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We present a novel contrast-enhanced continuous-terahertz-wave imaging modality based on magnetic induction heating of superparamagnetic iron oxide nanoparticles (SPIOs), which yields a highly sensitive increment in the reflection terahertz (THz) signal in SPIO solution upon exposure to an alternating magnetic field. In the differential and relative refection change focal-plane images before and after alternating magnetic field exposure, a dramatic contrast is demonstrated between water with and without SPIOs. This low-cost, simple, and stable contrast-enhanced continuous-THz-wave imaging system is suitable for miniaturization and real-time imaging application.
© 2016 Optical Society of America
1. Introduction
In recent years, the use of terahertz (THz) imaging in detecting the properties of various biological tissues has attracted increasing interest because THz radiation is non-ionizing, and low-frequency torsional and vibrational motions in biological molecules occur naturally in the THz region (0.1-10 THz) [1]. Many kinds of biological tissues such as those associated with breast cancer [2], liver cancer [3], basal cell carcinoma [4], lung cancer [5], burn wounds [6], brain tissues [7], articular cartilages [8], and the gastrointestinal tract [9,10] have been investigated via THz imaging.
In order to improve the imaging signal-to-noise ratio (SNR) and further increase the image contrast between normal and diseased tissues, researchers have proposed nanoparticle-contrast-agent-enabled THz imaging techniques [11]. In this approach, gold nanoparticles [11,12] or superparamagnetic iron oxide nanoparticles (SPIOs) [13] are adopted as contrast agents. Further, an infrared (IR) laser is integrated into a reflection-mode THz time-domain spectroscopic (THz-TDS) system to induce surface plasmon polaritons on the nanoparticles, thereby increasing the temperature of water in the tissue containing the nanoparticle contrast. Furthermore, the power absorption and refractive index of water in the THz region are temperature-dependent [14], and the tissues (particularly cancerous ones) contain a large amount of interstitial water, which enables the modulation of the THz reflection signal in tissues incorporated with nanoparticles under the irradiation of an IR laser. A highly sensitive differential signal was obtained with the use of this proposed nanoparticle-contrast-agent-enabled THz imaging technique and it shows potential value for cancer diagnosis [15] and nanoparticle drug delivery imaging [16].
In this context, most previous contrast-agent-enabled THz imaging studies [17] have utilized the THz-TDS system, wherein a femtosecond laser is always needed for the generation and detection of THz pulses; the use of this laser makes the process slightly complex for biomedical applications, particularly as regards real-time monitoring of surgical processes in the operating room. Furthermore, a pixel-by-pixel imaging strategy is required to detect THz pulses and achieve sufficient IR laser intensity for exciting surface plasmon polaritons on the nanoparticles. The imaging speed with this approach is too low for practical applications. In addition, THz waves can be partially absorbed by the water vapor in the air because of the high power absorption of water in the THz region [14].
In this backdrop, in this study, we propose a novel contrast-enhanced continuous-THz-wave imaging modality based on SPIOs. An alternating magnetic field generation equipment is integrated into a 0.2-THz reflection-mode continuous-THz-wave imaging system. All the SPIOs in the alternating magnetic field can be heated effectively and the heating power is depended on the property of the SPIOs, the frequency and intensity of the alternating magnetic field [18]. This enables heating a large area and deeper tissues by one time and is suitable for real-time monitoring. In addition, the continuous-THz-wave imaging strategy is first introduced in the contrast-enhanced THz imaging technique, which possesses the advantages of low cost, simplicity of use, and suitability for miniaturization to portable medical systems. The temperature of water around the SPIOs increases under the application of the alternating magnetic field. The refractive index and power absorption of water change significantly at 0.2 THz [14], which enhances the measurement sensitivity dramatically. Furthermore, the power absorption of water at 0.2 THz is relatively small [14], which is beneficial for practical application. To test the feasibility of this imaging modality, we utilize SPIO water solutions to simulate the THz response from cells after endocytosis of SPIOs.
