Methods for estimating stiffness characteristics (i.e., shear modulus of elasticity or Young's modulus) have attracted the attention of researchers for several decades due to the very high sensitivity of these mechanical characteristics to the morphological structure and state of biological tissues. The possibilities of using measurements of these elastic moduli for biomedical diagnostics have been discussed since the 1970s, when the term elastogram itself was introduced [1]. However, at that time, these measurements were carried out on isolated samples of biological tissue using mechanical devices similar to those used in materials science (i.e., averaging over the sample volume at least several tens or even hundreds of cubic millimeters), so that such elastographic methods are widely used for biomedical purposes were not received. Nevertheless, important data were obtained demonstrating that the shear moduli G and Young E (in soft biological tissues related as E=3*G) can vary many times not only for different tissues, but also for one type of tissue, depending on her condition (normal or pathological). Below, for brevity, the term "rigidity" will be used, since it is fabrics with increased values of shear and Young's moduli that are subjectively perceived as more "rigid".

This conclusion about the wide variability of the stiffness properties of biological tissues contrasts sharply with the fact that the volumetric compression modulus, which determines the propagation velocity of ultrasound in biological tissues, varies very little (by a few percent) in the same soft biological tissues and is determined mainly by the volumetric compression modulus of the saturating these tissues are water. It is precisely because of such a high sensitivity of the stiffness of biological tissues to its structure and state (i.e., potentially high information content for biomedical conclusions) that the methods for its assessment, which have received the general name "elastography", are of great interest. In Russia, the pioneering work of A. Sarvazyan [2] can be noted in this direction.

A kind of boom in interest in the development of elastography has taken place since the 1990s, when principles were proposed for assessing the stiffness of biological tissues in a non-invasive manner using ultrasonic waves. Although the speed of ultrasound itself practically does not depend (more precisely, it depends very weakly) on the magnitude of the shear modulus, ultrasonic waves can be used as a tool for visualizing the auxiliary deformation produced in the biological tissue (by analyzing which, one can draw conclusions about the stiffness properties of the biological tissue) [3] . Also, focused ultrasound can be used to excite shear waves (and visualize their propagation), and the speed of shear waves already directly provides information on the magnitude of the shear modulus [2, 4].

As a result of the active work of many groups in the world, by the end of the 1990s. ultrasonic scanners with the function of elastography were created and brought to the market in the 2000s, i.e. providing the possibility of non-invasive evaluation of the stiffness properties of biological tissues. Along with this, similar principles have been implemented on the basis of MRI imaging methods. Appropriate devices are available on the medical market and have become actively used in the clinic, especially in oncology, since tumors usually have significantly increased rigidity compared to normal tissues [5].

In parallel with these works, optical coherence tomography was created in the 1990s, which gives structural images similar in appearance to ultrasound, but with a significantly higher spatial resolution (up to a few microns), although at smaller spatial scales (of the order of 1-2 mm in depth). and several mm in the lateral direction, and this size can be increased to tens of millimeters by "stitching" several OCT images).

In 1998, Schmitt [6] proposed the idea of transferring elastographic principles to OCT to implement high-resolution mapping of deformations and elastic properties of biological tissues. After that, over the next 20 years, various grappas in the world carried out active research on (ed.) the implementation of Optical Coherent Elastography (OCE). In this area, they initially began to try to apply approaches similar to those used in medical ultrasound, among which two main directions can be distinguished - a wave approach based on the use of OCT imaging of the propagation of auxiliary shear or surface waves to estimate the shear modulus (because the speed of these waves determined by the shear modulus), as well as a quasi-static approach based on mapping the auxiliary created deformations of the biological tissue ("compression" approach) and obtaining conclusions about the distribution of the Young's modulus of the biological tissue based on the distribution of deformations. Despite the apparent simplicity of the compression option proposed for use in OCT by Schmitt [6], its implementation turned out to be far from trivial due to a number of features of OCT scans (their high sensitivity to medium deformation, which causes blinking and “boiling” of speckles on OCT scans) , as a result of which the implementation of the wave approach, which has been actively used in recent years in a number of groups in the world, turned out to be simpler. The wave approach can be implemented non-contact, which has made it attractive for use in ophthalmology, in particular for the control of corneal strengthening procedures by "stitching" (i.e. cross-linking with auxiliary ultraviolet irradiation) collagen in the cornea in patients suffering from keratoconus.

