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Objectives The development of compact diagnostic probes and instruments with an ability to direct access to organs and tissues and integration of these instruments into surgical workflows is an important task of modern physics and medicine. The need for such tools is essential for surgical oncology, where intraoperative visualization and demarcation of tumor margins define further prognosis and survival of patients. In this paper, the possible solution for this intraoperative imaging problem is proposed and its feasibility to detect tumorous tissue is studied experimentally. Methods For this aim, the sapphire scalpel was developed and fabricated using the edge-defined film-fed growth technique aided by mechanical grinding, polishing, and chemical sharpening of the cutting edge. It possesses optical transparency, mechanical strength, chemical inertness, and thermal resistance alongside the presence of the as-grown hollow capillary channels in its volume for accommodating optical fibers. The rounding of the cutting edge exceeds the same for metal scalpels and can be as small as 110 nm. Thanks to these features, sapphire scalpel combines tissue dissection with light delivering and optical diagnosis. The feasibility for the tumor margin detection was studied, including both gelatin-based tissue phantoms and ex vivo freshly excised specimens of the basal cell carcinoma from humans and the glioma model 101.8 from rats. These tumors are commonly diagnosed either non-invasively or intraoperatively using different modalities of fluorescence spectroscopy and imaging, which makes them ideal candidates for our feasibility test. For this purpose, fiber-based spectroscopic measurements of the backscattered laser radiation and the fluorescence signals were carried out in the visible range. Results Experimental studies show the feasibility of the proposed sapphire scalpel to provide a 2-mm-resolution of the tumor margins' detection, along with an ability to distinguish the tumor invasion region, which results from analysis of the backscattered optical fields and the endogenous or exogenous fluorescence data. Conclusions Our findings justified a strong potential of the sapphire scalpel for surgical oncology. However, further research and engineering efforts are required to optimize the sapphire scalpel geometry and the optical diagnosis protocols to meet the requirements of oncosurgery, including diagnosis and resection of neoplasms with different localizations and nosologies.

This article describes a sapphire cryoprobe as a promising solution to the significant problem of modern cryosurgery that is the monitoring of tissue freezing. This probe consists of a sapphire rod manufactured by the edge-defined film-fed growth technique from Al

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.

In the paper, the double-Debye and double-overdamped-oscillator models are considered for parametrization of the terahertz (THz) dielectric response of human brain tissues. Experimental data can be accurately reproduced for the intact tissues and gliomas using both models. While the double-Debye dielectric model is widely used in THz biophotonics, the double-overdamped-oscillator model appears to be more physically rigorous, since it satisfies the sum rule. In our opinion, the described double-overdamped-oscillator model is important for further research and development in THz biophotonics and neurodiagnosis of tumors.

The paper is devoted to problem of waveguide designing for the THz frequency range of electromagnetic spectra. We proposed different types of THz waveguides on the base of the sapphire shaped crystals. Due to the advantages of the shaped crystal growth technique and unique combination of sapphire physical properties, the sapphire waveguides with relatively low losses, near-zero dispersion and inertness of the waveguide characteristics with respect to external conditions can be used effectively for guiding of the THz radiation in the harsh environments.

The second part of the review work discusses the current state of research in the diagnosis of malignant neoplasms using terahertz (THz) spectroscopy and imaging. Particular attention is paid to potential applications of THz technology in early non-invasive, minimally invasive and intraoperative diagnostics, as well as in histological studies. The nature of the contrast observed between normal and pathological tissues in the THz range is discussed. Finally, the problems of THz technology transfer into a clinical practive are discussed. Во второй части обзорной работы обсуждается современное состояние исследований в области диагностики злокачественных новообразований с помощью терагерцовой (ТГц) спектроскопии и визуализации. Особое внимание уделяется потенциальным приложениям ТГц техники в ранней неинвазивной, малоинвазивной и интраоперационной диагностике, а также в гистологических исследованиях. Обсуждается природа контраста, наблюдаемого между тканями в нормальном состоянии и при наличии патологии в ТГц диапазоне. Наконец, рассматриваются проблемы ТГц техники, препятствующие ее внедрению в клиническую практику.