2. Experimental method and materials
The SPIOs used in this study were magnetic iron oxide nanoparticles synthesized by means of a previously reported cold plasma approach [19]. The morphology of the applied SPIOs was confirmed via a transmission electron microscope (TEM) image, which is shown in Fig. 1(a). The average particle diameter was 7.7 ± 1.3 nm. The precipitate was separated with the use of a magnet and then dissolved in high-purity water to obtain SPIO water solutions of different concentrations. Because tissues (particularly cancerous tissues) contain a large amount of interstitial water, the SPIO water solutions were utilized to simulate the THz response from cells after endocytosis of SPIOs.
Fig. 1 (a) Typical transmission electron microscope (TEM) image of superparamagnetic iron oxide nanoparticles (SPIOs) used in this study. (b) Histogram of the size distribution of SPIOs with average diameter of 7.7 ± 1.3 nm.
The SPIO-based contrast-enhanced reflection-mode continuous-THz-wave imaging system used in our study is shown in Fig. 2. Unlike in previous approaches, we integrated alternating magnetic field generation equipment into the THz imaging system (for the first time to the best of our knowledge) to achieve magnetic induction heating of SPIOs and further modulation of THz signals. A vertical equally spaced three-ring solenoid induction coil (diameter: 10 cm, height: 10 cm) was utilized to generate the alternating magnetic field. With the application of a varying high-frequency alternating current (287 kHz) to the solenoid induction coil, high-frequency alternating magnetic fields of different amplitudes can be obtained with this setup.
Fig. 2 Schematic of superparamagnetic iron oxide nanoparticle (SPIO)-based contrast-enhanced reflection-mode continuous-terahertz-wave imaging system.
The imaging sample was placed at the center of the solenoid induction coil. In order to measure the reflected signal change from a focused spot on the sample, THz radiation generated by a 0.2-THz Gunn oscillator (Radiometer Physics) was focused onto the sample by means of a polyethylene lens. The diameter of the THz-wave beam on the sample surface was about 4 mm. The output power of the Gunn oscillator is 10 mW and the corresponding THz power density on the sample is 0.80 mW/mm2. The reflective THz wave was refocused by a parabolic mirror, and the refocused THz wave beam was detected by a pyroelectric detector (Microtech SN:171344). The distance between the parabolic mirror and the pyroelectric detector and the distance between the parabolic mirror and sample were precisely adjusted to satisfy the imaging formula. The output signal from the pyroelectric detector was fed to a lock-in amplifier referenced to a modulation frequency of 15 Hz. The reflected THz signals from the SPIO solutions of different densities and under different alternating magnetic field strengths were recorded to test the feasibility of this contrast-enhanced imaging modality. In addition, to further demonstrate the potential of this imaging modality for real-time imaging applications, we adopted the focal-plane imaging strategy, and the pyroelectric detector was moved stepwise (0.5-mm steps in 0.5-s intervals) by means of a programmed stepper. The focal-plane THz images of water with and without SPIOs (before and after alternating magnetic field exposure) were acquired.
3. Results and discussion
The alternating magnetic field strength dependence of the reflected THz signal from the SPIO solution with a concentration of 4 g/L is illustrated in Fig. 3. From the figure, we note that the amplitude of reflected THz signal from the SPIO solution (4 g/L) increases dramatically upon switching on the alternating magnetic field (0 s), whereas there is almost no change in its absence. In addition, the reflection change increases as the intensity of the alternating magnetic field increases. In our experiment, the relative reflection amplitude change was more than 15% for the 4 g/L SPIO solution after 300 s of exposure to the alternating magnetic field with the strength of 15 mT.
Fig. 3 Alternating magnetic field strength dependence of reflected THz signal from superparamagnetic iron oxide nanoparticle (SPIO) solution with concentration of 4 g/L. (a) Time-varying reflection changes for varying alternating magnetic field intensities. (b) Reflection changes as function of alternating magnetic field strength at different time instants.