One of the leaders in the development of wave OCT elastography is the group of prof. Larina from the University of Texas at Houston. In other areas of application, the wave approach turned out to be not so convenient, in particular, its application is problematic for studying tissues that are not as homogeneous as the cornea. In addition, this approach studies the tissue response to very low-amplitude wave actions, and obtaining nonlinear stress-strain curves is extremely difficult and, in fact, has not even been discussed in the wave approach yet, although the nonlinear nature of deformation for biological tissues is the rule, not the exception. (even with seemingly small deformations of the order of a percent). At the same time, such a nonlinear behavior can both strongly distort the estimate of the elastic modulus and provide additional information that can be very useful for diagnostic purposes. Looking ahead, it can be noted that in the compression approach, this information can be obtained in a natural way.

The compression approach, however, turned out to be more difficult to implement, so that practically useful demonstrations of it have been obtained only in the last 3-5 years. Moreover, breakthrough results were obtained not on the basis of correlation tracking of scatterer displacements, as was originally assumed (by analogy with medical ultrasound and correlation analysis of photographs for mapping deformations in engineering applications), but on the basis of phase principles (see, for example, review [7] from University of Western Australia - UWA). A detailed analysis of the reasons for this situation was carried out in the works of the staff of the IAP RAS [8, 9, 10]. At the same time, IAP RAS developed original, yet unparalleled in many respects methods for mapping local deformations, so that at present the world's leading groups in the development of compression tomography are groups from UWA and IAP RAS. For example, examples of deformation mapping that have no analogues so far are presented in recent works [11, 12], where deformations and changes in the structure and stiffness properties of the cornea and cartilage were studied on the basis of new elastographic capabilities of OCT under their moderate heating under infrared laser irradiation (these tissues are avascular collagen tissues in composition and exhibit many common properties). Here one can also note the obtaining of nonlinear stress-strain curves [13,14,15] based on advanced methods developed at the IAP RAS.

A variant of compression elastography developed at UWA is beginning to be used in preclinical and clinical studies, primarily to control the margins of breast cancer resection, and in the future - intraoperatively [16,17]. At the same time, the specificity of the UWA results is the construction, first of all, of planar C-scans (i.e., lateral in two coordinates) based on synthesis from a set of B-scans (i.e., depth cuts). At the same time, however, no attention is paid to the non-linear properties of the tissue, which in such variants of the OCE examination cannot be effectively investigated, but can significantly distort the results of the elastographic examination if they are not taken into account.

1. Sapuntsov, L. E., S. I. Mitrofanova, and T. V. Savchenko. "The use of elastography to assess the rheologic properties of the soft tissues of the human limb with normal and disturbed peripheral lymphatic circulation." Bulletin of Experimental Biology and Medicine 88.6: 1501-1503 (1979)

2. AP Sarvazyan, OV Rudenko, SD Swanson, JB Fowlkes, SY Emelianov, Shear wave elasticity imaging: a new ultrasonic technology of medical diagnostics Ultrasound in medicine & biology 24 (9), 1419-1435, (1998)

3. Ophir J, Cespedes I, Ponnekanti H, Yazdi Y, Li X. Elastography: a quantitative method for imaging the elasticity of biological tissues. Ultrason. Imaging. ;13:111–134 (1991).

4. Bercoff J, Tanter M., Fink M. Supersonic shear imaging: a new technique for soft tissue elasticity mapping. IEEE transactions on ultrasonics, ferroelectrics, and frequency control. 2004;51(4):396-409. DOI: 10.1109/TUFFC.2004.1295425

5. Parker KJ, Doyley MM, Rubens DJ. Imaging the elastic properties of tissue: the 20 year perspective. Phys. Med. Biol. 2011;56(1):R1–R29. DOI: 10.1088/0031-9155/57/16/5359

6. J. Schmitt, “OCT elastography: imaging microscopic deformation and strain of tissue.,” Opt. Express, vol. 3, no. 6, pp. 199–211, (1998).

7. SciRep2015 Kennedy

8. V. Y. Zaitsev, V. M. Gelikonov, L. A. Matveev, G. V. Gelikonov, A. L. Matveyev, P. A. Shilyagin, and I. A. Vitkin, “Recent trends in multimodal optical coherence tomography. I. Polarization-sensitive oct and conventional approaches to OCT elastography,” Radiophys. Quantum Electron., vol. 57, no. 1, (2014).