We propose a new method of terahertz microscopy for imaging of biological tissues with a subwavelength spatial resolution. It makes it possible to surmount the Abbe diffraction limit and ensures a subwavelength resolution due to the solid immersion effect, i.e., due to decreasing dimensions of the electromagnetic beam caustic as the beam is focused in free space at a small distance (smaller than the wavelength) behind a medium with a high refractive index. An experimental setup that realizes the proposed method is developed. It uses a backward-wave oscillator and a Golay cell as a source and a detector of the terahertz radiation, respectively. In this setup, the radiation is focused behind a silicon hemisphere to realize the solid immersion effect. A record-high spatial resolution of 0.15λ is demonstrated experimentally for optical systems based on the solid immersion effect (the measurements have been performed at a wavelength of λ = 500 μm using a metal–air interface as a test object). Microscopy based on the solid immersion effect does not imply using diaphragms or near-field probes of other types for achieving the subwavelength spatial resolution, and, correspondingly eliminates energy losses associated with these elements. The proposed method has been applied for imaging of soft biological tissues, which has made it possible to demonstrate its potential for the use in biology and medicine.

A method for wavelet filtration procedure training for optical coherence tomography (OCT) images using the experimental measurements of test objects that were constructed by means of water solutions of monodisperse nanoparticles and several microscopic inclusions has been described in the present paper. The choice of test-object parameters (concentration of water solution, size of nanoparticles, and shape, dimensions, and mutual position of inclusions) has allowed the modeling of various working conditions of OCT and setting different criteria for estimation of filtration efficiency. In the present work, the optimal filter for the considered example of a test object has been selected among the combinations of various basic functions of five wavelet families, soft and hard threshold filtering methods, four decomposition levels, and threshold values in a range of 0.05–3.05. The mutual position of the micro-inclusions has been used as a criterion for evaluating the filtration efficiency. As a result, it has been shown that the determined wavelet filter leads to effective suppression of the scattering noise in OCT images and preserve information about the structure of the object under study.

Optical coherence tomography of the ex vivo human and rat brain tissue samples is performed. The analysis of attenuation coefficient, coefficient based on effective refractive index, and their standard deviations was obtained from OCT measurements. The comparison of these physically reasonable features demonstrates the high variance of brain tissue optical properties and reveals the advantages and weaknesses of OCT as a diagnostic tool for neurosurgery.

Terahertz (THz) technologies demonstrate significant potential for medical and biological applications. Despite a low penetration depth of THz waves into biological tissues due to the absorption by interstitial water, tissue freezing can be used for overcoming this limitation up to a certain limit. Moreover, application of low temperatures leads to changes of tissue dielectric properties, which yields additional perspectives of THz spectroscopy for study of different states and conditions of tissues, in particular, for observation of their freezing during cryoablation. In this work, the contrast of refractive index featured by unfrozen and frozen adipose and liver ex vivo tissue samples is demonstrated experimentally, along with the ability to detect the freezing depth using THz pulsed spectroscopy.

This special section presents recent results in the field of infrared (IR) and terahertz (THz) optoelectronics, which have been developing rapidly over the past decades. The progress of IR and THz technologies affects a variety of fundamental problems in material science, astrophysics, chemistry and biology, medical diagnosis, and high-resolution and multispectral imaging modalities.

In terahertz (THz) spectroscopy water content correlates with the tissue pathological changes. At the same time, water reduces the depth of THz-wave penetration in tissues. In order to unmask cells’ and tissues’ biophysical properties and to increase the tissues probing depth, immersion optical clearing (IOC) was recently introduced in the THz range. For studying common IOC agent’s optical properties in the frequency range of 0.1–2.5 THz, pulsed spectroscopy was used. Diffusion coefficients of IOC agents in ex vivo rat brain tissue were studied using the collimated transmission spectroscopy in the visible range. Two-dimensional nomogram was used to objectively compare IOC agents, based on their THz-wave absorption coefficients and diffusion rates.

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.

