North Carolina State University, Raleigh, NC-27695, USA. 3. Department of Biomedical Engineering, North Carolina State University, Raleigh, NC-27695, USA. 4. Department of Materials Science and Engineering, North Carolina State University, Raleigh, NC-27695, USA. *Current

Affiliation: Department of Orthopedic Surgery, University of Connecticut-Health Center, Farmington, CT-06030. ||

Corresponding author: Prof. Alan E. Tonelli, Email: [email protected]

Abstract Multifunctional scaffolds comprising PCL and α-cyclodextrin in pseudorotaxanated form have been fabricated using a conventional electrospinning process. Thorough in-depth characterizations were performed on the pseudorotaxane nanofibers prepared from chloroform (CFM) and CFM/dimethyl formamide (DMF) utilizing Scanning Electron Microscopy (SEM), Transmission Electron

Microscopy

(TEM),

Rheology,

Differential

Scanning

Calorimetry

(DSC),

Thermogravimetric Analyses (TGA), Wide angle X-ray Diffraction (WAXD), and Instron tensile testing. The results indicate the nanofibers obtained from chloroform retain the rotaxanated structure; while those obtained from chloroform/dimethyl formamide (CFM/DMF) had significantly dethreaded during electrospinning. As a consequence, the nanowebs obtained from CFM showed higher moduli and lower elongations at break compared to neat PCL nanowebs and PCL/α-CD nanowebs electrospun from CFM/DMF.

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Introduction The field of tissue engineering and regenerative medicine requires scaffolds that are not only biocompatible and possess appropriate physical and biological properties, but also require scaffolds that possess multiple functionalities that can aid in the rapid regeneration of their supported tissues 1. Poly (ε-caprolactone) (PCL), an aliphatic polyester belonging to the family of poly (α-hydroxy) esters has been approved by the Food and Drug Administration (FDA) for biomedical applications, and is widely used as sutures, implants, tissue engineering scaffolds, etc. In the past four decades, PCL has been extensively studied for biological applications, and is currently one of the most widely used biomaterials 2. In spite of these advantages, owing to its high hydrophobicity, biomedical devices made with PCL have very poor cell adhesion 3. Various techniques to enhance cellular adhesion have been proposed in the past: for instance, plasma treatment followed by grafting biological moieties, aminolysis, hydrolysis, and protein adsorption 4-7. Most of these techniques, however, cause significant changes to the bulk mechanical properties of PCL. Additionally, PCL degrades at a very slow pace (up to ~3 years) and also possesses low mechanical strength 8. These disadvantages motivated us to fabricate scaffolds with additional functionalities, which can offer sites for delivery of small molecules, for use in tissue engineering, drugs, etc. Here we report a novel strategy to improve the mechanical properties of electrospun PCL scaffolds by incorporating cyclodextrins, which are widely used in pharmaceutical applications, in the form of non-stoichiometric (n-s)-pseudorotaxanes formed between host α-CD and guest PCL. Cyclodextrins (CDs) belong to a family of cyclic α-1,4 linked oligosaccharides that are obtained from the bacterial degradation of starch 9. Most widely used are α-, β-, and γ-CDs, which contain 6, 7, and 8 glucopyranose units, respectively 10. CDs have a truncated cone like structure, which


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enables non-covalent inclusion complexation (IC) with small molecules or even longer molecules like polymers 11, 12. It is their capability to form ICs which is extensively utilized in fields such as pharmaceuticals, foods, textile processing, etc

13-15

. Recently, CDs have been combined with

polymers in the electrospinning process, and resulted in hybrid structures that were observed to be attractive candidates for air and water filtration, and wound odor absorbance

16-22

. In polymer

processing, CDs have been observed to be excellent nucleating agents, especially for biomedical polymers such as PCL, poly butylene succinate, poly ethylene glycol, and poly (3hydroxybutyrate)

23-26

. As mentioned earlier, CDs can form ICs with polymers and when the

stoichiometry (CD: polymer) is less than that required for full coverage, partially covered nonstoichiometric (n-s)-pseudorotaxanes are formed. Due to the constrained nature of the unthreaded un-included portions of the guest polymer chains, (n-s)-pseudorotaxanes have higher mechanical and thermal properties. In fact, we recently observed that when a small percent of (n-s)-polymerCD-pseudorotaxanes were added to the same bulk polymer; there was significant improvement in mechanical and thermal properties of the composites 27. Because their CD cavities are occupied by guest polymer chains, (n-s)-pseudorotaxanes are not able to include small molecule additives. However, the abundant hydroxyl groups on their outer rims, enable them to undergo bio-conjugation with a variety of molecules, including proteins like collagen, fibronectin, laminin etc.; DNA; RNA; cell adhesive peptides; drugs, etc., thus enabling applications in a variety of fields. (n-s)-Polymer-CD-pseudorotaxanes, especially in nanofibrous structures, may be attractive, as they should possess high surface areas. Many researchers have recently attempted to prepare both stoichiometric urea and CD host-based polymer ICs, as well as (n-s)-polymer-CD-pseudorotaxanated nanostructures. For instance, Liu et al. reported the formation of PEO-urea and PEO-thiourea nanofibers from methanol. Their system


