Institute of Precision Mechanics and Control

The purpose of this paper is to give an overview of the recent surgical intraoperational applications of indocyanine green fluorescence imaging methods, the basics of the technology, and instrumentation used. Well over 200 papers describing this technique in clinical setting are reviewed. In addition to the surgical applications, other recent medical applications of ICG are briefly examined.

The development of optical methods in modern medicine in the areas of diagnostics, therapy, and surgery has stimulated the investigation of optical properties of various biological tissues, since the efficacy of laser treatment depends on the photon propagation and fluence rate distribution within irradiated tissues. In this work, an overview of published absorption and scattering properties of skin and subcutaneous tissues measured in wide wavelength range is presented. Basic principles of measurements of the tissue optical properties and techniques used for processing of the measured data are outlined.

Tissue optical clearing technique provides a prospective solution for the application of advanced optical methods in life sciences. This paper gives a review of recent developments in tissue optical clearing techniques. The physical, molecular and physiological mechanisms of tissue optical clearing are overviewed and discussed. Various methods for enhancing penetration of optical-clearing agents into tissue, such as physical methods, chemical-penetration enhancers and combination of physical and chemical methods are introduced. Combining the tissue optical clearing technique with advanced microscopy image or labeling technique, applications for 3D microstructure of whole tissues such as brain and central nervous system with unprecedented resolution are demonstrated. Moreover, the difference in diffusion and/or clearing ability of selected agents in healthy versus pathological tissues can provide a highly sensitive indicator of the tissue health/pathology condition. Finally, recent advances in optical clearing of soft or hard tissue for in vivo imaging and phototherapy are introduced. [Formula: see text].

This tutorial-review introduces the fundamentals of polarized light interaction with biological tissues and presents some of the recent key polarization optical methods that have made possible the quantitative studies essential for biomedical diagnostics. Tissue structures and the corresponding models showing linear and circular birefringence, dichroism, and chirality are analyzed. As the basis for a quantitative description of the interaction of polarized light with tissues, the theory of polarization transfer in a random medium is used. This theory employs the modified transfer equation for Stokes parameters to predict the polarization properties of single- and multiple-scattered optical fields. The near-order of scatterers in tissues is accounted for to provide an adequate description of tissue polarization properties. Biomedical diagnostic techniques based on polarized light detection, including polarization imaging and spectroscopy, amplitude and intensity light scattering matrix measurements, and polarization-sensitive optical coherence tomography are described. Examples of biomedical applications of these techniques for early diagnostics of cataracts, detection of precancer, and prediction of skin disease are presented. The substantial reduction of light scattering multiplicity at tissue optical clearing that leads to a lesser influence of scattering on the measured intrinsic polarization properties of the tissue and allows for more precise quantification of these properties is demonstrated.

In this article, we discuss the optical immersion method based on refractive index matching of scatterers (e.g., collagen, elastin fibers, cells and cell compartments) and the ground material (interstitial fluid and/or cytoplasm) of tissue and blood under the action of exogenous optical clearing agents. We analyze the optical clearing of fibrous and cell-structured tissues and blood from the point of view of receiving more valuable, normally hidden, information from spectroscopic and polarization measurements, confocal microscopy, optical coherence and optical projection tomography, as well as from nonlinear spectroscopies, such as two-photon fluorescence and second-harmonic generation techniques. Some important applications of the immersion technique to glucose sensing, drug delivery monitoring, improvements of image contrast and imaging depth, nondistortive delivery of laser radiation and precision tissue laser photodisruption, among others, are also described.