The SPIO solution density dependence of the reflected THz signal under alternating magnetic field with the intensity of 15 mT is depicted in Fig. 4. From the figure, we note that a clear reflection change is observed even for a low concentration of 0.25 g/L. However, there is almost no amplitude change in the THz signal reflected from water without SPIOs under the application of the alternating magnetic field. In addition, the relative reflection amplitude change increases with increase in the SPIO density. For comparison, the temperature change for SPIO solution with concentration of 4 g/L under alternating magnetic field with the intensity of 15 mT was also measured and is shown in Fig. 4(a). It is demonstrated that the reflection change increases as the temperature increases.
Fig. 4 Superparamagnetic iron oxide nanoparticle (SPIO) solution density dependence of reflected THz signal under alternating magnetic field with strength of 15 mT. (a) Time-varying reflection changes for various SPIO solution concentrations and the temperature change for SPIO solution with concentration of 4 g/L. (b) Reflection changes with SPIO solution density at various time instants.
The SPIOs themselves have no effect on the reflected signal, and there is no interaction between the SPIOs and the THz wave. This is due to negligible reflection or absorption of THz waves by the SPIOs, given that the THz wavelength is three to four orders of magnitude larger than the SPIO dimensions [17]. Meanwhile, the alternating magnetic field itself also does not affect the reflected THz signal. Nonetheless, the exposure of SPIOs to the alternating magnetic field leads to increase in the water temperature due to the magnetic induction heating effect induced by Brown and Néel relaxation [18]. Higher water temperature was achieved with higher SPIO solution density and alternating magnetic field strength, which generated a stronger reflected THz signal due to the higher refractive index and power absorption of water at higher temperatures [14].
To further demonstrate the superiority of our contrast-enhanced continuous-THz-wave imaging modality for real-time imaging applications, we conducted focal-plane imaging experiments using water with and without 4 g/L SPIOs. The pyroelectric detector was moved stepwise to simulate the functioning of a pyroelectric array camera. The images before and after application of alternating magnetic field with the intensity of 15 mT were acquired. To reduce the image inhomogeneity induced by the continuous magnetic induction heating during the stepwise movement of the pyroelectric detector, the exposure time of the alternating magnetic field was set to about 15 min to achieve near-saturation of the magnetic induction heating and to maintain a nearly constant temperature. Here, we remark that the introduction of a real-time pyroelectric array camera to replace the stepwise movement of the pyroelectric detector can significantly reduce the application time of the alternating magnetic field, and image homogeneity can be further improved.
The focal-plane THz imaging results obtained for water with and without 4 g/L SPIOs before and after 15 min of application of alternating magnetic field with the intensity of 15 mT are shown in Figs. 5(a) and 5(b). In order to improve the image smoothness and SNR, the obtained images were processed via linear interpolation and a Gaussian low-pass filter. Furthermore, the differential and relative reflection change images (Figs. 5(c) and 5(d)) were calculated to demonstrate the superiority of our contrast-enhanced THz imaging method. The THz reflection images from water with and without SPIOs were nearly identical (Fig. 5(a)). Nevertheless, the image of water with SPIOs increased in brightness upon alternating magnetic field application when compared with the THz-only image, whereas there was almost no change in water without SPIOs (Fig. 5(b)). Furthermore, a surprising result emerged as regards the difference between the images before and after exposure to the alternating magnetic field (Fig. 5(c)). The differential image of water without SPIOs was almost indecipherable, while a clear contrast was observed in the image of water with SPIOs. The relative reflection change images were more homogenous (Fig. 5(d)), and the superiority of this contrast-enhanced continuous-THz-wave imaging modality was more obviously demonstrated. The average amplitude in the relative reflection change images of water with SPIOs was 29.41% ± 0.42%, while that of water without SPIOs was only 0.30% ± 0.03%.
