- Email: [email protected]
Fe3O4 nanofibers for magnetic hyperthermia
Journal Pre-proof In situ melt electrospun polycaprolactone/Fe3O4 nanofibers for magnetic hyperthermia
Peng-Yue Hu, Ying-Tao Zhao, Jun Zhang, Shu-Xin Yu, Jia-Shu Yan, Xiao-Xiong Wang, Mao-Zhi Hu, Hong-Fei Xiang, Yun-Ze Long PII:
S0928-4931(19)34122-0
DOI:
https://doi.org/10.1016/j.msec.2020.110708
Reference:
MSC 110708
To appear in:
Materials Science & Engineering C
Received date:
5 November 2019
Revised date:
23 January 2020
Accepted date:
28 January 2020
Please cite this article as: P.-Y. Hu, Y.-T. Zhao, J. Zhang, et al., In situ melt electrospun polycaprolactone/Fe3O4 nanofibers for magnetic hyperthermia, Materials Science & Engineering C (2018), https://doi.org/10.1016/j.msec.2020.110708
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© 2018 Published by Elsevier.
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In situ melt electrospun polycaprolactone/Fe3O4 nanofibers for magnetic hyperthermia Peng-Yue Hu†,a, Ying-Tao Zhao†,a, Jun Zhang*,a, Shu-Xin Yua, Jia-Shu Yana, Xiao-Xiong Wanga, Mao-Zhi Hub, Hong-Fei Xiangc, Yun-Ze Long*,a
Collaborative Innovation Center for Nanomaterials & Devices, College of Physics,
Qingdao University, Qingdao 266071, P. R. China
Equipment Division, Qingyun County People’s Hospital, Dezhou 253000, P. R.
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b
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China c
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a
Department of Spine Surgery, Affiliated Hospital of Qingdao University, Qingdao
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Abstract
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266071, P. R. China
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Magnetic fibrous membrane used to generate heat under the alternating magnetic field (AMF) has attracted wide attention due to their application in magnetic
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hyperthermia. However, there is not magnetic fibrous membrane prepared by melt electrospinning (e-spinning) which is a solvent-free, bio-friendly technology. In this work, polycaprolactone (PCL)/Fe3O4 fiber membrane was prepared by melt e-spinning and using homemade self-powered portable melt e-spinning apparatus. The hand-held melt e-spinning apparatus has a weight of about 450 g and a precise size of 24 cm in length, 6 cm in thickness and 13 cm in height, which is more portable for widely using in the medical field. The PCL/Fe3O4 composite fibers with diameters of 4-17 μm, are very uniform. In addition, the magnetic composite fiber membrane has excellent heating efficiency and thermal cycling characteristics. The results indicated that self-powered portable melt e-spinning apparatus and PCL/Fe3O4 fiber membrane may provide an attractive way for hyperthermia therapy. Keywords: magnetic hyperthermia; nanofiber; melt electrospinning; apparatus; 1
Journal Pre-proof in-situ deposition. ______________________ †
These two authors contributed equally to this work.
*
Corresponding author.
E-mail: [email protected] (Y.Z. Long) or [email protected] (J. Zhang)
1. Introduction
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Hyperthermia is another effective tumor treatment method besides the traditional chemotherapy and radiotherapy for its synergistical effect in antitumor.1-3 Different
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from healthy cells, cancer cells are sensitive to the temperatures ranging from 41 to
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45 °C, which is the mechanism for using high temperatures as a treatment for cancer.4-5 Although many targeting strategies have been proposed, such as magnetic
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targeting and molecular targeting, the insufficient directionality still limits the
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application of magnetic nanoparticles in cancer therapy.6-7 When magnetic particles are injected directly into tumor tissue, they are more likely to leak from the tumor site
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into the body because of their small size, and then they are rapidly cleared by the immune system and enriched in specific organs, increasing the risk.8-9 In recent years,
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some of these issues have been reduced due to improvements in the synthesis and functionalization of nanoparticles, for example, a silica shell coating on the magnetic nanoparticles to decrease their toxicity10; precise control of size and morphology as well as surface modification for providing chemical groups for attaching biomolecules and minimizing blood proteins adsorption.11 In addition, despite direct injection being the only method currently employed at clinical level, one of the main goals of using magnetic nanoparticles is to inject them intravenously and, by functionalizing them with targeting ligands or using external magnetic fields, direct them so that they can reach the tumour and all the metastasized regions.12 Compared to complex modification work on magnetic particles, magnetic composite fibers are light in weight, easy to preparation, flexible, and capable of accurately delivering magnetic nanoparticles to cancer cells. Therefore, this is an ideal method via hyperthermia for 2
Journal Pre-proof solid tumor tissue. In previous studies, composite nanofiber membranes are usually prepared in advance and then attached to the surface of tumor tissue.13-16 However, this method has obvious disadvantages. The pre-prepared nanofiber membrane is difficult to form a uniform and continuous wrap layer on the surface of the tumor tissue, which is disadvantageous for close fitting and easy to fall off, thereby resulting in poor thermotherapy effect of the tumor tissue. Therefore, direct in situ electrospinning (e-spinning) onto the surface of tumor tissue may be a good method to prevent the
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shedding of the composite fiber membrane and increase the fit of the composite fiber
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to the tumor tissue.17 However, the nanofiber membranes used in in-situ magnetic hyperthermia reported in the current article were all prepared by solution e-spinning.18
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But for solution e-spinning, the utilization of the precursor solution is less than 20%;
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the volatilization of the solvent causes environmental problems; the residue of the toxic solvent causes the fiber membrane to be toxic; and some polymers have no
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suitable solvent at room temperature resulting in the inability to spin the fiber.19-22
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And the melt e-spinning technology is a solvent-free, bio-friendly technology.23-25 Interestingly, there is no literature reporting on in-situ e-spinning fibers for magnetic
inorganic
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hyperthermia by melt e-spinning. The main reason is that the high surface activity of nanoparticles
can
lead
to
spontaneous
agglomeration
between
nanoparticles.26-28 Magnetic particles do not disperse well in polymer melts and are always aggregated on a large scale. Besides, due to the existence of heating devices and electrostatic interference problems, melt e-spinning devices is relatively complicated, cumbersome and not portable, thereby limiting the development of melt e-spinning technology in the medical field.29-32 In this paper, a new magnetic hyperthermia method for cancer was proposed (as shown in Fig. 1). We have solved the problem of large-scale agglomeration of magnetic particles in the melt, and have designed a hand-held melt e-spinning device for medical applications. Polycaprolactone (PCL) was chosen for fibers because of its biocompatibility and biodegradability.33 These fibrous membranes can be e-spun in 3
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2. Experimental
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Fig. 1 A new magnetic hyperthermia method for cancer.
2.1 Materials
Polycaprolactone (PCL, average Mw~80 000, Aladdin) and ferric oxide particles (Fe3O4, Aladdin) are selected as the melt e-spinning materials. The acetone was purchased from Sinopharm Chemical Reagent Co., Ltd.