9. V. Y. Zaitsev, I. a. Vitkin, L. a. Matveev, V. M. Gelikonov, a. L. Matveyev, and G. V. Gelikonov, “Recent Trends in Multimodal Optical Coherence Tomography. II. The Correlation-Stability Approach in OCT Elastography and Methods for Visualization of Microcirculation,” Radiophys. Quantum Electron., vol. 57, no. 3, pp. 210–225, (2014).

10. V. Y. Zaitsev, A. L. Matveyev, L. A. Matveev, G. V. Gelikonov, A. A. Sovetsky, and A. Vitkin, “Optimized phase gradient measurements and phase-amplitude interplay in optical coherence elastography,” J. Biomed. Opt., vol. 21, no. 11, p. 116005, (2016).

11. V. Y. Zaitsev, A. L. Matveyev, L. A. Matveev, G. V. Gelikonov, A. I. Omelchenko, O. I. Baum, S. E. Avetisov, A. V. Bolshunov, V. I. Siplivy, D. V. Shabanov, A. Vitkin, and E. N. Sobol, “Optical coherence elastography for strain dynamics measurements in laser correction of cornea shape,” J. Biophotonics, vol. 10, no. 11, pp. 1450–1463, (2017).

12. V. Y. Zaitsev, A. L. Matveyev, L. A. Matveev, G. V. Gelikonov, O. I. Baum, A. I. Omelchenko, D. V Shabanov, A. A. Sovetsky, A. V Yuzhakov, A. A. Fedorov, V. I. Siplivy, A. V. Bolshunov, and E. N. Sobol, “Revealing structural modifications in thermomechanical reshaping of collagenous tissues using optical coherence elastography,” J. Biophotonics, vol. 12, no. 3, p. e201800250, (2019).

13. V. Y. Zaitsev, A.L. Matveyev, L. A. Matveev, E. V. Gubarkova, A. A. Sovetsky, M. A. Sirotkina, G. V. Gelikonov, E. V. Zagaynova, N. D. Gladkova, and A. Vitkin, “Practical obstacles and their mitigation strategies in compressional optical coherence elastography of biological tissues,” J. Innov. Opt. Health Sci., vol. 10, no. 6, p. 1742006, (2017).

14. A. L. Matveyev, L. A. Matveev, A. A. Sovetsky, G. V Gelikonov, A. A. Moiseev, and V. Y. Zaitsev, “Vector method for strain estimation in phase-sensitive optical coherence elastography,” Laser Phys. Lett., vol. 15, pp. 065603(1–6), (2018).

15. A. A. Sovetsky, A. L. Matveyev, L. A. Matveev, D. V Shabanov, and V. Y. Zaitsev, “Manually-operated compressional optical coherence elastography with effective aperiodic averaging : demonstrations for corneal and cartilaginous tissues,” Laser Phys. Lett., vol. 15, pp. 085602(1–8), (2018).

16. W. M. Allen, L. Chin, P. Wijesinghe, R. W. Kirk, B. Latham, D. D. Sampson, C. M. Saunders, and B. F. Kennedy, “Wide-field optical coherence micro-elastography for intraoperative assessment of human breast cancer margins,” Biomed. Opt. Express, vol. 7, no. 10, pp. 4139–4152, (2016).

17. L. Chin, B. Latham, C. M. Saunders, D. D. Sampson, and B. F. Kennedy, “Simplifying the assessment of human breast cancer by mapping a micro-scale heterogeneity index in optical coherence elastography,” J. Biophotonics 10(5), 690–700 (2017).

The project is a unique high-tech product, an optical coherence elastograph (OCE), which makes it possible to build elastographic maps in addition to structural images obtained by optical coherence tomography (OCT) scanners developed, assembled and sold in Russia by the only company BioMedTech LLC. Optical coherent elastographs have all the capabilities of OCT, one of the most modern and high-tech diagnostic methods that allows studying the structures of biological tissue with the resolution of individual groups of cells. Due to the high diagnostic contrast of elastograms, which is absent in structural OCT images, OCE can commercially go far beyond ophthalmology. Using the main advantages: micron resolution, speed of examination, compactness of equipment, safety for humans (a low-intensity light beam is used) and sensitivity to changes in the mechanical state of biological tissue and its various morphological components, the developed and created OKE in Nizhny Novgorod have already been tested in laboratory and clinical conditions, while in the world of OCE is at the stage of laboratory development.