Fig. 5 Focal-plane THz imaging results of water with and without 4 g/L superparamagnetic iron oxide nanoparticles (SPIOs) before and after 15 min of exposure to alternating magnetic field with the strength of 15 mT. For clarity, the color bar range was set to be identical for water with and without SPIOs. (a) Focal-plane imaging results of water with and without SPIOs before alternating magnetic field exposure. (b) Focal-plane imaging results of water with and without SPIOs after alternating magnetic field exposure. (For comparison, the maximum amplitude in the image of water with SPIOs after alternating magnetic field exposure was set as 1.) (c) Differential images between (b) and (a). (d) Images of relative reflection change.
From these results, we can conclude that the SPIO water solution can be differentiated (as indicated by the very high contrast) from the water without SPIOs upon application of the alternating magnetic field. These preliminary results suggest that highly sensitive THz imaging for cancer diagnosis can be achieved with SPIO contrast agents. In addition, the demarcation of cancerous tumors can be identified as the differential signal and relative reflection change emerging when phase-conjugated SPIOs are specifically targeted at the tumor [17]. The in vivo THz imaging study of cancer with phase-conjugated SPIOs based on the proposed technique will be conducted in the near future. Furthermore, SPIOs are widely used contrast agents in magnetic resonance imaging (MRI) modality [13], and this proposed THz imaging modality can be utilized in combination with MRI to achieve dual-modality THz/MRI imaging based on SPIOs.
In comparison with existing contrast-enhanced THz imaging techniques [11–13,15–17], in our case, we first adopted a continuous-THz-wave imaging strategy in the imaging system, which possesses the advantages of low cost, simplicity of use, and suitability for miniaturization to portable medical systems. Moreover, the absorption of water vapor at low THz frequencies is small [14], and thus, this modality is more feasible for practical applications. Other high-quality strong continuous-THz-wave sources such as the backward-wave oscillator (BWO) can be incorporated into this system to further improve the SNR and image resolution. In particular, a pyroelectric array camera can be employed to replace the stepwise movement of the pyroelectric detector for achieving real-time imaging.
In addition, we introduced the magnetic induction heating approach based on SPIOs in the contrast-enhanced THz imaging modality for the first time, which has the advantages of heating a large area by one time and heating deeper tissues that the IR light cannot reach. This aspect is particularly suitable for real-time imaging and imaging of deeper-lying tissues. Moreover, magnetic hyperthermia has also been widely applied to treat cancer [18,20], and the proposed imaging method can be used for real-time monitoring of the magnetic induction heating effect in cancer tissues during the treatment, which will form our future study.
However, certain aspects need careful attention as regards practical application of this imaging modality. First, the homogeneity of the alternating magnetic field is crucial for homogeneous temperature distribution within the tumor tissues with SPIOs. An optimized magnetic induction coil can be utilized to further improve the magnetic field homogeneity [21]. Moreover, the magnetic induction coil should be placed at some distance from other metal components in the system to avoid unwanted magnetic induction heating.
4. Conclusion
In conclusion, we proposed a novel contrast-enhanced continuous-THz-wave imaging modality based on SPIOs in this study. The method offers the advantages of low cost and simplicity of operation, and it is particularly suitable for real-time imaging applications. Our preliminary results demonstrated that highly sensitive image-signal enhancement was obtained when imaging water with SPIOs under alternating magnetic field exposure. Moreover, a strong contrast between water with and without SPIOs was obtained in the differential and relative reflection change focal-plane images before and after alternating magnetic field exposure. We believe that our proposed contrast-enhanced continuous-THz-wave imaging modality can facilitate cancer diagnosis and monitoring of nanoparticle drug delivery.
Acknowledgments
The authors acknowledge support from the National Natural Science Foundation of China under grant no. 11374007 and the Foundation for the Author of National Excellent Doctoral Dissertation of PR China under grant no. 201237. This work was funded by the National Keystone Basic Research Program (973 Program) under grant no. 2014CB339806-1. The study was also supported by the Hong Kong Scholars Program through Project G-YZ53.
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