In our work, we developed a method of THz solid immersion microscopy for continuous-wave reflection-mode imaging of soft biological tissues with a sub-wavelength spatial resolution. We have analyzed the performance of the developed THz solid immersion lens and demonstrated a 0.15λ-resolution of the proposed imaging modality at λ = 500 μm. We have applied the developed method for the THz imaging of various soft biological tissues and reconstructed refractive index distribution of the objects. The observed results justify capabilities of the proposed THz imaging modality in biophotonics.

Significance: Terahertz (THz) radiation has demonstrated a great potential in biomedical applications over the past three decades, mainly due to its non-invasive and label-free nature. Among all biological specimens, skin tissue is an optimal sample for the application of THz-based methods because it allows for overcoming some intrinsic limitations of the technique, such as a small penetration depth (0.1 to 0.3 mm for the skin, on average). Aim: We summarize the modern research results achieved when THz technology was applied to the skin, considering applications in both imaging/detection and treatment/modulation of the skin constituents. Approach: We perform a review of literature and analyze the recent research achievements in THz applications for skin diagnosis and investigation. Results: The reviewed results demonstrate the possibilities of THz spectroscopy and imaging, both pulsed and continuous, for diagnosis of skin melanoma and non-melanoma cancer, dysplasia, scars, and diabetic condition, mainly based on the analysis of THz optical properties. The possibility of modulating cell activity and treatment of various diseases by THz-wave exposure is shown as well. Conclusions: The rapid development of THz technologies and the obtained research results for skin tissue highlight the potential of THz waves as a research and therapeutic instrument. The perspectives on the use of THz radiation are related to both non-invasive diagnostics and stimulation and control of different processes in a living skin tissue for regeneration and cancer treatment.

Terahertz (THz) technology holds strong potential for the intraoperative label-free diagnosis of brain gliomas, aimed at ensuring their gross-total resection. Nevertheless, it is still far from clinical applications due to the limited knowledge about the THz-wave–brain tissue interactions. In this work, rat glioma model 101.8 was studied ex vivo using both the THz pulsed spectroscopy and the 0.15λ-resolution THz solid immersion microscopy (λ is a free-space wavelength). The considered homograft model mimics glioblastoma, possesses heterogeneous character, unclear margins, and microvascularity. Using the THz spectroscopy, effective THz optical properties of brain tissues were studied, as averaged within the diffraction-limited beam spot. Thus measured THz optical properties revealed a persistent difference between intact tissues and a tumor, along with fluctuations of the tissue response over the rat brain. The observed THz microscopic images showed heterogeneous character of brain tissues at the scale posed by the THz wavelengths, which is due to the distinct response of white and gray matters, the presence of different neurovascular structures, as well as due to the necrotic debris and hemorrhage in a tumor. Such heterogeneities might significantly complicate delineation of tumor margins during the intraoperative THz neurodiagnosis. The presented results for the first time pose the problem of studying the inhomogeneity of brain tissues that causes scattering of THz waves, as well as the urgent need to use the radiation transfer theory for describing the THz-wave — tissue interactions.

Significance: Uncontrolled cryoablation of tissues is a strong reason limiting the wide application of cryosurgery and cryotherapy due to the certain risks of unpredicted damaging of healthy tissues. The existing guiding techniques are unable to be applied in situ or provide insufficient spatial resolution. Terahertz (THz) pulsed spectroscopy (TPS) based on sensitivity of THz time-domain signal to changes of tissue properties caused by freezing could form the basis of an instrument for observation of the ice ball formation. Aim: The ability of TPS for in situ monitoring of tissue freezing depth is studied experimentally. Approach: A THz pulsed spectrometer operated in reflection mode and equipped with a cooled sample holder and ex vivo samples of bovine visceral adipose tissue is applied. Signal spectrograms are used to analyze the changes of THz time-domain signals caused by the interface between frozen and unfrozen tissue parts. Results: Experimental observation of TPS signals reflected from freezing tissue demonstrates the feasibility of TPS to detect ice ball formation up to 657-μm depth. Conclusions: TPS could become the promising instrument for in situ control of cryoablation, enabling observation of the freezing front propagation, which could find applications in various fields of oncology, regenerative medicine, and THz biophotonics.

