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A novel preparation of magnetic hydroxyapatite nanotubes

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A novel preparation of magnetic hydroxyapatite nanotubes

  1. 1. A novel preparation of magnetic hydroxyapatite nanotubes Rajendra K. Singh a,b , Ahmed M. El-Fiqi a,b , Kapil D. Patel a,b , Hae-Won Kim a,b,c, ⁎ a Institute of Tissue Regeneration Engineering (ITREN), Dankook University, South Korea b Department of Nanobiomedical Science, WCU Research Center, Dankook University Graduate School, South Korea c Department of Biomaterials Science, School of Dentistry, Dankook University, South Korea a b s t r a c t a r t i c l e i n f o Article history: Received 13 June 2011 Accepted 29 January 2012 Available online 4 February 2012 Keywords: Ceramics Nanomaterials Magnetic materials We report here the novel preparation of magnetic hydroxyapatite nanotubes (MHAnt). Poly(caprolactone) (PCL)–magnetite nanoparticles (MNPs) composite nanofiber was used as a template for the MHAnt. The sur- face of the composite nanofiber was activated in an alkaline solution and then an apatite mineral phase was deposited through a series of solution-mediated processes. After heat-treatment at 500 °C, a hollow tube of HA-MNPs was created in which HA formed an outer shell and most of the MNPs lined the inner shell surface. The inner shell size was about 650 nm and the shell thickness was about 137 nm. The developed MHAnt showed a saturation magnetization of 27.20 emu/g, exhibiting a ferromagnetic property. The newly devel- oped MHAnt may be useful in biomedical applications such as hyperthermia treatment of bone cancer. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Nanomaterials containing drugs and acting as drug-delivery sys- tems offer great promise in medical applications [1,2]. Providing addi- tional functionality to such systems including magnetic properties opens novel opportunities to their therapeutic efficacy. Magnetic ma- terials such as iron oxide nanoparticles have commonly been used in medical fields such as magnetic resonance imaging (MRI) and drug delivery vehicles for cancer treatment [3,4]. Additionally, some poly- mer microspheres or microtubes with ferromagnetic properties have recently been developed for cell separation and analysis, hyperther- mia treatment of tumors and selective killing of cancer cells [5,6]. Of particular interest for these magnetic nanomaterials is the possibility to use external magnetic fields to guide the drug carriers to precisely target areas of the body and thus significantly reduce unnecessary damage to healthy tissue [7]. Moreover, applying the magnetic force will facilitate hyperthermia therapy of target tissues. For the treatment of bone repair and related cancer therapy, the materials and carriers that are compatible to bone tissue is preferred. Hydroxyapatite (HA) exhibits unique advantages when used in bone reconstruction because its chemical structure is similar to the inor- ganic composition of human bone; therefore, it has been the most commonly used biomaterial for targeting bone repair [8,9]. Develop- ment of HA into specific nanomaterial forms, including nanospheres, nanofibers and nanotubes, has also shown promise for the develop- ment of materials for use as delivery systems of drugs and proteins and as matrices for bone cell regulation [10,11]. When therapeutic agents are delivered through HA nanocarriers, the healing potential of the defective or diseased bone should be greatly enhanced [10,11]. Here, we attempted to develop a nanotubular form of HA that also has magnetic properties. The combination of magnetic properties with the biocompatible HA composition is considered to open the door to a new class of biofunctional nanomaterials targeting bone. The nanotub- ular form of HA has previously been exploited in our group by using a polymer nanofiber as a template [12]; therefore, we utilized that meth- odology here. To impart magnetic properties, magnetite nanoparticles were embedded within the HA nanotubes. The processing route to pro- duce the magnetic HA nanotubes (MHAnt) is described and their useful characteristics, including magnetic properties, were investigated. 