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is simple because both PEO-urea and PEO-thiourea have higher solubility in methanol; furthermore, PEO typically needs much lower polymer concentrations for electrospinning

28-30

.

Uyar et al, reported successful formation of nanofibers containing (n-s)-pseudorotaxanated-PEGα-CD-IC using a carrier polymer (PEO) 31. Zhan et al. and Oster et al., studied the formation of PCL/α-CD pseudorotaxane nanofibers 32, 33. Zhan et al. had in fact reported that by electrospinning the PCL/α-CD pseudorotaxanes from a combination of chloroform (CFM) and N,N-dimethyl formamide (DMF), the pseudorotaxane structure can be retained in the nanofibers

32

. However,

Oster et al. 33 reported that the pseudorotaxane structure is not retained by electrospinning in such systems, unless star PCL is used instead of linear PCL. We previously reported the formation of uncomplexed PCL/CD systems, and had hypothesized that uncomplexed PCL/α-CD when electrospun from CFM/DMF would be unable to form inclusion complexes 20, 21. Our observations validated this hypothesis, and PCL and α-CD did not undergo complexation during electrospinning. The hypothesis was based on the fact that chloroform has a very low hydrogen-bond accepting capability (hydrogen-bonding acceptor value of 0.02), while, DMF an aprotic polar solvent has a higher hydrogen-bond accepting capability (0.74). In addition, a recent study evaluating the channel structures of CDs observed that solvents such as DMF tend to have the lowest stability, while chloroform had the highest 34. The primary aim of this study was to fabricate PCL/α-CD pseudorotaxane nanofibrous scaffolds from CFM, with electrospun neat PCL and (n-s)-pseudorotaxanes from CFM/DMF serving as controls, and further to optimize the process to obtain nanofibers in the sub-micron range. The secondary aim of this study was to evaluate the rheological, morphological, mechanical, and thermal properties and degradation patterns of these electrospun scaffolds, with comparison to those obtained by Zhan et al.. We hypothesize that electrospinning PCL/α-CD pseudorotaxane


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from CFM would retain the pseudorotaxane structure in the nanofiber matrix; while a combination of CFM and DMF would cause de-threading of PCL and α-CD, resulting in uncomplexed PCL/αCD, which we had previously reported 20, 21. Although CFM is an ideal solvent for this system, it possesses one of the lowest conductivities of the solvents used for electrospinning. Using CFM alone as a solvent may therefore restrict successful electrospinning. To overcome this, we hypothesized that addition of benzyl triethyl ammonium chloride (BTEAC), a non-polar salt that has excellent miscibility with CFM, would enhance the electrospinnability of the system. Furthermore, the salt can be easily removed from the nanofiber structure by leaching it out in a methanol solution. The electro-spun scaffolds successfully obtained in this research offer promise for a variety of applications including tissue engineering, drug delivery, etc.

Experimental Materials Poly (ε-caprolactone) (PCL) with a molecular weight of 60,000-80,000 was purchased from Sigma-Aldrich. Chloroform (Cat # C2432, 99.5% pure with amylenes as stabilizer), N,N- Dimethyl Formamide (Cat # 227056, Anhydrous 99.8%), Benzyl trimethyl ammonium chloride (BTEAC) (Cat# 146552, 99% pure), Methanol ( Cat# 322415, 99.8% purity) were also purchased from Sigma-Aldrich, St. Louis, MO, USA. Acetone (Cat # A184, ACS grade) was purchased from Fisher scientific, New Hampshire, USA. α-cyclodextrin (Cavamax W6) was obtained as a gift from Wacker Chemie, Adrian, MI, USA. Preparation of PCL/α-CD pseudorotaxanes PCL/α-CD pseudorotaxanes with varying stoichiometries (P-3, P-6, and P-12) were prepared similarly to our previously reported protocol