Abstract Over the past few decades, significant attention has been paid to the biomedical applications of terahertz (THz) technology. Nowadays, THz spectroscopy and imaging have allowed numerous demanding problems in the biological, medical, food, plant and pharmaceutical sciences to be solved. Among the biomedical applications, the label-free diagnosis of malignant and benign neoplasms represents one of the most attractive branches of THz technology. Despite this attractiveness, THz diagnosis methods are still far from being ready for use in medical practice. In this review, we consider modern research results in the THz diagnosis of malignant and benign neoplasms, along with the topical research and engineering problems which restrain the translation of THz technology to clinics. We start by analyzing the common models of THz-wave–tissue interactions and the effects of tissue exposure to THz waves. Then, we discuss the existing modalities of THz spectroscopic and imaging systems, which have either already been applied in medical imaging, or hold strong potential. We summarize the earlier-reported and original results of the THz measurements of neoplasms with different nosology and localization. We pay attention to the origin of contrast between healthy and pathological tissues in the THz spectra and images, and discuss the prospects of THz technology in non-invasive, minimally invasive and intraoperative diagnosis, as well as in aiding histology. Finally, we review the challenging problems of THz diagnosis, as well as attempts to solve them, which should bring THz technology much closer to medical practice. This review allows one to objectively uncover the benefits and weaknesses of THz technology in the diagnosis of malignant and benign neoplasms.

This is the second section of the review-tutorial paper describing fundamentals of tissue optics and photonics. As the first section of the paper was mostly devoted to description of biological tissue structures and their specificity related to interactions with light [1], this section 3 describes light-tissue interactions themselves that caused by tissue dispersion, scattering, and absorption properties, including light reflection and refraction, absorption, elastic, and quasi-elastic scattering. The major tissue absorbers and modes of elastic scattering, including Rayleigh and Mie scattering, will be presented.

Kinetics, biodistribution, and histological studies were performed to evaluate the particle-size effects on the distribution of 15 nm and 50 nm PEG-coated colloidal gold (CG) particles and 160 nm silica/gold nanoshells (NSs) in rats and rabbits. The above nanoparticles (NPs) were used as a model because of their importance for current biomedical applications such as photothermal therapy, optical coherence tomography, and resonance-scattering imaging. The dynamics of NPs circulation in vivo was evaluated after intravenous administration of 15 nm CG NPs to rabbit, and the maximal concentrations of gold were observed 15-30 min after injection. Rats were injected in the tail vein with PEG-coated NPs (about 0.3 mg Au/kg rats). 24 h after injection, the accumulation of gold in different organs and blood was determined by atomic absorption spectroscopy. In accordance with the published reports, we observed 15 nm particles in all organs with rather smooth distribution over liver, spleen and blood. By contrast, the larger NSs were accumulated mainly in the liver and spleen. For rabbits, the biodistribution was similar (72 h after intravenous injection). We report also preliminary data on the light microscopy and TEM histological examination that allows evaluation of the changes in biotissues after gold NPs treatment.

Nanocomposites (NCs) consisting of a gold nanorod core and a mesoporous silica shell doped with hematoporphyrin (HP) have been fabricated in order to improve the efficiency of cancer treatment by combining photothermal and photodynamic therapies (PDT + PTT) in vivo. In addition to the long-wavelength plasmon resonance near 810–830 nm, the fabricated NCs exhibited a 400-nm absorbance peak corresponding to bound HP, generated singlet oxygen under 633-nm excitation near the 632.5-nm Q-band, and produced heat under a 808-nm near-infrared (NIR) laser irradiation. These modalities were used for a combined PDT + PTT treatment of large (about 3 cm3) solid tumors in vivo with a xenorafted tumor rat model. NCs were directly injected into tumors and irradiated simultaneously with 633-nm and 808-nm lasers to stimulate the combined photodynamic and photothermal activities of NCs. The efficiency of the combined therapy was evaluated by optical coherence tomography, histological analysis, and by measurements of the tumor volume growth during a 21-day period. The NC-mediated PDT led to weak changes in tissue histology and to a moderate 20% decrease in the tumor volume. In contrast, the combined PDT + PTT treatment resulted in the large-area tumor necrosis and led to dramatic decrease in the tumor volume.