Sapphire appticator for cryosurgery with the ability of monitoring freezing of biological tissue is proposed. The conception is based on diffuse optical spectroscopy. The design of applicator allows to detect spatially resolved optical signals reflected and scattered from tissue. We demonstrate the results of experimental studies using tissue phantoms and ex vivo samples.

In this work, we consider several novel modalities of THz imaging, which overcome the Abbe diffraction limit and hold strong potential in THz biophotonics. Among them: the THz solid immersion microscopy, the THz imaging relying on photonic jets and photonic hooks, and the THz scanning-probe near-field microscopy based on a flexible sapphire fiber.

In this talk, we present the results of the ex vivo experimental studies by means of optical coherence tomography of malignant and healthy tissues of brain, including samples of human brain glioma of different grades and rat glioblastoma model. The extraction of features based on attenuation and homogeneity helps to analyze differences of tissues.

In this work, we summarize and discuss a set of medical instruments based on sapphire shaped crystals, which are able to combine several modalities, such as tissue resection, aspiration, intraoperative diagnosis, laser therapy and coagulation. Due to the application of sapphire, these types of medical instruments are biocompatible and resist multiple sterilization and direct contact with biological tissues and liquids. Application of the edge-defined film-fed growth (EFG) technique leads to the fabrication of sapphire instruments with complex form and shape aimed at solution of different medical tasks.

In this work, a thorough analysis of hyperosmotic agents for the immersion optical clearing (IOC) in terahertz (THz) range was performed. It was aimed at the selection of agents for the efficient enhancement of penetration depth of THz waves into biological tissues. Pulsed spectroscopy in the frequency range of 0.1 to 2.5 THz was applied for investigation of the optical properties of common IOC agents. Using the collimated transmission spectroscopy in visible range, binary diffusion coefficients of tissue water and agent in ex vivo rat brain tissue were measured. IOC agents were objectively compared using two-dimensional nomogram, accounting for their THz-wave absorption coefficients and binary diffusion coefficients. The results of this study demonstrate an interplay between the penetration depth enhancement and the diffusion rate and allow for pointing out glycerol as an optimal agent among the considered ones for particular applications in THz biophotonics.

A continuously-tunable terahertz (THz) bandpass filter based on the resonant electromagnetic-wave transmission through a metal-hole array featuring a gradually changing period was developed and fabricated on a silicon substrate using optical lithography. A gradient geometry of the metal-hole array yields a wide tunability of the filter transmission, when operating with a focussed THz beam. The filter was studied numerically, using the finite element method, and experimentally, using the THz pulsed spectroscopy. We find that the central wavelength of the filter transmission band can be tuned in the wide range of λc = 400–800 μm with the relative bandwidth of Δλ/λc ≃ ~0.4. Finally, Kapton-based anti-reflection coating was applied to the filter flat side, in order to suppress an interference pattern in the filter transmission spectrum. We believe that the developed filter holds strong potential for multispectral THz imaging and sensing due to its conceptual simplicity and case of operation. Moreover, the presented filter concept can be translated to other spectral ranges, where appropriate technologies are available for the fabrication of gradient sub-wavelength metal-hole arrays.

Terahertz (THz) spectroscopy and imaging allow to differentiate between healthy tissues and tumors of different types, due to keen sensitivity to the water content. However, a high absorption of THz waves by water molecules limits application of THz technology for medical diagnosis. Among the existing methods for tissue clearing only immersive optical clearing (IOC) is acceptable for in vivo study. In order to choose optimal agents for IOC, we reconstructed THz dielectric properties of common agents using methods of THz pulsed spectroscopy and we measured diffusion coefficients of agents in rat brain analyzing collimated transmittance in visible range.