2.2 Preparation of e-spinning PCL/Fe3O4 magnetic nanofibers First, 0.17 g of Fe3O4 nanoparticles were added into 3 g of acetone, and the mixture was sonicated in an Erlenmeyer flask for 4 h. At the same time, 3.4 g of PCL particles were dissolved in 23.6 g of acetone and stirred for 4 h to prepare a pure PCL solution. Then, the pure PCL solution was introduced into the Fe3O4 nanoparticle 4
Journal Pre-proof dispersion and stirred by a mechanical stirrer for 4 h. Finally, the obtained homogeneous mixed solution was placed in a 40 °C drying oven. After the acetone was completely evaporated, a PCL/Fe3O4 solid material was obtained, and the Fe3O4 particles were uniformly dispersed in the material without large-scale agglomeration. PCL/Fe3O4 composites with different Fe3O4 contents were prepared by this method. The obtained PCL/Fe3O4 material was placed in the hand-held e-spinning device. After turning on the hand-held e-spinning device heating switch and preheating for 4 min, the high voltage transfer switch was turned on to perform melt e-spinning, and
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PCL/Fe3O4 fibers were deposited on the collector. The PCL/Fe3O4 composite fibers
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with different Fe3O4 nanoparticles loadings of 5 wt%, 9 wt%, 13 wt%, 17 wt% and 21 wt% were denoted as PCL/Fe3O4-5, PCL/Fe3O4-9, PCL/Fe3O4-13, PCL/Fe3O4-17 and
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PCL/Fe3O4-21, respectively, as shown in the Table 1. In addition, as shown in Fig. 1,
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the magnetic fiber membranes can easier be in situ e-spun on the surface of the tumor by using the hand-held apparatus. Then under the alternating magnetic field (AMF),
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the magnetic fiber membranes generate heat and reach about 45 ℃. The heat can
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transfer to cancerous tissue and cause the die of cancer cells.
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Table 1 Composition of the deposited fibers
Simple
Composition
Content of Fe3O4 (%)
Content of polycaprolactone (%)
PCL/Fe3O4-5
5
95
PCL/Fe3O4-9
9
91
PCL/Fe3O4-13
13
87
PCL/Fe3O4-17
17
83
PCL/Fe3O4-21
21
79
2.3 Characterization A Scanning electron microscope (SEM, TM-100, Hitachi) was used to characterize the morphology of the melt e-spun fibers. The size of morphology of 5
Journal Pre-proof Fe3O4 nanoparticles were tested by transmission electron microscopy (TEM, JEM-200EX). The hydrodynamic size of Fe3O4 nanoparticles measured by dynamic light scattering (DLS, 802DLS). X-ray powder diffraction (XRD, RINT2000 wide-angle goniometer) analysis was carried out using a Rigaku X-ray diffractometer to investigate the crystalline structure of Fe3O4 and PCL/Fe3O4 fibers. The thermal properties of PCL/Fe3O4 composite fibers were measured by the Thermogravimetric analysis instrument (TG209F1, NETZSCH), and a Differential scanning calorimeter (DSC250, TA) was used to test the transition temperature of PCL/Fe3O4 composite
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fibers. The nanofiber membrane was examined by the Fourier transform infrared
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spectroscopy (FTIR; Thermo Scientific Nicolet iN10). The magnetic properties of PCL/Fe3O4 composite fibers were measured by a Physical Property Measurement
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System (PPMS, Quantum Design). The high-frequency alternating magnetic field
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(AMF) is generated by a magnetic field generator (SP-04AC Shenzhen Shuangping
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Power Technology Co., Ltd.). Its rated power is 3 kW, and the water-cooled induction coil is made of copper. The number of turns is two and the inner diameter is 30 mm.
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The maximum magnetic field strength and magnetic field frequency of the alternating
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magnetic field generator are 12.5 Oe and 153 kHz, respectively.
3. Results and discussion
3.1 Design of the self-powered hand-held melt e-spinning apparatus
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Fig. 2 (a) 3D model diagram of hand-held melt e-spinning apparatus. (b) Schematic
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diagram of hand-held melt e-spinning apparatus. (c) Melt e-spinning schematic by hand-held melt e-spinning apparatus. the apparatus was operated by one hand and the
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other hand receives the PCL fibers.
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As we all know, traditional melt e-spinning devices have four components: a heating device, a high-voltage power supply, a feeding device and a collection device. The volume of the traditional device is relatively large and the parts of the device are separated, so the device is not portable. Besides, the typical spinning voltage and heating unit for e-spinning requires a 220 V working voltage. This greatly limits the wide application of e-spinning technology in biomedical applications. As shown in Fig. 2, the hand-held melt device was designed for the first time and had many innovative modifications compared to traditional melt devices. The hand-held melt e-spinning apparatus has a weight of about 450 g and a precise size of 24 cm in length, 6 cm in thickness and 13 cm in height, which is more portable. In addition, the high voltage unit and heating unit of the apparatus are fully powered by a rechargeable lithium battery which can be integrated inside the device and this device can work 7
Journal Pre-proof normally without mains power. And the built-in power supply allows the apparatus to operate continuously for more than 2 h. Finally, the device is equipped with a high heat-transfer electrical-insulation unit to solve the electrostatic interference between the heating unit and the high voltage unit. This is the key for integration. As shown in Fig. 2c, the apparatus was operated by one hand, and the fibers could be deposited on another hand directly. It is convenient for surgeon and doctor to use because of its portability. In addition, this portable melt device may also be used in wound dressing,
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Table 2 Temperature of the deposited fibers
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hemostasis and so on by a versatile method of replacing with other materials.
Temperature of spinneret (℃)
Temperature of fibers just dropped on skin (℃)
180-200
126-132
39.1
36-38
180-200
126-132
35.5
36-38
180-200
126-132
32.2
PCL/
4
36-38
Fe3O4
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fibers
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Temperature of material barrel (℃)
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Temperature of skin before e-spinning (℃)
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fibers
Spinning distance (cm)
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Melt e-spinning refers to melt polymers to form fibers under the high-voltage electrostatic field force. It undergoes the process of stretching, whipping and solidification in air, and finally becomes fibers falling onto the receiving plate. If the polymer fibers are directly received by the biological tissue, the temperature of the fibers should not be too high to avoid damage to the biological tissues. Therefore, as shown in Table 2, the temperature of the deposited fibers on the skin were measured by infrared thermometer under different e-spinning distances. The temperature of spinneret is around 132 ℃ and temperature of fibers just dropped on skin is about 35 ℃. And the purpose of monitoring these two temperature is that although fiber temperature leaving from the spinneret is high (~132 ℃), these fibers cannot burn the skin when they deposited onto the skin (~35 ℃). Therefore, it is suitable for melt e-spun fibers to apply in in-situ magnetic hyperthermia. 8
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3.2 Morphological, structural and magnetic properties of PCL/Fe3O4 fibers
Fig. 3 (a) TEM image of Fe3O4 nanoparticles. (b) TEM image of PCL/Fe3O4-17
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composite fiber. (c) SEM image of PCL/Fe3O4-17 composite fiber. The red circle is
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the exposed nanoparticles.
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The morphology of the Fe3O4 nanoparticles are shown in Fig. 3a. The Fe3O4 nanoparticles showed a spherical or square shape. The average diameter of a single
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Fe3O4 nanoparticle was 50-100 nm. And the nanoparticles without coating are colloidally stable. TEM image shows that these nanoparticles are slight aggregation, and additional DLS measurement (Fig. S1) show that about 6~10 nanoparticles were aggregated together to form clusters. This phenomenon is consistent with previous reports.34-35 In the common melt e-spinning process, it is difficult to disperse the nanoparticles by directly mixing the particles with PCL. From the TEM of composite fibers, nanoparticle clusters are dispersed throughout the whole fiber. It indicates that nanoparticles could well dispersed in the PCL for the following melt e-spinning via a method of adding acetone with evaporation. As shown in Fig. 3c, the Fe3O4 nanoparticles are successfully dispersed in the fiber and partially exposed on the surface. Semi-naked Fe3O4 particles demonstrate the successful incorporation of Fe3O4 nanoparticles into PCL fibers. The SEM of the 9
Journal Pre-proof cross section of the PCL/Fe3O4 fiber was tested, as shown in Fig. S2. In addition, some nanoparticles seem to be agglomerated in the fiber (Fig. 3b, c), which is probable due to the nanoparticles were aggregated together to form clusters with about 6~10 nanoparticles (Fig. 3a) before mixing with PCL. It caused by the magnetic
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assembly.34
Fig. 4 SEM images of the PCL/Fe3O4 composite fibers with different Fe3O4 nanoparticles loadings of (a) 5 wt%, (b) 9 wt%, (c) 13 wt%, (d) 17 wt% and (e) 21 wt%. (f) Diameter distribution bar chart of the melt e-spun fibers. SEM images of the melt e-spun PCL/Fe3O4 composite fibers produce d at different spinning distance: (g) 4 cm, (h) 5 cm, (i) 6 cm, (j) 7 cm, (k) 8 cm. (l) Diameter distribution bar chart of the melt e-spun fibers.