27, 35

. The numerical values indicate the percentage


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(%) coverage of PCL chains by α-CD, i.e., 3, 6, and 12% of the PCL chains are covered by α-CDs, respectively, in samples P-3, P-6, and P-12. The preparation of pseudorotaxanes was as follows: 1 g of PCL was dissolved in 200 mL of acetone at 60 °C under rigorous stirring. Depending on the stoichiometry, 0.25 g (or 0.5 g or 1 g) of α-CD was dissolved in 4 mL (or 8 mL or 12 mL) of DI water at 60 °C under rigorous stirring. Once completely dissolved, the α-CD/water solution was added in a drop-by-drop fashion to the PCL/acetone solution under vigorous stirring. The combined solution was continuously stirred and maintained at 60 °C for 1 hour. Afterword, the stirring was continued at room temperature for varying times depending on the stoichiometry. In the case of P-3, stirring was continued for 96 hours, for the other stoichiometries, stirring was discontinued after 72 hours, since by this time; a white precipitate had been produced. An average yield of ca. 70% was realized. The white precipitates obtained were filtered, washed with acetone and water to remove uncomplexed PCL and α-CD, and then dried under vacuum for 48 hours. Preparation of (n-s)-PCL-α-CD-pseudorotaxane Nanofibers Pseudorotaxane solutions were prepared by dissolving appropriate quantities of the pseudorotaxanes in 10 mL of chloroform. For instance, 1.2 g of PCL (control) was dissolved in 10 mL of CFM to yield a 12% solution. For preparing P-3, P-6, and P-12 solutions: 1.4, 1.6, and 1.8 g of P-3, P-6, and P-12 were dissolved in 10 mL of CFM to yield 11, 10.5, 7.8% solutions, respectively. Since only the unthreaded un-included portions of PCL chains are expected to interact with the CFM, only their percentage is reported. Through a systemic study, these solute percentages were observed to be the most stable and suitable for electrospinning. In particular, the P-6 and P-12 solutions were highly unstable and tended to precipitate at higher concentrations, while at lower concentrations, P-6 and P-12 were not capable of undergoing electrospinning. To


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these solutions, 2% (0.2 g) of BTEAC was added to aid in the electrospinning process, as both the CFM and PCL have poor electrical conductivity. The solutions were placed in a 10 mL syringe (Becton-Dickenson, Franklin Lakes, NJ), to which a blunted 21-G needle was attached. Spinning solutions were then delivered at a rate of 3 mL/hour by a high precision pump (New Era Pump Systems), and a potential difference was applied between the needle’s tip and the collector by a Gamma High Voltage Research instrument. A circular, stainless steel collector (5 in dia) covered with aluminum foil was used to collect nonwoven mats. The potential difference applied and the distance between the needle and the collector were 20 kV and 30 cm, respectively. All nanowebs were spun under 40% humidity and at 25 °C. The non-woven mats were soaked in methanol for 4 hours to remove the BTEAC and unevaporated CFM, dried under vacuum for 48 hours, and were stored in a desiccator until further use.

Analytical Characterization Fourier Transform Infrared spectroscopy (FTIR) and Differential Scanning Calorimetry (DSC) were employed to determine the stoichiometries of the (n-s)-PCL-α-CD-pseudorotaxanes. FTIR experiments were conducted using a Nicolet 470 spectrophotometer with a diamond crystal ATR sample head between the wavelengths 4000 to 400 cm-1 with a resolution of 4 cm-1. Sixty-four scans were carried out for each sample. DSC experiments were conducted to study the thermal transitions of the pseudorotaxanes using a Perkin Elmer Diamond 7 DSC instrument. Small amounts of sample (5 to 8 mg) were placed in aluminum pans, sealed, and a heat-cool-heat cycle was employed between the temperatures 0-80 °C at a scanning rate of 20 °C. Between the cycles, the pans were held at 80 or 0 °C for 1 min. In addition, thermal transitions of the pseudorotaxane nanofibers were also measured using the Perkin-Elmer Diamond D7 instrument. Same protocol as described for pseudorotaxane crystals were followed for nanofibers.