Cryodestruction is one of the promising medical techniques, which has a lot of advantages. Unfortunately, the monitoring of the ice-ball formation in biological tissue during their freezing is a severe problem. In order to solve it, we suggest applying diffuse reflectance spectroscopy and terahertz spectroscopy for monitoring and implement it by means of a special cryoapplicator, based on sapphire shaped crystals. Sapphire features high transparency in a wide spectral range, chemical resistance, and high thermal conductivity at the cryogenic temperatures, therefore, it is an appropriate material for cryotherapies. Moreover, the technique of growing shaped sapphire enables fabrication of applicators of complex shapes and cross-sections. We demonstrate an example of such applicator of an immersion type with several channels for optical fibers, experimental set-up for study its abilities and experimental results of approbation of such applicator.

Terahertz (THz) waves feature high sensitivity to the content and state of water in biological tissues. Therefore, during the past decades, THz technology has attracted significant attention in biophotonics, including diagnosis of malignant and benign neoplasms with different nosologies and localizations. The pathophysiological features of malignant tumors of the central nervous system determine appearance of several morphological phenomena, such as increased vascularity, edema, necrosis. These phenomena cause water content increase in the studied tissues and, thus, open new ways for the THz technology applications in the intraoperative neurodiagnosis, including delineation of tumor margins. This research area is rather novel and, despite the small amount of accumulated research material, is undoubtedly extremely promising for creation of new diagnostic approaches. In this review, available results in the considered exciting branch of THz technology are summarized, and potential projections of this topic into the future are constructed.

A sapphire shaped capillary needle designed for collimating and focusing of laser radiation was proposed and fabricated by the edge-defined film-fed growth technique. It features an as-grown surface quality, high transparency for visible and near-infrared radiation, high thermal and chemical resistance and the complex shape of the tip, which protects silica fibers. The needle's geometrical parameters can be adjusted for use in various situations, such as type of tissue, modality of therapy and treatment protocol. The focusing effect was demonstrated numerically and observed experimentally during coagulation of the ex vivo porcine liver samples. This needle in combination with 0.22NA optical fiber allows intensive and uniform coagulation of 150 mm3 volume interstitially and 30 mm3 superficially by laser exposure with 280 J without tissue carbonization and fiber damaging along with delicate treatment of small areas. The demonstrated results reveal the perspectives of the proposed sapphire microfocusing needle for laser surgery and therapy.

In this paper, we study the examples of sapphire capillary needles for interstitial laser thermotherapy and photodynamic therapy. Such needles are fabricated by means of the Edge-defined Film-fed Growth (EFG) technology, so that they feature an as-grown optical quality. The optical fiber, which is used for delivering laser radiation to tissue, is placed inside the capillary channel in the needle's body. The channel is closed at the one side, therefore, the fiber is protected from the direct contact with biological tissue. The needle's tip form plays a significant role in the formation of the particular radiation pattern and the corresponding volume of treatment. Using a tissue phantom, we have experimentally studied the radiation distribution formed by sapphire needles with different tip angle. The results demonstrate rather smooth spatial distribution of light, confirming the high surface quality of the needles and the ability to control the amount of exposed tissue by changing the tip angle.

Terahertz (THz) biophotonics attracts considerable interest as a promising tool for the diagnosis of malignancies with different nosology and localization. Nevertheless, the majority of modern THz spectroscopy and imaging modalities rely on lens- and mirror-based optical systems, which obey the Abbe diffraction limit and provide the spatial resolution of >λ; λ is electromagnetic wavelength. The resolution of several hundreds of microns, or even of several millimeters, strongly limits capabilities of THz technology in malignancy diagnosis, pushing further developments into the realm of sub-wavelength-resolution THz imaging. In our work, we developed a method of THz solid immersion microscopy for continuous-wave reflection-mode imaging of soft biological tissues with a sub-wavelength spatial resolution. In order to achieve strong reduction in the dimensions of beam caustic, an electromagnetic wave is focused into the evanescent field volume behind a medium with a high refractive index. We have experimentally demonstrated a 0.15λ-resolution of the proposed imaging modality at λ = 500 μm. The proposed technique does not involve any sub-wavelength near-field probes and diaphragms, thus, providing high energy throughout. We have applied the developed method for the THz imaging of various soft biological tissues: a plant leaf blade, cell spheroids, tissues of the breast ex vivo, human brain gliomas ex vivo and glioma models from rats ex vivo. The observed results justify the capabilities of the proposed THz imaging modality in biology and medicine.

