Terahertz solid immersion microscopy is a imaging modality, allowing to overcome Abbe diffraction limit and obtain resolution of 0.15λ. For numerical modelling of solid immersion systems and various objects used finite-difference time-domain method.
Significance: An increasing interest in the area of biological effects at exposure of tissues and cells to the terahertz (THz) radiation is driven by a rapid progress in THz biophotonics, observed during the past decades. Despite the attractiveness of THz technology for medical diagnosis and therapy, there is still quite limited knowledge about safe limits of THz exposure. Different modes of THz exposure of tissues and cells, including continuous-wave versus pulsed radiation, various powers, and number and duration of exposure cycles, ought to be systematically studied.
Aim: We provide an overview of recent research results in the area of biological effects at exposure of tissues and cells to THz waves.
Approach: We start with a brief overview of general features of the THz-wave–tissue interactions, as well as modern THz emitters, with an emphasis on those that are reliable for studying the biological effects of THz waves. Then, we consider three levels of biological system organization, at which the exposure effects are considered: (i) solutions of biological molecules; (ii) cultures of cells, individual cells, and cell structures; and (iii) entire organs or organisms; special attention is devoted to the cellular level. We distinguish thermal and nonthermal mechanisms of THz-wave–cell interactions and discuss a problem of adequate estimation of the THz biological effects’ specificity. The problem of experimental data reproducibility, caused by rareness of the THz experimental setups and an absence of unitary protocols, is also considered.
Results: The summarized data demonstrate the current stage of the research activity and knowledge about the THz exposure on living objects.
Conclusions: This review helps the biomedical optics community to summarize up-to-date knowledge in the area of cell exposure to THz radiation, and paves the ways for the development of THz safety standards and THz therapeutic applications.
We summarize and discuss multifunctional medical instruments based on sapphire shaped crystals. Such instruments are able to combine several modalities, such as interstitial exposure to laser radiation, fluorescent diagnosis, as well as tissue resection, aspiration and cryodestruction. Sapphire instruments enable biocomopatability, withstand extremely low and high temperatures, along with operation in harsh environment. Sapphire fibers and waveguides also allows imaging of biological objects in THz range. In visible and infrared ranges, these instruments can be combined with optical fibers via small internal channels, which can be produced during sapphire crystal growth by means of the edge-defined film-fed growth (EFG) technique. This talk covers the resent developments and experimental investigations of sapphire needles, cryoapplicators, scalpels, and fibers.
Terahertz (THz) solid immersion microscopy is a modality of THz imaging, which allows one to overcome the Abbe diffraction limit and provides high energy efficiency due to the absence of subwavelength apertures and probes in an optical scheme. It exploits the effect of a reduction in dimensions of electromagnetic-wave caustic, when it is formed in free space, at a small distance (<λ, where λ is an electromagnetic wavelength) behind a material with high refractive index. In our previous study, we introduced an original arrangement of the THz solid immersion lens (SIL), which provides superior spatial resolution of 0.15λ and is capable of imaging soft biological tissues. We applied the finite-difference time-domain technique for solving Maxwell’s equations in order to estimate the resolution limit and the depth of field for the proposed SIL arrangement as well as to define the confidence intervals for the alignment of optical elements. Next, we described the continuous-wave THz solid immersion microscope, which relies on the proposed SIL and exploits a backward-wave oscillator and a Golay cell as an emitter and a detector, respectively. Finally, we studied experimentally the spatial resolution of this microscope and visualized several representative objects featuring subwavelength structural inhomogeneities. The observed results revealed potential of the THz solid immersion microscopy in nondestructive testing and biophotonics.
KEYWORDS: Terahertz radiation, Solids, Microscopy, Numerical analysis, Spatial resolution, Optical spheres, Medical diagnostics, Nondestructive evaluation, Biological and chemical sensing, Near field optics
Terahertz (THz) solid immersion microscopy is a novel THz imaging modality, which provides both a sub- wavelength spatial resolution and a high energy efficiency, thanks to the absence of sub-wavelength apertures and probes in an optical scheme. In this work, we apply the finite-difference time-domain technique for solving the Maxwell's equations in order to analyze the performance of our original THz SIL arrangement. Namely, we estimate the theoretical limits for the spatial resolution and the depth of field of our optical system, as well as specify the confidential intervals for the alignment of optical elements. The observed results demonstrate the resolution of 0:15λ and the depth of field of 0:12λ(λ is an electromagnetic wavelength), justifying advanced performance of our THz SIL.
We have investigated the influence of indium content (x) increase on spectral characteristics of InxGa1-xAs photoconductor. To avoid the mismatch between crystalline parameters of InxGa1-xAs and GaAs wafer we proposed to incorporate a step-graded metamorphic buffer layer. We showed that x increase strongly enhances THz emission and broadens THz spectrum of InxGa1-xAs. Since no polarity rehearsal of the THz waveform occurs and electron diffusion mobility increases up to 90% with x increase we attribute the increase of THz intensity to photo-Dember effect contribution. The maximum efficiency of optical-to-THz conversion was obtained for In0.72Ga0.28 As at optical fluence ~0.01 μJ=cm2. The fabricated photoconductors can be used as promising photo-Dember or lateral photo-Dember THz emitters in pulsed THz spectroscopy and imaging, in particular, operating with long wave optical pump.