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Prior to electrospinning, rheological experiments were conducted on neat PCL and pseudorotaxane solutions using a Thermal Analysis AR-G2 rheometer (New Castle, DE) with parallel plate geometry (4.5 cm). Experiments were conducted between shear rates of 1 to 1000 s-1 and their corresponding shear viscosities were measured. Viscosities in the zero shear region were averaged and are reported as viscosity (in Pa.S). The morphologies of the pseudorotaxane nanofibers were visualized by Scanning Electron Microscopy (SEM) (Phenom-World, Eindhoven, The Netherlands) and with a High Resolution Transmission Electron Microscope (TEM) (HR-TEM) (JEOL 2000FX, Tokyo, Japan). For SEM measurements, a circular sample (1 mm dia) was cut from the non-woven mats and attached to a metal stub. The samples were then gold-coated for 45 s using a Polaron SC7620 (Quorum Technologies, ON, Canada) to yield a 10 nm coating. SEM images were obtained at various resolutions, and the fiber diameters were calculated from the average diameter of 100 fibers (resolution 3000X) using ImageJ software (National Institutes of Health, Bethesda, MD). Average fiber diameters are reported along with their mean and standard deviations. For TEM measurements, prior to the start of electrospinning, a carbon coated TEM stub was affixed to the aluminum foil and the electrospinning was conducted for 10 s. Later the stub was detached for TEM observation. The cluster of fibers was separated under an optical microscope to isolate nanofibers. The stub was attached to a sample holder, inserted into the TEM column and placed onto the stage and high vacuum was then applied. Experiments were performed at an acceleration potential of 180 keV, and images were collected in a computer attached to the instrument. The stage was moved in the X and Y directions, and various images were obtained on multiple fibers with diameter values of ca. 200, 400, 600 nm. With known pixel values in the X- and Y- direction, a scale bar was added to the images using ImageJ.


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Thermal degradation patterns of the nanofibers were observed on small samples (5 to 10 mg) using a Perkin Elmer Thermogravimetric analyzer (TGA) over the temperature range: 30 to 500 °C, at a heating rate of 10 °C/min. Nitrogen was used as a purge gas throughout the experiments, and pyris software was used to analyze the degradation patterns to obtain first derivative plots and to export the data in a format suitable for further processing. WAXD analyses were performed on neat PCL and pseudorotaxane nanofibers and films (control) using a PANalytical Empyrean X-ray diffractometer with a Cu Kα radiation source (λ=1.54 Ả). Samples were prepared by slicing a small piece of the nanoweb and affixing it to the sample holder with double-sided tape. All diffraction data were acquired in the range of 5 – 50o = 2θ using a step size and count rate of 0.0262 ° = 2θ and 37 sec/step, respectively. Mechanical evaluations of the PCL nanowebs were carried out utilizing a universal testing machine (Instron model 5544). Bluehill software version 2.0 was used to calculate the modulus and generate a report automatically at the end of testing of each nanoweb. Tensile tests were carried out on the electrospun neat PCL control, P-6 (CFM/DMF), and P-6 (CFM) webs. Test samples measured 2cm and 1 cm in length and width, respectively, with varying thickness. Sample thicknesses were randomly measured across the web specimens by using an electronic thickness gauge (Marathon electric). An average of 5 such measurements was utilized for the thickness calculation. The samples were stretched at the rate of 2 mm/min, for each group, and 10 such samples were measured. Tensile stress, strain, elongation, and load were automatically calculated as the specimens were stretched to failure. At the end of testing, these values were displayed as mean ± standard deviation. Statistical analyses and plotting of results were performed using Minitab ® 15 software. Individual comparisons were made using t-tests at the 95% confidence


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interval, with variances assumed to be equal and P-values less than 0.05 (P0.05) to that of neat PCL fibers, but their elongation, tensile stress, and maximum load values are significantly lower, indicating there is no significant improvement in the mechanical properties. Table 3. Mechanical properties of neat PCL (CFM), P-6 (CFM), and P-6 (CFM/DMF) nanofibers. Modulus Sample Neat PCL P-6 (CFM/DMF) P-6 (CFM)

Tensile strain at break (%) 152 ± 5.

Max Load

(MPa) 8.0 ± 1.7

Tensile stress at break (MPa) 2.9 ± 0.8

8.6 ± 2.7 16.0 ± 4.9

1.3 ± 0.5 1.9 ± 1.0

118 ± 37 59 ± 12

1.9 ± 0.5 3.2 ± 0.9

(N) 8.0 ± 1.3

From the standpoint of tissue engineering scaffolds, modulus is the most important criteria as it is the factor that determines the ability of the material to withstand the initial loading. However, P-6 (CFM/DMF) exhibits no increase in the modulus values. Furthermore, there are no significant changes in elongation at break values, which indicate an absence of significant increase in the stiffness values.