The penetration of light in biological tissues can be enhanced by using optical-clearing techniques. However, researches on the mechanism are limited to in vitro experiments. In this study, rat dorsal skin was used to discuss the mechanism for in vivo optical clearing. Glycerol solutions with different concentrations were applied by dermal injection; then the skin reflectance spectrum, SHG imaging and microstructural changes were monitored. The results showed that with the skin becoming transparent, the corresponding reflectance decreased, and the thickness of dermis and diameter of collagen fibril decreased, but no collagen fiber was dissolved or fractured. Hence, it can be concluded that the thickness decrease of dermis and corresponding more regular packing of tissue fibers plays an important role in the mechanism for glycerol-induced optical clearing of skin in vivo.

Flow cytometry (FCM) has been a fundamental tool of biological discovery for many years. Invasive extraction of cells from a living organism, however, may lead to changes in cell properties and prevents studying cells in their native environment. These problems can be overcome by use of in vivo FCM, which provides detection and imaging of circulating normal and abnormal cells directly in blood or lymph flow. The goal of this review is to provide a brief history, features, and challenges of this new generation of FCM methods and instruments. Spectrum of possibilities of in vivo FCM in biological science (e.g., cell metabolism, immune function, or apoptosis) and medical fields (e.g., cancer, infection, and cardiovascular disorder) including integrated photoacoustic-photothermal theranostics of circulating abnormal cells are discussed with focus on recent advances of this new platform.

Gold nanoparticles (AuNPs) of different size and shape are widely used as photosensitizers for cancer diagnostics and plasmonic photothermal (PPT)/photodynamic (PDT) therapy, as nanocarriers for drug delivery and laser-mediated pathogen killing, even the underlying mechanisms of treatment effects remain poorly understood. There is a need in analyzing and improving the ways to increase accumulation of AuNP in tumors and other crucial steps in interaction of AuNPs with laser light and tissues. In this review, we summarize our recent theoretical, experimental, and pre-clinical results on light activated interaction of AuNPs with tissues and cells. Specifically, we discuss a combined PPT/PDT treatment of tumors and killing of pathogen bacteria with gold-based nanocomposites and atomic clusters, cell optoporation, and theoretical simulations of nanoparticle-mediated laser heating of tissues and cells.

Terahertz absorption spectra and dispersion of biologically important substances such as sugar, water, hemoglobin, lipids and tissues are studied. The characteristic absorption lines in the frequency range of a terahertz spectrometer (0.1—3.5 THz) are found. The refraction indices and absorption coefficients of human tooth enamel and dentine are measured. The method of terahertz phase reflection spectroscopy is developed for strongly absorbing substances. Simple and reliable methods of time-resolved terahertz spectroscopy are developed.

Remote navigation and targeted delivery of biologically active compounds is one of the current challenges in the development of drug delivery systems. Modern methods of micro- and nanofabrication give us new opportunities to produce particles and capsules bearing cargo to deploy and possess magnetic properties to be externally navigated. In this work we explore multilayer composite magnetic microcapsules as targeted delivery systems in vitro and in vivo studies under natural conditions of living organism. Herein, we demonstrate magnetic addressing of fluorescent composite microcapsules with embedded magnetite nanoparticles in blood flow environment. First, the visualization and capture of the capsules at the defined blood flow by the magnetic field are shown in vitro in an artificial glass capillary employing a wide-field fluorescence microscope. Afterward, the capsules are visualized and successfully trapped in vivo into externally exposed rat mesentery microvessels. Histological analysis shows that capsules infiltrate small mesenteric vessels whereas large vessels preserve the blood microcirculation. The effect of the magnetic field on capsule preferential localization in bifurcation areas of vasculature, including capsule retention at the site once external magnet is switched off is discussed. The research outcome demonstrates that microcapsules can be effectively addressed in a blood flow, which makes them a promising delivery system with remote navigation by the magnetic field.