10
Journal Pre-proof Magnetic nanoparticles affect the viscosity and conductivity of the melt, which in turn affects the spinning process. As shown in Fig. 4a-f, we explored the influence of the different weight ratio of Fe3O4 nanoparticles to the composite fiber for fiber morphology. When the content of Fe3O4 nanoparticles is small, the spinning process is stable and the fibers are smooth and evenly distributed. With the increase of the content of Fe3O4 particles, the surface morphology of the fibers is obviously changed. It can be found that the surface of the fibers is gradually rough and the diameter of the fibers is increased. The fiber diameter even reached 15 μm. Moreover, the protrusions
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on the surface of the fiber are gradually increased, and the semi-naked Fe3O4 particles
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on the surface of the fiber can be clearly seen, as shown in the inset SEM picture of Fig. 4d.
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The morphology and diameter analysis of the melt e-spun composite fibers at
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different distances are shown in Fig. 4g-l. When the spinning distance is 5 cm, the fiber diameter can be controlled at 5 μm. As the distance increases, the average fiber
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diameter increases up to 15.1 μm. However, when the receiving distance is 8 cm or
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more, the melt e-spinning process cannot be performed, because the receiving
generated.
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distance is too large and the electric field strength is too small to cause the jet to be
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Fig. 5 (a) TG analysis curves, (b) DSC curves, (c) FTIR spectra and (d) XRD patterns
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of the melt e-spun PCL/Fe3O4 composite fibers.
TGA analysis was used to exam the proportion of Fe3O4 in the melt e-spun
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composite fibers and thermal stability of composite nanofiber membrane. As shown in Fig. 5a, the typical single mass-loss step of the melt e-spun PCL/Fe3O4 composite fibers was located at 320–375℃ because of the degradation of composite fiber membrane including depolymerization, dehydration and decomposition followed by the formation of a charred residue. TGA shows that the mass percentage of the composite fiber membrane are 0%, 6%, 10%, 15%, 17% and 22%, which are consistent with mass percentage of Fe3O4 used in the experiment. In addition, the thermal decomposition rate of pure fiber membrane is slightly lower than that of composite fiber membrane. This can be attributed to the interaction between the polymer and the nanoparticles. When the temperature reaches 460 ℃, the pure PCL nanofiber membrane has no significant change no significant residual weight compared to the composite fiber membrane. 12
Journal Pre-proof DSC analysis was used to further demonstrate whether the addition of Fe3O4 had effect on the crystallization behavior of PCL. It can be found from Fig. 5b that the melting temperature of pure PCL fiber is 52.8 ℃, and the mixing of magnetic Fe3O4 nanoparticles does change the melting temperature of PCL. The melting temperature of the composite fiber membrane increases by 1~3 ℃, and as the content of magnetic Fe3O4 nanoparticles increases, the melting temperature tends to increase. The reason may be that the physical composite between magnetic Fe3O4 particles and PCL does not have much influence on the molecular structure of PCL, but the presence of a
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certain amount of Fe3O4 particles changes the crystallinity of PCL, thus affecting the
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melting temperature of the PCL/Fe3O4 composite fiber.
Fig. 5c is the infrared spectra of PCL composite nanofibers with different Fe3O4
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contents. It can be seen from the figure that the pure PCL nanofibers have the
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following characteristic absorption peaks: C-H stretching vibration peak at 2948 and 2869 cm-1, C=O stretching vibration peak at 1725 cm-1. And the peak at 1250 cm-1
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reflects the -C-O-C- asymmetric stretching vibration of PCL.36-38 The above data is
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the characteristic peaks of PCL, which are consistent with the related literature. Except for the characteristic absorption peak of PCL, there is no other peaks
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appearing, indicating that there is no chemical change between PCL and Fe3O4. Fig. 5d shows the XRD pattern of pure PCL fiber membrane, Fe3O4 magnetic nanoparticles and the melt e-spun PCL/Fe3O4 composite fiber membrane. The position and relative intensity of the characteristic peaks of the composite film are in good agreement with the standard diffraction card JCPDS 39-1346, which corresponds to (220), (311), (400), (511) and (440) characteristic peak of Fe3O4 nanoparticles.39-40 PCL membrane contains three distinct reflections at the Bragg angles of about 21.4, 23.7 and 45 degree.41 With the increases of the percentage of Fe3O4, no significant change in PCL content. Therefore, there is no further change in the peak at 45 degree. And with the increasing of magnetic particles content, the intensity of PCL characteristic peaks gradually decreases. It indicates that the presence of magnetic nanoparticles reduces the crystallinity of PCL.42 13
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Fig. 6 (a-c) Magnetic performance demonstration diagram of the melt e-spun
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PCL/Fe3O4 composite fibers. (d) Magnetic hysteresis curves of the melt e-spun
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PCL/Fe3O4 composite fibers.
As shown in the Fig. 6a-c, we placed a 5×20 mm2 PCL/Fe3O4 fiber membrane at
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a position 3 cm from the magnet and slowly brought the composite fiber membrane close to the magnet. When the distance is 1 cm, the fiber membrane is significantly
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bent. The experiment verified the existence of magnetic properties of the PCL/Fe3O4 composite fiber membrane prepared by melt e-spinning. As shown in Fig. 6d, the magnetic hysteresis curves of the melt e-spun PCL/Fe3O4 composite fibers was measured by PPMS. The saturation magnetization (Ms) of PCL/Fe3O4 composite nanofiber membrane increases with the increase of Fe3O4 content, which is 5.86 emu g-1, 11.62 emu g-1, 19.66 emu g-1, 22.83 emu g-1, 31.24 emu g-1, and the saturation magnetization (Ms) of the original Fe3O4 nanoparticles is 89.05 emu g-1. The Mr/Ms and Hc of PCL/Fe3O4 fiber membranes are also discussed (Fig. S3 and Table S1). In addition, to compare the magnetization normalized to the mass of Fe3O4 inside the PCL, another M-H curve are showing and M is given in emu/g_Fe3O4 (Fig. S4). There are no obvious difference, at around 87 emu g-1. 14
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3.3 In vitro hyperthermia test
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Fig. 7 Temperature (T) – time (t) profile of the melt e-spun PCL/Fe3O4 composite
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fibers obtained (a) upon the application of an AMF, and (b) with and without the application of the magnetic field; the shaded area indicates the application of the
nanoparticle
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Magnetic
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magnetic field.