Terahertz (THz) pulsed spectroscopy is a convenient instrument for studying the THz dielectric response of healthy and abnormal tissue in a wide spectral range. One of the most promising applications of THz pulsed spectroscopy is associated with non-invasive, least-invasive and intraoperative medical diagnostics of malignancies in various localizations, including the skin, the breast, the colon, and the brain .
In our research, we developed a method for reconstructing the THz dielectric response of biotissues in vitro and in vivo using the THz pulsed spectroscopy [2–5]. We applied this method for studying healthy and pathological tissues of the skin and the brain.
(i) We observed statistical differences between THz dielectric properties of ordinary and dysplastic nevi of the skin in vivo. This highlights an ability for non-invasive early diagnosis of dysplastic nevi and melanomas of the skin using the THz spectroscopy and imaging [3–5].
(ii) By studying the THz dielectric permittivity of non-melanoma skin cancers in vitro (i.e. basal cell carcinoma and squamous cell carcinoma), we justify an ability for discriminating malignant tissues from surrounding normal skin using preoperative and intraoperative THz imaging [6,7].
(iii) Finally, the results of measuring the THz dielectric response of gelatin-fixed malignancies of the brain in vitro allow us to analyze an ability for discriminating brain gliomas from surrounding normal tissues during the neurosurgery using the THz technologies.
The observed results of THz measurements agrees well with the data of biotissues studying using other modern modalities of optical imaging, such as intraoperative exogenous fluorescence imaging and optical coherence tomography, as well as with the data of biotissue histology. These results highlight the prospective of THz spectroscopy, imaging and endoscopy use for non-invasive, least-invasive and intraoperative medical diagnosis of malignancies.
 O.A. Smolyanskaya,·M.M. Nazarov,·O.P. Cherkasova,·J.-P. Guillet,·J.-L. Coutaz, A.A. Konovko, Y.V.Kistenev,·P. Mounaix, I.A. Ozheredov, V.L. Vaks, A. Yaroslavsky,·N.V. Chernomyrdin, K.I. Zaytsev, S.A. Kozlov,·J.-H. Son, V. Wallace,·A.P. Shkurinov, ·V.V. Tuchin, “Terahertz biophotonics as a tool for studies of dielectricand spectral properties of tissues and bioliquids relatedto water content,” Progress in Quantum Electronics (2017, Submitted).
 IEEE Transactions on Terahertz Science and Technology 5(5), 817 (2015).
 Applied Physics Letters 106(5), 053702 (2015)
 European Journal of Cancer 51, S167 (2015).
 Optics and Spectroscopy 119(3), 404 (2015).
 Journal of Physics: Conference Series 486(1), 012014 (2014).
 Journal of Physics: Conference Series 584(1), 012023 (2015).
We have developed a method of the terahertz (THz) solid immersion microscopy for the reflection-mode imaging of soft biological tissues. It relies on the use of the solid immersion lens (SIL), which employs the electromagnetic wave focusing into the evanescent-field volume (i.e. at a small distance behind the medium possessing high refractive index) and yields reduction in the dimensions of the THz beam caustic. We have assembled an experimental setup using a backward-wave oscillator, as a source of the continuous-wave THz radiation featuring λ= 500 μm, a Golay cell, as a detector of the THz wave intensity, and a THz SIL comprised of a wide-aperture aspherical singlet, a truncated sphere and a thin scanning windows. The truncated sphere and the scanning window are made of high-resistivity float-zone silicon and form a unitary optical element mounted in front of the object plane for the resolution enhancement. The truncated sphere is rigidly fixed, while the scanning window moves in lateral directions, allowing for handling and visualizing the soft tissues. We have applied the experimental setup for imaging of a razor blade to demonstrate the advanced 0:2λ resolution of the proposed imaging arrangement. Finally, we have performed imaging of sub-wavelength-scale tissue spheroids to highlight potential of the THz solid immersion microscopy in biology and medicine.
We have performed the in vitro terahertz (THz) spectroscopy of human brain tumors. In order to fix tissues for the THz measurements, we have applied the gelatin embedding. It allows for preserving tissues from hydration/dehydration and sustaining their THz response similar to that of the freshly-excised tissues for a long time after resection. We have assembled an experimental setup for the reflection-mode measurements of human brain tissues based on the THz pulsed spectrometer. We have used this setup to study in vitro the refractive index and the amplitude absorption coefficient of 2 samples of malignant glioma (grade IV), 1 sample of meningioma (grade I), and samples of intact tissues. We have observed significant differences between the THz responses of normal and pathological tissues of the brain. The results of this paper highlight the potential of the THz technology in the intraoperative neurodiagnosis of tumors relying on the endogenous labels of tumorous tissues.
We have developed a method of terahertz (THz) solid immersion microscopy for imaging of biological objects and tissues. It relies on the solid immersion lens (SIL) employing the THz beam focusing into the evanescent-field volume and allowing strong reduction in the dimensions of the THz beam caustic. By solving the problems of the sample handling at the focal plane and raster scanning of its surface with the focused THz beam, the THz SIL microscopy has been adapted for imaging of soft tissues. We have assembled an experimental setup based on a backward-wave oscillator, as a continuous-wave source operating at the wavelength of λ = 500 μm, and a Golay cell, as a detector of the THz wave intensity. By imaging of the razor blade, we have demonstrated advanced 0.2λ-resolution of the proposed THz SIL configuration. Using the experimental setup, we have performed THz imaging of a mint leaf revealing its sub-wavelength features. The observed results highlight a potential of the THz SIL microscopy in biomedical applications of THz science and technology.