During the past decades, terahertz (THz) spectroscopy and imaging have attracted considerable attention in biophotonics and, in particular, in label-free diagnosis of malignancies with different nosology and localization, thanks to strong sensitivity of THz waves to the content and state (free or bound) of water in tissues. The water content is usually increased in malignancies due to the abnormal vascularity, edema, and (in some cases) presence of necrotic debris, thus, providing an ability of using THz technology for the detection of tumor margins either before or during surgery. Only few years ago, pilot papers dedicated to intraoperative diagnosis of brain tumors using THz waves have been published, opening this novel exciting application of THz technology. In this chapter, we start with brief introduction to THz technology, peculiarities of THz-wave–tissue interactions, and THz pulsed spectroscopy, as a main tool of THz biophotonics nowadays. Then, we review results of THz spectroscopy and imaging of brain tumors ex vivo and in vivo, considering glioma models from mice and rats, human brain gliomas of different grades, as well as pilot measurement of human brain meningioma. Finally, we consider recent THz measurements of traumatic brain injuries in rats, since they feature similar origin of contrast between normal and pathological tissues in the THz range, as compared to that of a tumor. The material of this chapter highlights a bright future of THz technology in the intraoperative diagnosis of human brain tumors.

Second half of the XX century was marked by a rapid development of sapphire shaped crystal growth technologies, driven by the demands for fast, low-cost, and technologically reliable methods of producing sapphire crystals of complex shape. Numerous techniques of shaped crystal growth from a melt have been proposed relying on the Stepanov concept of crystal shaping. In this review, we briefly describe the development of growth techniques, with a strong emphasize on those that yield sapphire crystals featuring high volumetric and surface quality. A favorable combination of physical properties of sapphire (superior hardness and tensile strength, impressive thermal conductivity and chemical inertness, high melting point and thermal shock resistance, transparency to electromagnetic waves in a wide spectral range) with advantages of shaped crystal growth techniques (primarily, an ability to produce sapphire crystals with a complex geometry of cross-section, along with high volumetric and surface quality) allows fabricating various instruments for waveguiding, sensing, and exposure technologies. We discuss recent developments of high-tech instruments, which are based on sapphire shaped crystals and vigorously employed in biomedical and material sciences, optics and photonics, nuclear physics and plasma sciences.

In this paper, we propose a computational approach for description of radiation transfer in a quasi-ordered medium and study the impact of scattering on electromagnetic wave propagation and image formation. It combines finite-difference time-domain method, Monte Carlo simulations, and radiative transfer theory. Using, as an example, terahertz (THz) imaging, we analyze the modulation transfer function (MTF) of the imaging system operated at 0.25 THz for scattering material layers placed between the object and the imaging plane. We experimentally study imaging of bar-pattern test objects through a quasi-ordered scattering medium. Both numerical and experimental results are in good agreement and demonstrate an impact of quasi-ordered scatterers on quality of THz images, i.e., particular combination of the electromagnetic wavelength and parameters of scattering materials could enhance MTF compared with ones with random particle structures.

In this paper, terahertz (THz) pulsed spectroscopy and solid immersion microscopy were applied to study interactions between water vapor and tissue scaffolds–the decellularized bovine pericardium (DBP) collagen matrices, in intact form, cross-linked with the glutaraldehyde or treated by plasma. The water-absorbing properties of biomaterials are prognostic for future cell-mediated reactions of the recipient tissue with the scaffold. Complex dielectric permittivity of DBPs was measured in the 0.4–2.0 THz frequency range, while the samples were first dehydrated and then exposed to water vapor atmosphere with 80.0 ± 5.0% relative humidity. These THz dielectric measurements of DBPs and the results of their weighting allowed to estimate the adsorption time constants, an increase of tissue mass, as well as dispersion of these parameters. During the adsorption process, changes in the DBPs’ dielectric permittivity feature an exponential character, with the typical time constant of =8–10 min, the transient process saturation at =30 min, and the tissue mass improvement by =1–3%. No statistically-relevant differences between the measured properties of the intact and treated DBPs were observed. Then, contact angles of wettability were measured for the considered DBPs using a recumbent drop method, while the observed results showed that treatments of DBP somewhat affects their surface energies, polarity, and hydrophilicity. Thus, our studies revealed that glutaraldehyde and plasma treatment overall impact the DBP–water interactions, but the resultant effects appear to be quite complex and comparable to the natural variability of the tissue properties. Such a variability was attributed to the natural heterogeneity of tissues, which was confirmed by the THz microscopy data. Our findings are important for further optimization of the scaffolds’ preparation and treatment technologies. They pave the way for THz technology use as a non-invasive diagnosis tool in tissue engineering and regenerative medicine.