hyperthermia
utilizes
the
performance
of
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superparamagnetic nanoparticles such as Fe2O3 or Fe3O4 to produce heat under alternating magnetic fields.43 Whether the nanoparticles are aggregated or evenly
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distributed, both the nanoparticles generate heat under alternating magnetic fields17, but the heating efficiency will decrease if the nanoparticles are agglomerated in a random way.44 The heating of aggregated nanoparticles is controlled by intermolecular interactions and hysteresis loss.45 And the heating of dispersed nanoparticles is mainly caused by Brownian and Néel relaxation.46 In addition, Carrey et al. proposed that all the losses, whether the magnetic nanoparticles are in the superparamagnetic regime or in the ferromagnetic regime, are always “hysteresis losses” insofar as they are simply given by the hysteresis loop area.47 For composite fibers, the magnetic nanoparticles are embedded and fixed inside the nanofibers, so that the nanoparticles can’t freely rotate and move in the magnetic field, and thus the Brownian relaxation has no effect on the magnetic heating that occurs under alternating magnetic fields. Therefore, only hysteresis loss and Néel relaxation play 15
Journal Pre-proof an important role for magnetic nanoparticles inside the structure to generate heat. In the composite fiber membrane, the magnetic nanoparticles are locally aggregated and partially dispersed, and in the alternating magnetic field, the actual heat generation performance of the magnetic nanoparticles is difficult to estimate.48 Therefore, the heat generation ability of the magnetic nanoparticles in the nanofiber membrane can be appropriately examined by experimentally measuring. Fig. 7a shows the time-dependent heating curve of composite fibers with different magnetic particle contents. The temperature rise of PCL/Fe3O4-5, PCL/Fe3O4-9, PCL/Fe3O4-13,
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PCL/Fe3O4-17 and PCL/Fe3O4-21 composite fiber membranes was 21±0.4 ℃,
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25.2±0.3 ℃, 27.1±0.5 ℃, 31.1±0.2 ℃ and 36.4±0.3 ℃, respectively. The heating temperature increases quickly with time and is basically balanced after reaching a
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certain temperature. And the experimental results obtained meet the conditions of
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magnetic hyperthermia.
In the case of cancer therapy, alternating cycle of high and low temperatures can
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better kill cancer cells due to the possibility of tumor metastasis.17 Therefore, it is
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necessary for composite fibrous membranes to possess a stable temperature cyclic profile during the heating process. In order to test the thermal cycle of the PCL/Fe3O4
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composite fiber membrane, the PCL/Fe3O4-17 membrane was exposed to the AMF. There is no significant change in the temperature curve during the three cycles of the alternating magnetic field. As shown in Fig. 7, the temperature changed from 15 to 45 ℃ in 37 s. It indicates that composite fiber membrane can efficiently and rapidly convert the alternating magnetic field energy into thermal energy. We further immersed these fiber membranes in PBS and tested their changes of heating performance (Fig. S5). More importantly, the advantages of the composite fibrous membranes for hyperthermia are their repeatable heating without decreasing the heating efficiency.
4. Conclusion In this study, we presented a hand-held melt e-spinning apparatus using a 16
Journal Pre-proof rechargeable battery to provide a high voltage and heating power, which can work without any extra electricity supply. PCL/Fe3O4 composite fibers with diameters of 4-17 μm were prepared by using this portable melt e-spinning apparatus. These magnetic composite nanofiber membranes can convert electromagnetic energy to heat, thereby effectively increasing the temperature of the hyperthermia. These results indicate that in situ melt e-spinning of magnetic composite fiber membranes by using hand-held e-spinning devices is a potential approach to magnetic hyperthermia. In addition, this portable melt device may also be easily extended to wound dressing,
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hemostasis and other usage by a versatile method of replacing with other materials.
Author Statement
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The authors declare that this work was done by the authors named in this article and
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all liabilities pertaining to claims relating to the content of this article will be borne by
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them. J Z and Y-T Z designed the experiments and give the intellectual input. P-Y H and Y-T Z carried out the research work. S-X Y, M-Z H, J-S Y, X-X W and H-F X
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analyzed the data. P-Y H and Y-T Z wrote the paper. Y-T Z supervised the whole research work. P-Y H and Y-T Z contributed equally to this work and should be
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considered as co-first authors. All authors have reviewed and approved the content of the submitted manuscripts.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (51973100, 51673103, 11904193 and 81802190), Shandong Provincial Natural Science Foundation, China (ZR2019BH084) and Young Taishan Scholars Program (tsqn201909190).
Consent for publication All authors agreed to submit this manuscript. 17
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Conflict of interest None
Notes and references
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Materials & Interfaces, 2018, 10(15), 12323-12330. 9. J. Huang, Y. Li, A. Orza, Q. Lu, P. Guo, L. Wang, L. Yang and H. Mao, Advanced Functional Materials, 2016, 26, 3818-3836. 10. C. Blanco-Andujar, F. J. Teran, and D. Ortega, in: Iron Oxide Nanoparticles for Biomedical Applications, Elsevier, 2018, 197-245. 11. E. A. Périgo, G. Hemery, O. Sandre, D. Ortega, E. Garaio, and F. Plazaola, Applied Physics Reviews, 2015, 2(4), 041302. 12. A. Sohail, Z. Ahmad, O. A. Bég, S. Arshad, and L. Sherin, Bulletin du Cancer, 2017, 104(5), 452-461. 13. A. GhavamiNejad, A. R. K. Sasikala, A. R. Unnithan, R. G. Thomas, Y. Y. Jeong, M. Vatankhah‐Varnoosfaderani, C. S. Kim, Advanced Functional Materials, 2015, 25(19), 2867-2875. 14. Y. J. Kim, M. Ebara and T. Aoyagi, Advanced Functional Materials, 2013, 23, 5753-5761. 15. T. I. Yang, and S. H. Chang, Nanotechnology, 2016, 28(5), 055601. 16. J. Zhang, J. Li, S. Chen, N. Kawazoe and G. Chen, Journal of Materials Chemistry B, 2016, 5(2), 245-253. 18
Journal Pre-proof 17. C. Song, X.-X. Wang, J. Zhang, G.-D. Nie, W.-L. Luo, J. Fu, S. Ramakrishna and Y.-Z. Long, Nanoscale Research Letters, 2018, 13(1), 273. 18. S. Wang, C. Wang, B. Zhang, Z. Sun, Z. Li, X. Jiang and X. Bai, Materials Letters, 2010, 64, 9-11. 19. L. X. Y. D. and Y. N. Xia, Advanced Materials, 2004, 16, 1151-1170. 20. N. Bhardwaj and S. C. Kundu, Biotechnology Adv, 2010, 28, 325-347. 21. B. Zhang, X. Yan, H. W. He, M. Yu and Y. Z. Long, Polymer Chemistry, 2016, 8(2), 333-352. 22. R. Deng, L. Yong, Y. Ding, P. Xie and W. Yang, Journal of Applied Polymer Science, 2009, 114, 166-175.