2. Experimental Magnetite nanoparticles were prepared according to the following procedure: ferrous chloride tetrahydrate (FeCl2·4H2O) in 1 M HCl and ferric chloride hexahydratate (FeCl3·6H2O) were mixed at room tem- perature (Fe2+ /Fe3+ =½). The mixture was then dropped into 200 ml of 1.5 M NaOH solution while stirring vigorously for about 30 min. The resulting precipitate was then isolated using a magnetic field, after which the solution was decanted by centrifugation at 8000 rpm. The separation procedure was conducted twice, after which 200 ml of 0.02 M HCl solution was added to the precipitate with continuous agitation. The product was then separated by centrifugation and dried at 40 °C. All steps were conducted under nitrogen gas. The magnetite nanoparticles were dispersed in citric acid solution (0.05 M) under magnetic stirring, and the pH was adjusted to 5.5 using NH3 solu- tion (28 wt.%). After 4 h, the nanoparticles were precipitated in acetone and then washed with acetone by magnetic decantation to remove the redundant citric acid. The samples were then dried at 40 °C. Materials Letters 75 (2012) 130–133 ⁎ Corresponding author at: Institute of Tissue Regeneration Engineering (ITREN), Dankook University, South Korea. Tel.: +82 41 550 3081; fax: +82 41 550 3085. E-mail address: kimhw@dku.edu (H.-W. Kim). 0167-577X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.matlet.2012.01.129 Contents lists available at SciVerse ScienceDirect Materials Letters journal homepage: www.elsevier.com/locate/matlet
  2. 2. Nanofiber templates were prepared according to our previous study, with slight modification [12]. A 10 w/v% suspension of poly(caprolactone) (PCL, Mw=80,000) in dichromethane/ethanol solvent which containing magnetite nanoparticles (20 wt.% relative to PCL) was prepared. The mixture suspension was electrospun into a random nanofiber mesh at a field strength of 15 kV/10 cm. The nanofiber surface was activated in 2 M NaOH solution for 4 h, after which they were washed and alternatively soaked in 150 mM CaCl2 and Na2HPO4 solution. This process was followed by an apatite miner- alization within 1.5 times simulated body fluid (1.5× SBF) at 37 °C for seven days. The specimen was then heat-treated at 500 °C for 5 h to remove out the polymer phase and to form hollow nanotubes. The crystal phase and chemical bond status of the samples were characterized by X-ray diffraction (XRD, Rigaku) and Fourier trans- form infrared (FT-IR, Varian 640-IR) spectroscopy, respectively. The surface electrical potential of the nanotubes was examined using a zeta potential measurement (Malvern Zetasizer Nano) at pH=7.0 and 25 °C. The instrument determines the electrophoretic mobility of the particles automatically and converts it to the zeta (ζ) potential using Smoluchowski's equation. The morphology of the samples was characterized by scanning electron microscopy (SEM, Hitachi S-3000H) and transmission electron microscope (TEM, JEOL-7100). Based on the TEM images, the size of the magnetic nanoparticles (MNPs) and the apatite nanotubes was measured, and the existence of MNPs within the nanotubes was also confirmed. The magnetic properties of the samples were studied using a superconducting quantum interference device (SQUID, Quantum Design MPMS-XL7) in an applied magnetic field of ±20 kOe at room temperature. The magnetic properties of the particles were evaluated in terms of satu- ration magnetization and area. 3. Results and discussion The crystalline phases of the MHAnt were investigated with XRD as shown in Fig. 1. For references, the MNPs and their composite nanofiber with PCL before and after the mineralization were also characterized. As expected, typical magnetite peaks (‘M’) were Fig. 1. XRD patterns of the samples: (a) MNPs, (b) PCL-MNPs composite nanofiber, (c) mineralized composite nanofiber and (d) MHAnt after heat-treatment at 500 °C. M: MNPs; P: PCL; A: apatite. Dashed lines in (d) are HA reference peaks (JCPDS card No. 24–33). Fig. 2. (a) TEM image of MNPs. (b) SEM image of composite nanofiber and inset TEM image showing the presence of MNPs on the surface region. SEM images of the mineralized nanofibers (c) before and (d) after heat-treatment. Inset in (d) shows a hollow tubular structure. 131 R.K. Singh et al. / Materials Letters 75 (2012) 130–133