Sapphire shaped crystals are considered as a favorable material platform of the terahertz (THz) waveguide and fiber optics. Unique physical properties of sapphire, along with advantages of the Edge-defined Film-fed Growth (EFG) technique, yield fabrication of the THz waveguides and fibers with a complex cross-section geometry directly from the Al2O3-melt, where no labour-intensive mechanical processing is required. Wide variability of the as-grown sapphire shaped crystal geometries yields different physical mechanisms of electromagnetic waveguidance. In this review, recent advantages in the THz waveguides and fibers based on the EFG-grown sapphire shaped crystals are discussed. While possessing moderate THz-wave absorbtion and quite high dispersion, flexible sapphire fibers with a simple step-index cross-section geometry yield strong confinement of guided modes in a fiber core due to a high refractive index of sapphire in the THz range. This effect opens novel opportunities of sapphire fibers in high-resolution THz imaging, using the principles of either scanning-probe near-field optical microscopy or optical fiber bundles. In turn, antiresonant and photonic crystal hard hollow-core waveguides demonstrate advanced optical performance, along with wide capabilities in THz endoscopy and sensing in harsh environments. This review highlights that the EFG-grown sapphire shaped crystals hold strong potential in different branches of THz 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.

In this paper, we present the step-index sapphire fiber, applied as a THz probe. The low THz attenuation of sapphire makes it attractive for fabrication of THz optical components. Moreover, it has a high refractive index in THz range, which guarantees a strong modal confinement in a fiber core. The advantages of the edge-defined film-fed growth (EFG) technique allow for fabrication of fibers with close-to-cylindrical shape, the length of 1 m and longer, and the subwavelength diameter of 150 − 400 μm. In order to improve the coupling efficiency, the fiber has polished flat ends. We apply the fabricated 300-μm-diameter sapphire fiber for the THz near-field scanning-probe microscopy. The spatial resolution of our experimental setup is defined by the fiber diameter, thus, it reaches ~ λ/4 for the radiation wavelength λ = 1200 μm. The obtained images of the test objects demonstrate the advanced resolution, which is close to the theoretical limit and beyond the Abbe diffraction limit.

We present the terahertz (THz) near-field microscope, in which a flexible sapphire fiber serves as a scanning probe. High refractive index of sapphire at THz frequencies allows for a strong confinement of guided modes in a fiber core, and, thus, for a sub-wavelength resolution THz imaging. In turn, low THz-wave absorption in sapphire allows for guiding the THz waves in a fiber over tens of centimeters with rather high energy efficiency. The developed THz microscope operates in a transmission mode and uses a backward wave oscillator, as a continuous-wave THz source with the output wavelength of λ = 1200 µm, a Golay cell, as a detector of THzwave intensity, and a 300 µm-diameter flexible sapphire fiber with at input and output ends, as a scanning probe. In our THz microscope arrangement, the input end of a sapphire fiber is mounted on a motorized translation stage, which yield two- or even three-dimensional imaging of electromagnetic field formed at the shadow side of an object; while the output fiber end is rigidly fixed in front of the detector aperture. The experimental setup was applied for imaging of representative test objects, and the observed results demonstrated its advanced spatial resolution of ~ λ=4, which is beyond the Abbe diffraction limit. In our opinion, the sub-wavelength spatial resolution, along with a high energy throughout, open a wide range of the developed THz microscope applications in material science, non-destructive testing, and biophotonics.