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23. J. Lyons and F. Ko, Polymer News, 2005, 30, 170-178. 24. F. M. Wunner, O. Bas, N. T. Saidy, P. D. Dalton, E. M. D.-J. Pardo and D. W. Hutmacher, Journal of Visualized Experiments Jove, 2017, (130), e56289. 25. K. F. Eichholz and H. D. A., Acta Biomaterialia, 2018, S1742706118303271-. 26. J. Zhang, X. Li, J. C. Zhang, J. S. Yan, H. Zhu, J. J. Liu, and Y. Z. Long, Chemical Engineering Journal, 2020, 382, 122779. 27. X. Li, J. Zhang, J. C. Zhang, X. X. Wang, J. J. Liu, R. Li, and Y. Z. Long, Advanced Optical Materials, 2019, 1900364. 28. J. Zhang, S. Li, D. D. Ju, X. Li, J. C. Zhang, X. Yan, and F. Song, Chemical Engineering Journal, 2018, 349, 554-561. 29. C.-C. Qin, X.-P. Duan, L. Wang, L.-H. Zhang, M. Yu, R.-H. Dong, X. Yan, H.-W. He and Y.-Z. Long, Nanoscale, 2015, 7(40), 16611-16615. 30. X. Yan, X.-P. Duan, S.-X. Yu, Y.-M. Li, X. Lv, J.-T. Li, H.-Y. Chen, X. Ning and Y.-Z. Long, RSC Advances, 2017, 7, 33132-33136. 31. X. Yan, M. Yu, L.-H. Zhang, X.-S. Jia, J.-T. Li, X.-P. Duan, C.-C. Qin, R.-H. Dong and Y.-Z. Long, Nanoscale, 2016, 8, 209-213. 32. L. H. Zhang, X.-P. Duan, X. Yan, M. Yu, X. Ning, Y. Zhao and Y.-Z. Long, RSC Advances, 2016, 10.1039.C1036RA09558E. 33. R. Augustine, A. Saha, V. P. Jayachandran, S. Thomas, and N. Kalarikkal. Int J Polym Mater Polym Biomater, 2015, 64(10), 526–533. 34. J. Zhang, J. Li, S. Chen, N. Kawazoe, and G. Chen, Journal of Materials Chemistry B, 2016, 4(34), 5664-5672. 35. T. Harifi, and M. Montazer, Journal of Materials Chemistry B, 2014, 2(3), 272-282. 36. S. Y. Gu, K. Chang, and S. P. Jin, Journal of Applied Polymer Science, 2018, 135(3), 45686. 37. R. Augustine, N. Kalarikkal, and S. Thomas, Polymer-Plastics Technology and Engineering, 2016, 55(5), 518-529. 19
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38. A. Elzubair, C. N. Elias, J. C. M. Suarez, H. P. Lopes, and M. V. B. Vieira, Journal of Dentistry, 2006, 34(10), 784-789. 39. B. G. Pai, A. V. Kulkarni, and S. Jain, Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2017, 105(4), 795-804. 40. Q. Liu, L. B. Zhong, Q. B. Zhao, C. Frear, and Y. M. Zheng, ACS Applied Materials & Interfaces, 2015, 7(27), 14573-14583. 41. R. Augustine, N. Kalarikkal, and S. Thomas, Polymer-Plastics Technology and Engineering, 2016, 55(5), 518-529. 42. Y. Xudong, H. Yang, H. Jiyong, W. Lu, and W. Fujun, New Chemical Materials. 2016, 44(11),178-180. 43. P. Guardia, R. Di Corato, L. Lartigue, C. Wilhelm, A. Espinosa, M. Garcia-Hernandez, F. Gazeau, L. Manna and T. Pellegrino, ACS Nano, 2012, 6, 3080-3091. 44. L. C. Branquinho, M. S. Carrião, A. S. Costa, N. Zufelato, M. H. Sousa, R.
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Journal Pre-proof Declaration of competing interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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may be considered as potential competing interests:
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☐The authors declare the following financial interests/personal relationships which
21
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Highlights 1. Solved the problem of large-scale agglomeration of magnetic nanoparticles in the melt. 2. A hand-held portable melt e-spinning device was designed for medical applications.
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3. PCL/Fe3O4 composite fibers are prepared by the melt electrospinning tchnology. 4. the PCL/Fe3O4 composite fibers exhibits good heating efficiency
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magnetic hyperthermia.
22
in vitro
Peng-Yue Hu, Ying-Tao Zhao, Jun Zhang, Shu-Xin Yu, Jia-Shu Yan, Xiao-Xiong Wang, Mao-Zhi Hu, Hong-Fei Xiang, Yun-Ze Long PII:
S0928-4931(19)34122-0
DOI:
https://doi.org/10.1016/j.msec.2020.110708
Reference:
MSC 110708
To appear in:
Materials Science & Engineering C
Received date:
5 November 2019
Revised date:
23 January 2020
Accepted date:
28 January 2020
Please cite this article as: P.-Y. Hu, Y.-T. Zhao, J. Zhang, et al., In situ melt electrospun polycaprolactone/Fe3O4 nanofibers for magnetic hyperthermia, Materials Science & Engineering C (2018), https://doi.org/10.1016/j.msec.2020.110708
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© 2018 Published by Elsevier.
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In situ melt electrospun polycaprolactone/Fe3O4 nanofibers for magnetic hyperthermia Peng-Yue Hu†,a, Ying-Tao Zhao†,a, Jun Zhang*,a, Shu-Xin Yua, Jia-Shu Yana, Xiao-Xiong Wanga, Mao-Zhi Hub, Hong-Fei Xiangc, Yun-Ze Long*,a
Collaborative Innovation Center for Nanomaterials & Devices, College of Physics,
Qingdao University, Qingdao 266071, P. R. China
Equipment Division, Qingyun County People’s Hospital, Dezhou 253000, P. R.
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b
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China c
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a
Department of Spine Surgery, Affiliated Hospital of Qingdao University, Qingdao
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Abstract
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266071, P. R. China
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Magnetic fibrous membrane used to generate heat under the alternating magnetic field (AMF) has attracted wide attention due to their application in magnetic
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hyperthermia. However, there is not magnetic fibrous membrane prepared by melt electrospinning (e-spinning) which is a solvent-free, bio-friendly technology. In this work, polycaprolactone (PCL)/Fe3O4 fiber membrane was prepared by melt e-spinning and using homemade self-powered portable melt e-spinning apparatus. The hand-held melt e-spinning apparatus has a weight of about 450 g and a precise size of 24 cm in length, 6 cm in thickness and 13 cm in height, which is more portable for widely using in the medical field. The PCL/Fe3O4 composite fibers with diameters of 4-17 μm, are very uniform. In addition, the magnetic composite fiber membrane has excellent heating efficiency and thermal cycling characteristics. The results indicated that self-powered portable melt e-spinning apparatus and PCL/Fe3O4 fiber membrane may provide an attractive way for hyperthermia therapy. Keywords: magnetic hyperthermia; nanofiber; melt electrospinning; apparatus; 1
Journal Pre-proof in-situ deposition. ______________________ †
These two authors contributed equally to this work.
*
Corresponding author.