The device is able to bring laboratory research and development of skin and oncological agents and preparations to a new level. In vivo morphological segmentation of TCEs, closely matching histology, can be used to investigate the efficacy of various drugs in mice and volunteers. By evaluating the effectiveness of anticancer drugs in the laboratory, RCE allows non-invasive monitoring of the state of cancer cells grown in the ears of mice at the stage of growth and treatment. Thus, the method can significantly reduce the number of required laboratory mice and improve the quality of studies.

Surgery, in which OCE can become an indispensable interoperative assistant to the surgeon in high-precision operations for brain cancer, breast cancer, and operations with autogenous implants, can become another new commercial direction in addition to laboratory research. The technology has been successfully tested on surgically extracted samples in the tasks of determining the quality of the margin of resection of breast cancer and brain cancer. Based on the statistics of 500 elastograms of 150 breast cancer samples, the program was trained for automatic morphological segmentation and automatic determination of the molecular type of cancer using the automatically obtained morphological composition. Interoperative OCE examination of autologous implants is able to control the quality of implant processing (operations using the pericardium as a heart valve, operations using costal cartilage to restore the structural integrity of the larynx).

High-resolution OCE scanning of the dermis and epidermis with visualization of their mechanical state opens up a new era after integral skin assessments using various indenter methods and vacuum cutometry. Conducted elastographic mapping of the skin of the hands of volunteers revealed age-related changes in skin stiffness, changes in stiffness under the action of various cosmetic products and procedures on the skin. Significant changes in firmness have been documented in studies of the immediate effect of moisturizer and alcohol and the residual effect after a course of treatments. The technology allows us to reach a new stage in the development of cosmetology, when the tasks of personification with an individual approach to each client come to the fore. While the market for the proposed cosmetic products and procedures is growing, there is a need for a method of operational in vivo diagnostics of the morphofunctional state of the skin in its individual layers. Preliminary observation would make it possible to determine the necessary effects on the skin, and dynamic observation of the skin condition during therapy would make it possible to control the course of treatment and increase the effectiveness of procedures by selecting individual parameters for the intensity and frequency of exposure, excluding the likelihood of complications.

The above applications are not the only ones, the list of potential applications is constantly being supplemented by us, during the participation in the Archipelago 2121, Medsi mentors recommended testing the device in the differentiation of cervical cancer in order to reduce the resection of normal tissue along with cancer. The range of new open and proven applications and the unique characteristics and technology give confidence and lay the foundation for entering the Russian and foreign markets. While other methods lack resolution, agility, or non-invasiveness for the tasks presented above, RCE can fill the laboratory needs already at the moment, with a future goal of becoming a certified medical device and entering medical practice.

List of recent articles:

1. VY Zaitsev, AL Matveyev, LA Matveev, AA Sovetsky, MS Hepburn, A Mowla, BF Kennedy, “Strain and elasticity imaging in compression optical coherence elastography: the two‐decade perspective and recent advances”, Journal of Biophotonics, e202000257 (2021);
2. AA Sovetsky , et al. “Full-optical method of local stress standardization to exclude nonlinearity-related ambiguity of elasticity estimation in compressional optical coherence elastography”, Laser Physics Letters 17(6) (2020);
3. AA Plekhanov , M A Sirotkina, A A Sovetsky et al. “Histological validation of in vivo assessment of cancer tissue inhomogeneity and automated morphological segmentation enabled by Optical Coherence Elastography” Scientific Reports, 10(1), 1-16 (2020);
4. YM Alexandrovskaya, O I Baum, A A Sovetsky, et al. “Observation of internal stress relaxation in laser-reshaped cartilaginous implants using OCT-based strain mapping”, Laser Physics Letters, 17(8), 085603 (2020);
5. MA Sirotkina, E V Gubarkova, A A Plekhanov, A A Sovetsky, et al. "In vivo assessment of functional and morphological alterations in tumors under treatment using OCT-angiography combined with OCT-elastography," Biomed. Opt. Express 11, 1365-1382 (2020);
6. Ekaterina V Gubarkova, Alexander A Sovetsky, Vladimir Yu Zaitsev, Alexander L Matveyev, Dmitry A Vorontsov, Marina A Sirotkina, Lev A Matveev, Anton A Plekhanov, Nadezhda P Pavlova, Sergei S Kuznetsov, Alexey Yu Vorontsov, Elena V Zagaynova, Natalia D Gladkova, “OCT-elastography-based optical biopsy for breast cancer delineation and express assessment of morphological/molecular subtypes” Biomedical optics express, 10(5), 2244-2263 (2019)