P-6 (CFM) on the other hand possess considerably high modulus values (16.0 ± 4.9), which are almost twice that of both neat PCL and P-6 (CFM/DMF) (P=0.00227) nanowebs. Also they exhibit significantly reduced elongation values (2-fold decrease) compared with neat PCL, indicating significant increase in the stiffness. However, they unfortunately exhibited low load bearing capability compared to that of neat PCL nanofibers. As done with the thermal and crystallographic analyses, we performed mechanical evaluation to distinguish the nanofibers obtained from electrospinning from chloroform and chloroform/DMF. Similar to thermal transitions, degradation temperatures, and WAXD analyses, mechanical evaluation of the nanofibers indicated vast


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difference in the mechanical properties of nanofibers obtained from CFM/DMF compared to those obtained from CFM, indicating the differences in the molecular structure of those nanofibers. Conclusions We have presented the first successful preparation of PCL/α-CD pseudorotaxane nanofibers by electrospinning. Through extensive use of characterization techniques, we infer that the pseudorotaxane structure is intact in the nanofibrous structure. The pseudorotaxane nanowebs obtained from CFM showed significantly higher moduli and lower elongations at break than the neat PCL nanoweb and the PCL/α-CD nanoweb electrospun from CFM/DMF. Furthermore, rheological, thermal transitions, and degradations and crystallographic analyses indicate the α-CD present in the pseudorotaxane nanofibrous structure reported by Zhan et al.32 has significantly, if not completely, unthreaded and reverted to its native cage form. This study further explains why, Oster et al. 33 were unsuccessful in preparing linear pseudorotaxane nanofibers. The strategy of using a solvent like CFM, with added non-polar salt, to electrospin pseudorotaxanes can possibly be extended to other polymers, especially biomedical polymers, making them suitable for a variety of applications. Supplementary Information: The Supporting Information is available free of charge on the ACS Publications website. Rheological measurements (shear rate vs viscosity plots) of the electrospinning solutions, FTIR spectra and SEM micrographs of the electrospun mats. Author Information: Corresponding Author


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* Telephone: +1-919-515-6588. Email:[email protected] Notes: The authors declare no competitive financial interest References: 1. Boudou, T.; Crouzier, T.; Ren, K.; Blin, G.; Picart, C., Multiple functionalities of polyelectrolyte multilayer films: new biomedical applications. Advanced materials (Deerfield Beach, Fla.) 2010, 22, (4), 441-67. 2. Nair, L. S.; Laurencin, C. T., Biodegradable polymers as biomaterials. Progress in Polymer Science 2007, 32, (8–9), 762-798. 3. Zhang, H.; Hollister, S., Comparison of bone marrow stromal cell behaviors on poly(caprolactone) with or without surface modification: studies on cell adhesion, survival and proliferation. Journal of biomaterials science. Polymer edition 2009, 20, (14), 1975-93. 4. Yan, D.; Jones, J.; Yuan, X. Y.; Xu, X. H.; Sheng, J.; Lee, J. C.; Ma, G. Q.; Yu, Q. S., Plasma treatment of electrospun PCL random nanofiber meshes (NFMs) for biological property improvement. Journal of biomedical materials research. Part A 2013, 101, (4), 963-72. 5. Zhu, Y.; Gao, C.; Liu, X.; Shen, J., Surface modification of polycaprolactone membrane via aminolysis and biomacromolecule immobilization for promoting cytocompatibility of human endothelial cells. Biomacromolecules 2002, 3, (6), 1312-9. 6. Hartman, O.; Zhang, C.; Adams, E. L.; Farach-Carson, M. C.; Petrelli, N. J.; Chase, B. D.; Rabolt, J. F., Biofunctionalization of electrospun PCL-based scaffolds with perlecan domain IV peptide to create a 3-D pharmacokinetic cancer model. Biomaterials 2010, 31, (21), 5700-18. 7. Grafahrend, D.; Heffels, K. H.; Beer, M. V.; Gasteier, P.; Moller, M.; Boehm, G.; Dalton, P. D.; Groll, J., Degradable polyester scaffolds with controlled surface chemistry combining minimal protein adsorption with specific bioactivation. Nature materials 2011, 10, (1), 67-73. 8. Williams, C.; Loushine, R. J.; Weller, R. N.; Pashley, D. H.; Tay, F. R., A comparison of cohesive strength and stiffness of Resilon and gutta-percha. Journal of endodontics 2006, 32, (6), 553-5. 9. Saenger, W., Cyclodextrin inclusion compounds in research and industry. Angewandte Chemie International Edition in English 1980, 19, (5), 344-362. 10. Del Valle, E. M. M., Cyclodextrins and their uses: a review. Process Biochemistry 2004, 39, (9), 1033-1046.


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For Table of Content Use Only: Manuscript title: Fabrication and Characterization of Poly (ε-caprolactone)/αCyclodextrin Pseudorotaxane Nanofibers. Authors: Ganesh Narayanan, Remil Aguda, Matthew Hartman, Ching-Chang Chung, Ramiz Boy, Bhupender S. Gupta, Alan E. Tonelli.


Fabrication and Characterization of Poly(Îµ ... - ACS Publications

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