E-mail: [email protected] (Y.Z. Long) or [email protected] (J. Zhang)
1. Introduction
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Hyperthermia is another effective tumor treatment method besides the traditional chemotherapy and radiotherapy for its synergistical effect in antitumor.1-3 Different
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from healthy cells, cancer cells are sensitive to the temperatures ranging from 41 to
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45 °C, which is the mechanism for using high temperatures as a treatment for cancer.4-5 Although many targeting strategies have been proposed, such as magnetic
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targeting and molecular targeting, the insufficient directionality still limits the
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application of magnetic nanoparticles in cancer therapy.6-7 When magnetic particles are injected directly into tumor tissue, they are more likely to leak from the tumor site
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into the body because of their small size, and then they are rapidly cleared by the immune system and enriched in specific organs, increasing the risk.8-9 In recent years,
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some of these issues have been reduced due to improvements in the synthesis and functionalization of nanoparticles, for example, a silica shell coating on the magnetic nanoparticles to decrease their toxicity10; precise control of size and morphology as well as surface modification for providing chemical groups for attaching biomolecules and minimizing blood proteins adsorption.11 In addition, despite direct injection being the only method currently employed at clinical level, one of the main goals of using magnetic nanoparticles is to inject them intravenously and, by functionalizing them with targeting ligands or using external magnetic fields, direct them so that they can reach the tumour and all the metastasized regions.12 Compared to complex modification work on magnetic particles, magnetic composite fibers are light in weight, easy to preparation, flexible, and capable of accurately delivering magnetic nanoparticles to cancer cells. Therefore, this is an ideal method via hyperthermia for 2
Journal Pre-proof solid tumor tissue. In previous studies, composite nanofiber membranes are usually prepared in advance and then attached to the surface of tumor tissue.13-16 However, this method has obvious disadvantages. The pre-prepared nanofiber membrane is difficult to form a uniform and continuous wrap layer on the surface of the tumor tissue, which is disadvantageous for close fitting and easy to fall off, thereby resulting in poor thermotherapy effect of the tumor tissue. Therefore, direct in situ electrospinning (e-spinning) onto the surface of tumor tissue may be a good method to prevent the
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shedding of the composite fiber membrane and increase the fit of the composite fiber
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to the tumor tissue.17 However, the nanofiber membranes used in in-situ magnetic hyperthermia reported in the current article were all prepared by solution e-spinning.18
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But for solution e-spinning, the utilization of the precursor solution is less than 20%;
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the volatilization of the solvent causes environmental problems; the residue of the toxic solvent causes the fiber membrane to be toxic; and some polymers have no
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suitable solvent at room temperature resulting in the inability to spin the fiber.19-22
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And the melt e-spinning technology is a solvent-free, bio-friendly technology.23-25 Interestingly, there is no literature reporting on in-situ e-spinning fibers for magnetic
inorganic
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hyperthermia by melt e-spinning. The main reason is that the high surface activity of nanoparticles
can
lead
to
spontaneous
agglomeration
between
nanoparticles.26-28 Magnetic particles do not disperse well in polymer melts and are always aggregated on a large scale. Besides, due to the existence of heating devices and electrostatic interference problems, melt e-spinning devices is relatively complicated, cumbersome and not portable, thereby limiting the development of melt e-spinning technology in the medical field.29-32 In this paper, a new magnetic hyperthermia method for cancer was proposed (as shown in Fig. 1). We have solved the problem of large-scale agglomeration of magnetic particles in the melt, and have designed a hand-held melt e-spinning device for medical applications. Polycaprolactone (PCL) was chosen for fibers because of its biocompatibility and biodegradability.33 These fibrous membranes can be e-spun in 3
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the surface of the tumor tissue.
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2. Experimental
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Fig. 1 A new magnetic hyperthermia method for cancer.
2.1 Materials
Polycaprolactone (PCL, average Mw~80 000, Aladdin) and ferric oxide particles (Fe3O4, Aladdin) are selected as the melt e-spinning materials. The acetone was purchased from Sinopharm Chemical Reagent Co., Ltd.
2.2 Preparation of e-spinning PCL/Fe3O4 magnetic nanofibers First, 0.17 g of Fe3O4 nanoparticles were added into 3 g of acetone, and the mixture was sonicated in an Erlenmeyer flask for 4 h. At the same time, 3.4 g of PCL particles were dissolved in 23.6 g of acetone and stirred for 4 h to prepare a pure PCL solution. Then, the pure PCL solution was introduced into the Fe3O4 nanoparticle 4
Journal Pre-proof dispersion and stirred by a mechanical stirrer for 4 h. Finally, the obtained homogeneous mixed solution was placed in a 40 °C drying oven. After the acetone was completely evaporated, a PCL/Fe3O4 solid material was obtained, and the Fe3O4 particles were uniformly dispersed in the material without large-scale agglomeration. PCL/Fe3O4 composites with different Fe3O4 contents were prepared by this method. The obtained PCL/Fe3O4 material was placed in the hand-held e-spinning device. After turning on the hand-held e-spinning device heating switch and preheating for 4 min, the high voltage transfer switch was turned on to perform melt e-spinning, and
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PCL/Fe3O4 fibers were deposited on the collector. The PCL/Fe3O4 composite fibers
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with different Fe3O4 nanoparticles loadings of 5 wt%, 9 wt%, 13 wt%, 17 wt% and 21 wt% were denoted as PCL/Fe3O4-5, PCL/Fe3O4-9, PCL/Fe3O4-13, PCL/Fe3O4-17 and
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PCL/Fe3O4-21, respectively, as shown in the Table 1. In addition, as shown in Fig. 1,
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the magnetic fiber membranes can easier be in situ e-spun on the surface of the tumor by using the hand-held apparatus. Then under the alternating magnetic field (AMF),
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the magnetic fiber membranes generate heat and reach about 45 ℃. The heat can
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transfer to cancerous tissue and cause the die of cancer cells.
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Table 1 Composition of the deposited fibers
Simple
Composition
Content of Fe3O4 (%)
Content of polycaprolactone (%)
PCL/Fe3O4-5
5
95
PCL/Fe3O4-9
9
91
PCL/Fe3O4-13
13
87
PCL/Fe3O4-17
17
83
PCL/Fe3O4-21
21
79
2.3 Characterization A Scanning electron microscope (SEM, TM-100, Hitachi) was used to characterize the morphology of the melt e-spun fibers. The size of morphology of 5
Journal Pre-proof Fe3O4 nanoparticles were tested by transmission electron microscopy (TEM, JEM-200EX). The hydrodynamic size of Fe3O4 nanoparticles measured by dynamic light scattering (DLS, 802DLS). X-ray powder diffraction (XRD, RINT2000 wide-angle goniometer) analysis was carried out using a Rigaku X-ray diffractometer to investigate the crystalline structure of Fe3O4 and PCL/Fe3O4 fibers. The thermal properties of PCL/Fe3O4 composite fibers were measured by the Thermogravimetric analysis instrument (TG209F1, NETZSCH), and a Differential scanning calorimeter (DSC250, TA) was used to test the transition temperature of PCL/Fe3O4 composite
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fibers. The nanofiber membrane was examined by the Fourier transform infrared
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spectroscopy (FTIR; Thermo Scientific Nicolet iN10). The magnetic properties of PCL/Fe3O4 composite fibers were measured by a Physical Property Measurement
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System (PPMS, Quantum Design). The high-frequency alternating magnetic field
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(AMF) is generated by a magnetic field generator (SP-04AC Shenzhen Shuangping
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Power Technology Co., Ltd.). Its rated power is 3 kW, and the water-cooled induction coil is made of copper. The number of turns is two and the inner diameter is 30 mm.
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The maximum magnetic field strength and magnetic field frequency of the alternating
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magnetic field generator are 12.5 Oe and 153 kHz, respectively.
3. Results and discussion
3.1 Design of the self-powered hand-held melt e-spinning apparatus
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Fig. 2 (a) 3D model diagram of hand-held melt e-spinning apparatus. (b) Schematic
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diagram of hand-held melt e-spinning apparatus. (c) Melt e-spinning schematic by hand-held melt e-spinning apparatus. the apparatus was operated by one hand and the
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other hand receives the PCL fibers.
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As we all know, traditional melt e-spinning devices have four components: a heating device, a high-voltage power supply, a feeding device and a collection device. The volume of the traditional device is relatively large and the parts of the device are separated, so the device is not portable. Besides, the typical spinning voltage and heating unit for e-spinning requires a 220 V working voltage. This greatly limits the wide application of e-spinning technology in biomedical applications. As shown in Fig. 2, the hand-held melt device was designed for the first time and had many innovative modifications compared to traditional melt devices. The hand-held melt e-spinning apparatus has a weight of about 450 g and a precise size of 24 cm in length, 6 cm in thickness and 13 cm in height, which is more portable. In addition, the high voltage unit and heating unit of the apparatus are fully powered by a rechargeable lithium battery which can be integrated inside the device and this device can work 7
Journal Pre-proof normally without mains power. And the built-in power supply allows the apparatus to operate continuously for more than 2 h. Finally, the device is equipped with a high heat-transfer electrical-insulation unit to solve the electrostatic interference between the heating unit and the high voltage unit. This is the key for integration. As shown in Fig. 2c, the apparatus was operated by one hand, and the fibers could be deposited on another hand directly. It is convenient for surgeon and doctor to use because of its portability. In addition, this portable melt device may also be used in wound dressing,
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Table 2 Temperature of the deposited fibers
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hemostasis and so on by a versatile method of replacing with other materials.