  3. 3. shown in the as-prepared iron oxide nanoparticles (Fig. 1(a)) and ad- ditional PCL peaks (‘P’) were also shown in the composite nanofiber (Fig. 1(b)). After mineralization, the poorly crystallized apatite peaks at 2θ≈26° and 32° (‘A’) were well developed (Fig. 1(c)). After heat-treatment at 500 °C, the apatite peaks became more pro- nounced (Fig. 1(d)), and the magnetite peaks were also preserved. There were no other peaks observed except those of apatite and magnetite. The morphologies of the produced samples were examined by SEM and TEM, as shown in Fig. 2. The particle size of the magnetite nano- particles was found to be 12±1.34 nm, as deduced from the TEM image (Fig. 2(a)). The nanoparticles were observed to be easily dis- persed in the dichloromethane/ethanol solvent where the PCL could also be dissolved to prepare the composite suspension for electrospin- ning. A nanofiber mesh with sizes of hundreds of nanometers was well generated without any bead formation from SEM image (Fig. 2(b)). A high magnification TEM image shown in the inset revealed that the black dotted MNPs were primarily positioned at the surface region of the nanofiber. This was likely responsible for the inorganic particles being segregated at the border region of the fiber during the electro- spinning process. Previously, we observed a similar phenomenon dur- ing the electrospinning of a tricalcium phosphate sol and a polymer mixture, where the inorganic sol was distributed outer surface region while the polymer was inner [13]. This distribution of MNPs in large quantity at the surface region is highly beneficial to obtain MHAnt. The surface of the composite nanofibers was then functionalized with apatite mineral as shown in the SEM image (Fig. 2(c)). Surface activation with alkaline solution and further solution-mediated nucle- ation and crystallization processes led to the successful deposition of an apatite mineral phase on the nanofiber surface. Further heat- treatment of the mineralized nanofiber at 500 °C revealed a hollow tu- bular structure (Fig. 2(d)). The high resolution image of the MHAnt was revealed by TEM (Fig. 3). Hollow-structured long tubes were well developed and con- sisted of a number of highly elongated mineral nanocrystallites with a morphology similar to bone mineral and that generally observed in apatite obtained by biomimetic processes. The width of the inner hol- low part of the tube was measured to be 650 nm (±80 nm) and the wall thickness was 137 nm (±24 nm). Although magnetite nanopar- ticles were not clearly discerned from the apatite nanocrystallites, some particulate forms (representative regions are indicated by ar- rows) in dark-colored area are considered to indicate their presence. The nanocrystallite morphology of the apatite embedded with the MNPs was actually slightly different from the pure apatite without the nanoparticles, as previously reported; a more dotted structure was observed MHAnt than in pure HA nanotubes which have a more plate-like structure. Therefore, we examined the atomic composition of the areas with EDS. In addition to the Ca and P peaks, a high level of Fe peaks was found, confirming the existence of iron oxide MNPs. The magnetic properties of the MHAnt were investigated using SQUID magnetometry. The magnetization curve as a function of an applied magnetic field (Fig. 4) shows a ferromagnetic property (i.e. the narrow hysteresis loop and low coercivity) and a saturation magnetization (Ms) of 27.20 emu/g. In fact, the Ms of pure magnetite nanoparticles was measured to be around 71 emu/g, while that of bulk magnetite is known to be 92 emu/g [14]. When compared to the pure magnetite materials, the currently developed magnetic HA had a much lower Ms value, which is easily understandable when considering the decrease in the relative mass fraction of the magnetite. Although the Ms value of the MHAnt did not reach that of pure magnetite, the prop- erties revealed in this study including the ferromagnetic behavior and fairly high Ms should indicate that the MHAnt can be used as biocom- patible magnetic materials. Another important parameter for the mag- netic characterization is the magnetic loss/cycle or the area of the hysteresis loop. The integrated hysteresis loop area calculated for a maximum applied field of 20 kOe was found to be 57.22×103 erg/g. Since the area under the loop is proportional to the energy loss and hence the heat generated by a sample under a magnetic field it is sug- gested the nanotubes find possible uses in hyperthermia treatment. Taken together, this study provides useful information of the applicabil- ity of the developed HA hollow magnetic nanotubes in biomedicine, ei- ther used directly as a delivery system of therapeutic molecules or as a secondary phase in artificial bone matrices, to treat the bone disease and trauma via hyperthermia treatment or other therapeutic efficacies potentiated under magnetic fields. 4. Conclusions Magnetic hydroxyapatite nanotubes (MHAnt) were produced using a template made of magnetite nanoparticles/PCL polymer and Fig. 3. TEM nanostructure image of the MHAnt and the EDS profile in the inset showing the existence of Fe and thus MNPs. Arrows pointing to dark dotted areas indicate the possible presence of MNPs. Fig. 4. Magnetic properties of the magnetic HA nanotubes as determined by SQUID magnetometry. The magnetization versus magnetic field curve shows that the nano- tubes exhibit a ferromagnetic property with a saturation magnetization of 27.20 emu/g. The inset shows an enlargement of the curve in the initial range. 132 R.K. Singh et al. / Materials Letters 75 (2012) 130–133
  4. 4. its subsequent surface mineralization and thermal treatment. The MHAnt showed a hollow tubular structure with an inner shell size of about 650 nm and a shell thickness of about 137 nm. The MHAnt exhibited a ferromagnetic property with a saturation magnetization of 27.20 emu/g. The MHAnt developed herein may find usefulness in many biomedical applications, including the treatment of bone re- pair and related diseases. Acknowledgments This work was supported by the Priority Research Centers Pro- gram (No. 2009–0093829) and WCU program (R31-10069) through the National Research Foundation of Korea (NRF) funded by the Min- istry of Education, Science and Technology. Authors highly thank the help of IBST, Dankook University. References [1] Kumar CSSR, Mohammad F. Adv Drug Deliv Rev 2011;63:789–808. [2] Shin US, Yoon IK, Lee GS, Jang WC, Knowles JC, Kim HW. J Tissue Eng 2011;2011: 10 Article ID 67428. [3] Ferrari M. Nat Rev Cancer 2005;5:161–71. [4] Corot C, Robert P, Idee JM, Port M. Adv Drug Deliv Rev 2006;58:1471–504. [5] Ugelstad J, Prestvik WS, Stenstad P, Kilaas L, Kvalheim G. Selective Cell Separation with Monosized Magnetizable Polymer Beads in Magnetism in Medicine. Berlin: Wiley-VCH; 1998. p. 471. [6] Tartaj P, Morales MP, Sabino VV, Teresita GC, Serna CJ. J Phys D: Appl Phys 2003;36:R182–97. [7] Medeiros SF, Santos AM, Fessi H, Elaissari A. Int J Pharm 2011;403:139–61. [8] Muller-Mai CM, Stupp SI, Voigt C, Gross U. J Biomed Mater Res 1995;29:9–18. [9] Edwards JT, Brunski JB, Higuchi HW. J Biomed Mater Res 1997;36:454–68. [10] Hengst V, Oussoren C, Kissel T, Storm G. Int J Pharm 2007;331:224–7. [11] Liu TY, Chen SY, Liu DM, Liou SC. J Control Release 2005;107:112–21. [12] Kim MK, Kim JJ, Shin US, Kim HW. Mater Lett 2010;64:2655–8. [13] Eltohamy M, Shin US, Won JE, Kim JJ, Kim HW. Mater Lett 2011;65:2043–6. [14] Cullity RD. Introduction to Magnetic Materials. Reading: Addison-Wesley; 1972. 133 R.K. Singh et al. / Materials Letters 75 (2012) 130–133

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