This is the third part of the review-tutorial paper describing fundamentals of tissue optics and photonics. The first part of the paper was mostly devoted to description of tissue structures and their specificity related to interactions with light [1]. The second part presented light-tissue interactions originated from tissue dispersion, scattering, and absorption properties, including light reflection and refraction, absorption, elastic, and quasi-elastic scattering [2]. This last part of the paper, underlines mostly photothermal and nonlinear interactions such as temperature rise and tissue damage, photoacoustic and acoustooptical, nonlinear sonoluminescence, Raman scattering, multiphoton autofluorescence, second harmonic generation (SHG), terahertz (THz) radiation interactions, and finally photochemical interactions with description of two widely spread therapeutic applications: photodynamic therapy (PDT) and low level light therapy (LLLT).

1. Materials for dynamic holographic 3D display 2. Photopolymerizable nanocomposite materials for holographic applications 3. Photopolymers for the recording of holographic waveguides 4. Shrinkage in holographic recording materials: photopolymers 5. Advances in holographic photorefractive materials and devices 6. Industrial-scale recording material and mass production of vHOEs 7. Non-imaging holographic optics for solar energy conversion 8. Data security and holographic data storage 9. Multimodal 3D data acquisition using digital holography 10. EUV and SXR holography and tomography with compact short wavelength sources 11. Holographic wavefront sensors 12. Holographic microscopy goes incoherent 13. Digital polarized holography for life science applications 14. Using PA-LCoS microdisplays for holographic data storage 15. Playing the piano with the brain: holographic imaging and manipulation of neural activity 16. Holography in astronomical spectrographs 17. Digital holography based on the spatial coherence function 18. Autofocus in holography 19. Interference lithography for nanostructures fabrication 20. Applications of deep learning in digital holography 21. Digital focusing in laser speckle contrast imaging 22. Ultrafast digital holography and spatio-temporal metrology 23. From a conventional digital holography to wide-sense digital holography 24. Building functional 3D waveguide microstructures with nonlinear waves of light References

This is the first section of the review-tutorial paper describing fundamentals of tissue optics and photonics mostly devoted to biological tissue structures and their specificity related to light interactions at its propagation in tissues. The next sections of the paper will describe light-tissue interactions caused by tissue dispersion, scattering, and absorption properties, including light reflection and refraction, absorption, elastic quasi-elastic and inelastic scattering. The major tissue absorbers and types of elastic scattering, including Rayleigh and Mie scattering, will be presented.

We have developed a method of terahertz (THz) solid immersion (SI) 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 the THz 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, which is beyond the Abbe diffraction limit and represents a considerable improvement over the previously-reported arrangements of SI imaging setups. The proposed technique does not involve any sub-wavelength near-field probes and diaphragms, thus, avoiding the THz beam attenuation due to such elements. We have applied the developed method for THz imaging of various soft tissues: a plant leaf blade, cell spheroids, and tissues of the breast ex vivo. Our THz images clearly reveal sub-wavelength features in tissues, therefore, promising applications of THz SI microscopy in biology and medicine.

A review of specific features and methods of optical clearing and related interaction of light with biotissues is presented. Physical and molecular mechanisms of immersion, compression, and photodynamic/photothermal optical clearing of some fibrous and cellular biotissues are discussed. The possibility of efficient control of the biotissue optical properties, particularly, the reduction of light scattering in biotissues is demonstrated, which facilitates the increased efficiency of various optical visualisation methods (optical biopsy) used in medical purposes

This study is focused on the measurements of the refractive index of hemoglobin solutions in the visible/near-infrared (NIR) spectral range at room temperature for characteristic laser wavelengths: 480, 486, 546, 589, 644, 656, 680, 930, 1100, 1300, and 1550 nm. Measurements were performed using the multiwavelength Abbe refractometer. Aqua hemoglobin solutions of different concentrations obtained from human whole blood were investigated. The specific increment of refractive index on hemoglobin concentration and the Sellmeier coefficients were calculated.