Temperature of spinneret (℃)
Temperature of fibers just dropped on skin (℃)
180-200
126-132
39.1
36-38
180-200
126-132
35.5
36-38
180-200
126-132
32.2
PCL/
4
36-38
Fe3O4
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fibers
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Temperature of material barrel (℃)
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Temperature of skin before e-spinning (℃)
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fibers
Spinning distance (cm)
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Melt e-spinning refers to melt polymers to form fibers under the high-voltage electrostatic field force. It undergoes the process of stretching, whipping and solidification in air, and finally becomes fibers falling onto the receiving plate. If the polymer fibers are directly received by the biological tissue, the temperature of the fibers should not be too high to avoid damage to the biological tissues. Therefore, as shown in Table 2, the temperature of the deposited fibers on the skin were measured by infrared thermometer under different e-spinning distances. The temperature of spinneret is around 132 ℃ and temperature of fibers just dropped on skin is about 35 ℃. And the purpose of monitoring these two temperature is that although fiber temperature leaving from the spinneret is high (~132 ℃), these fibers cannot burn the skin when they deposited onto the skin (~35 ℃). Therefore, it is suitable for melt e-spun fibers to apply in in-situ magnetic hyperthermia. 8
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3.2 Morphological, structural and magnetic properties of PCL/Fe3O4 fibers
Fig. 3 (a) TEM image of Fe3O4 nanoparticles. (b) TEM image of PCL/Fe3O4-17
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composite fiber. (c) SEM image of PCL/Fe3O4-17 composite fiber. The red circle is
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the exposed nanoparticles.
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The morphology of the Fe3O4 nanoparticles are shown in Fig. 3a. The Fe3O4 nanoparticles showed a spherical or square shape. The average diameter of a single
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Fe3O4 nanoparticle was 50-100 nm. And the nanoparticles without coating are colloidally stable. TEM image shows that these nanoparticles are slight aggregation, and additional DLS measurement (Fig. S1) show that about 6~10 nanoparticles were aggregated together to form clusters. This phenomenon is consistent with previous reports.34-35 In the common melt e-spinning process, it is difficult to disperse the nanoparticles by directly mixing the particles with PCL. From the TEM of composite fibers, nanoparticle clusters are dispersed throughout the whole fiber. It indicates that nanoparticles could well dispersed in the PCL for the following melt e-spinning via a method of adding acetone with evaporation. As shown in Fig. 3c, the Fe3O4 nanoparticles are successfully dispersed in the fiber and partially exposed on the surface. Semi-naked Fe3O4 particles demonstrate the successful incorporation of Fe3O4 nanoparticles into PCL fibers. The SEM of the 9
Journal Pre-proof cross section of the PCL/Fe3O4 fiber was tested, as shown in Fig. S2. In addition, some nanoparticles seem to be agglomerated in the fiber (Fig. 3b, c), which is probable due to the nanoparticles were aggregated together to form clusters with about 6~10 nanoparticles (Fig. 3a) before mixing with PCL. It caused by the magnetic
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assembly.34
Fig. 4 SEM images of the PCL/Fe3O4 composite fibers with different Fe3O4 nanoparticles loadings of (a) 5 wt%, (b) 9 wt%, (c) 13 wt%, (d) 17 wt% and (e) 21 wt%. (f) Diameter distribution bar chart of the melt e-spun fibers. SEM images of the melt e-spun PCL/Fe3O4 composite fibers produce d at different spinning distance: (g) 4 cm, (h) 5 cm, (i) 6 cm, (j) 7 cm, (k) 8 cm. (l) Diameter distribution bar chart of the melt e-spun fibers.
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Journal Pre-proof Magnetic nanoparticles affect the viscosity and conductivity of the melt, which in turn affects the spinning process. As shown in Fig. 4a-f, we explored the influence of the different weight ratio of Fe3O4 nanoparticles to the composite fiber for fiber morphology. When the content of Fe3O4 nanoparticles is small, the spinning process is stable and the fibers are smooth and evenly distributed. With the increase of the content of Fe3O4 particles, the surface morphology of the fibers is obviously changed. It can be found that the surface of the fibers is gradually rough and the diameter of the fibers is increased. The fiber diameter even reached 15 μm. Moreover, the protrusions
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on the surface of the fiber are gradually increased, and the semi-naked Fe3O4 particles
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on the surface of the fiber can be clearly seen, as shown in the inset SEM picture of Fig. 4d.
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The morphology and diameter analysis of the melt e-spun composite fibers at
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different distances are shown in Fig. 4g-l. When the spinning distance is 5 cm, the fiber diameter can be controlled at 5 μm. As the distance increases, the average fiber
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diameter increases up to 15.1 μm. However, when the receiving distance is 8 cm or
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more, the melt e-spinning process cannot be performed, because the receiving
generated.
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distance is too large and the electric field strength is too small to cause the jet to be
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Fig. 5 (a) TG analysis curves, (b) DSC curves, (c) FTIR spectra and (d) XRD patterns
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of the melt e-spun PCL/Fe3O4 composite fibers.
TGA analysis was used to exam the proportion of Fe3O4 in the melt e-spun
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composite fibers and thermal stability of composite nanofiber membrane. As shown in Fig. 5a, the typical single mass-loss step of the melt e-spun PCL/Fe3O4 composite fibers was located at 320–375℃ because of the degradation of composite fiber membrane including depolymerization, dehydration and decomposition followed by the formation of a charred residue. TGA shows that the mass percentage of the composite fiber membrane are 0%, 6%, 10%, 15%, 17% and 22%, which are consistent with mass percentage of Fe3O4 used in the experiment. In addition, the thermal decomposition rate of pure fiber membrane is slightly lower than that of composite fiber membrane. This can be attributed to the interaction between the polymer and the nanoparticles. When the temperature reaches 460 ℃, the pure PCL nanofiber membrane has no significant change no significant residual weight compared to the composite fiber membrane. 12
Journal Pre-proof DSC analysis was used to further demonstrate whether the addition of Fe3O4 had effect on the crystallization behavior of PCL. It can be found from Fig. 5b that the melting temperature of pure PCL fiber is 52.8 ℃, and the mixing of magnetic Fe3O4 nanoparticles does change the melting temperature of PCL. The melting temperature of the composite fiber membrane increases by 1~3 ℃, and as the content of magnetic Fe3O4 nanoparticles increases, the melting temperature tends to increase. The reason may be that the physical composite between magnetic Fe3O4 particles and PCL does not have much influence on the molecular structure of PCL, but the presence of a
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certain amount of Fe3O4 particles changes the crystallinity of PCL, thus affecting the
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melting temperature of the PCL/Fe3O4 composite fiber.