An intraoperative diagnosis of brain tumors is one of the most urgent and challenging problem of the modern neurosurgery. The most important measure of the effectiveness of treatment is the complete tumor resection. The existing methods of the intraoperative neurodiagnosis of tumors are plagued with limited sensitivity, especially for low-grade gliomas, and, furthermore, can remain rather expensive. The recently reported results of optical coherence tomography (OCT) application for finding differences between healthy and malignant tissues make it become one of the promising label-free diagnostic instruments. Nevertheless, the wide use of OCT in clinical practice is limited by the lack of complete study of its opportunities in neurosurgery, which leads to a huge scientific interest. Our research, aimed at the study of the ability of OCT for the intraoperative diagnosis of brain gliomas of different grades, has the goal to observe the differences between OCT signals obtained for ex vivo samples of various types of human brain glioma and intact brain tissue. We propose a 3D-feature based data analysis that demonstrates promising results in differentiation of tissue classes.

The problem of complete resection of human brain glioma during neurosurgery is still one of the most challenging, since the existed diagnostic methods are plagued with limited sensitivity and specificity; they remain laborious, time-consuming and/or rather expensive. The present work includes the ex vivo study of malignant brain gliomas featuring different grades (according to the World Health Organization) by means of two methods, i.e. optical coherence tomography (OCT) and terahertz pulsed spectroscopy (TPS). Both OCT and TPS studies were done just after the tissue resection and included gelatin embedding of the samples for conservation of water content. The further histological examination using hematoxylin and eosin (H&E) stained microscopy approved the diagnosis. The results demonstrate the potential of TPS to differentiate intact and malignant tissues and the potential of OCT to differentiate low- and high-grade gliomas as well as intact tissue and low-grade gliomas. Thus, combination of these modalities seems to be rather prospective for the further development of the advanced intraoperative diagnostic tools.

We developed a method for reconstructing the THz dielectric response of a thin liquid sample. A self-made sample cuvette was designed for the transmission-mode THz pulsed spectroscopy of liquids. Numerical simulations and theoretical studies of the proposed reconstruction procedure were performed in order to optimize the sample geometry and predict uncertainties in reconstructed dielectrical properties. A number of agents for immersion optical clearing of tissues was studied using the proposed method in the THz range. The developed method can be applied for all types of sufficiently transparent liquid samples.

Intraoperative diagnosis of brain tumors remains a challenging problem of modern neurosurgery. A complete resection of tumor is the most important factor, determining an efficiency of its treatment, while an incomplete resection, caused by inaccurate detection of tumor margins, increases a probability of the tumor recurrence. The existing methods of the intraoperative neurodiagnosis of tumors are plagued with limited sensitivity and specificity; they remain laborious, time-consuming and/or rather expensive. Therefore, the development of novel methods for the intraoperative diagnosis of gliomas relying on modern instruments of medical imaging is a topical problem of medicine, physics, and engineering. In our research, we studied the ability of dual-modality imaging that combines such methods as optical coherence tomography (OCT) and terahertz (THz) pulsed spectroscopy, for intraoperative diagnosis of brain tumors with a strong emphasize on a human brain gliomas. We performed experimental studies of the frequency-dependent THz dielectric properties and OCT imaging of healthy (intact) and pathological brain tissues ex vivo in order to analyze the prospect for differentiation between tissue classes. The observed results highlight a potential of the considered instruments in the label-free intraoperative neurodiagnostics.

We performed the transmission-mode terahertz (THz) pulsed spectroscopy of several THz-wave penetration- enhancing agents (PEAs): glycerol, propylene glycol, ethylene glycol, and polyethylene glycol, featuring the molecular weight of 200, 300 and 400. We vacuumized the THz beam path in order to reduce an impact of water vapor on measured data. We reconstructed optical properties and dielectric constants of the abovementioned PEAs in the spectral range of 0.1 to 2.5 THz. We analyzed measured THz optical properties along with the literature data for coefficients of PEAs' diffusion into tissues in order to objectively uncover strength and weaknesses of their use in the immersion optical clearing of tissues at THz frequencies.