Fig. 5c is the infrared spectra of PCL composite nanofibers with different Fe3O4
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contents. It can be seen from the figure that the pure PCL nanofibers have the
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following characteristic absorption peaks: C-H stretching vibration peak at 2948 and 2869 cm-1, C=O stretching vibration peak at 1725 cm-1. And the peak at 1250 cm-1
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reflects the -C-O-C- asymmetric stretching vibration of PCL.36-38 The above data is
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the characteristic peaks of PCL, which are consistent with the related literature. Except for the characteristic absorption peak of PCL, there is no other peaks
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appearing, indicating that there is no chemical change between PCL and Fe3O4. Fig. 5d shows the XRD pattern of pure PCL fiber membrane, Fe3O4 magnetic nanoparticles and the melt e-spun PCL/Fe3O4 composite fiber membrane. The position and relative intensity of the characteristic peaks of the composite film are in good agreement with the standard diffraction card JCPDS 39-1346, which corresponds to (220), (311), (400), (511) and (440) characteristic peak of Fe3O4 nanoparticles.39-40 PCL membrane contains three distinct reflections at the Bragg angles of about 21.4, 23.7 and 45 degree.41 With the increases of the percentage of Fe3O4, no significant change in PCL content. Therefore, there is no further change in the peak at 45 degree. And with the increasing of magnetic particles content, the intensity of PCL characteristic peaks gradually decreases. It indicates that the presence of magnetic nanoparticles reduces the crystallinity of PCL.42 13
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Fig. 6 (a-c) Magnetic performance demonstration diagram of the melt e-spun
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PCL/Fe3O4 composite fibers. (d) Magnetic hysteresis curves of the melt e-spun
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PCL/Fe3O4 composite fibers.
As shown in the Fig. 6a-c, we placed a 5×20 mm2 PCL/Fe3O4 fiber membrane at
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a position 3 cm from the magnet and slowly brought the composite fiber membrane close to the magnet. When the distance is 1 cm, the fiber membrane is significantly
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bent. The experiment verified the existence of magnetic properties of the PCL/Fe3O4 composite fiber membrane prepared by melt e-spinning. As shown in Fig. 6d, the magnetic hysteresis curves of the melt e-spun PCL/Fe3O4 composite fibers was measured by PPMS. The saturation magnetization (Ms) of PCL/Fe3O4 composite nanofiber membrane increases with the increase of Fe3O4 content, which is 5.86 emu g-1, 11.62 emu g-1, 19.66 emu g-1, 22.83 emu g-1, 31.24 emu g-1, and the saturation magnetization (Ms) of the original Fe3O4 nanoparticles is 89.05 emu g-1. The Mr/Ms and Hc of PCL/Fe3O4 fiber membranes are also discussed (Fig. S3 and Table S1). In addition, to compare the magnetization normalized to the mass of Fe3O4 inside the PCL, another M-H curve are showing and M is given in emu/g_Fe3O4 (Fig. S4). There are no obvious difference, at around 87 emu g-1. 14
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3.3 In vitro hyperthermia test
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Fig. 7 Temperature (T) – time (t) profile of the melt e-spun PCL/Fe3O4 composite
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fibers obtained (a) upon the application of an AMF, and (b) with and without the application of the magnetic field; the shaded area indicates the application of the
nanoparticle
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Magnetic
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magnetic field.
hyperthermia
utilizes
the
performance
of
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superparamagnetic nanoparticles such as Fe2O3 or Fe3O4 to produce heat under alternating magnetic fields.43 Whether the nanoparticles are aggregated or evenly
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distributed, both the nanoparticles generate heat under alternating magnetic fields17, but the heating efficiency will decrease if the nanoparticles are agglomerated in a random way.44 The heating of aggregated nanoparticles is controlled by intermolecular interactions and hysteresis loss.45 And the heating of dispersed nanoparticles is mainly caused by Brownian and Néel relaxation.46 In addition, Carrey et al. proposed that all the losses, whether the magnetic nanoparticles are in the superparamagnetic regime or in the ferromagnetic regime, are always “hysteresis losses” insofar as they are simply given by the hysteresis loop area.47 For composite fibers, the magnetic nanoparticles are embedded and fixed inside the nanofibers, so that the nanoparticles can’t freely rotate and move in the magnetic field, and thus the Brownian relaxation has no effect on the magnetic heating that occurs under alternating magnetic fields. Therefore, only hysteresis loss and Néel relaxation play 15
Journal Pre-proof an important role for magnetic nanoparticles inside the structure to generate heat. In the composite fiber membrane, the magnetic nanoparticles are locally aggregated and partially dispersed, and in the alternating magnetic field, the actual heat generation performance of the magnetic nanoparticles is difficult to estimate.48 Therefore, the heat generation ability of the magnetic nanoparticles in the nanofiber membrane can be appropriately examined by experimentally measuring. Fig. 7a shows the time-dependent heating curve of composite fibers with different magnetic particle contents. The temperature rise of PCL/Fe3O4-5, PCL/Fe3O4-9, PCL/Fe3O4-13,
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PCL/Fe3O4-17 and PCL/Fe3O4-21 composite fiber membranes was 21±0.4 ℃,
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25.2±0.3 ℃, 27.1±0.5 ℃, 31.1±0.2 ℃ and 36.4±0.3 ℃, respectively. The heating temperature increases quickly with time and is basically balanced after reaching a
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certain temperature. And the experimental results obtained meet the conditions of
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magnetic hyperthermia.
In the case of cancer therapy, alternating cycle of high and low temperatures can
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better kill cancer cells due to the possibility of tumor metastasis.17 Therefore, it is
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necessary for composite fibrous membranes to possess a stable temperature cyclic profile during the heating process. In order to test the thermal cycle of the PCL/Fe3O4
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composite fiber membrane, the PCL/Fe3O4-17 membrane was exposed to the AMF. There is no significant change in the temperature curve during the three cycles of the alternating magnetic field. As shown in Fig. 7, the temperature changed from 15 to 45 ℃ in 37 s. It indicates that composite fiber membrane can efficiently and rapidly convert the alternating magnetic field energy into thermal energy. We further immersed these fiber membranes in PBS and tested their changes of heating performance (Fig. S5). More importantly, the advantages of the composite fibrous membranes for hyperthermia are their repeatable heating without decreasing the heating efficiency.
4. Conclusion In this study, we presented a hand-held melt e-spinning apparatus using a 16
Journal Pre-proof rechargeable battery to provide a high voltage and heating power, which can work without any extra electricity supply. PCL/Fe3O4 composite fibers with diameters of 4-17 μm were prepared by using this portable melt e-spinning apparatus. These magnetic composite nanofiber membranes can convert electromagnetic energy to heat, thereby effectively increasing the temperature of the hyperthermia. These results indicate that in situ melt e-spinning of magnetic composite fiber membranes by using hand-held e-spinning devices is a potential approach to magnetic hyperthermia. In addition, this portable melt device may also be easily extended to wound dressing,
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hemostasis and other usage by a versatile method of replacing with other materials.
Author Statement
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The authors declare that this work was done by the authors named in this article and
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all liabilities pertaining to claims relating to the content of this article will be borne by
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them. J Z and Y-T Z designed the experiments and give the intellectual input. P-Y H and Y-T Z carried out the research work. S-X Y, M-Z H, J-S Y, X-X W and H-F X
na
analyzed the data. P-Y H and Y-T Z wrote the paper. Y-T Z supervised the whole research work. P-Y H and Y-T Z contributed equally to this work and should be
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considered as co-first authors. All authors have reviewed and approved the content of the submitted manuscripts.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (51973100, 51673103, 11904193 and 81802190), Shandong Provincial Natural Science Foundation, China (ZR2019BH084) and Young Taishan Scholars Program (tsqn201909190).
Consent for publication All authors agreed to submit this manuscript. 17
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Conflict of interest None
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Journal Pre-proof Declaration of competing interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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may be considered as potential competing interests:
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☐The authors declare the following financial interests/personal relationships which
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Highlights 1. Solved the problem of large-scale agglomeration of magnetic nanoparticles in the melt. 2. A hand-held portable melt e-spinning device was designed for medical applications.
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3. PCL/Fe3O4 composite fibers are prepared by the melt electrospinning tchnology. 4. the PCL/Fe3O4 composite fibers exhibits good heating efficiency
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magnetic hyperthermia.
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in vitro