Tissue Elasticity as a Diagnostic Marker of Molecular Mutations in Morphologically Heterogeneous Colorectal Cancer.

The presence of molecular mutations in colorectal cancer (CRC) is a decisive factor in selecting the most effective first-line therapy. However, molecular analysis is routinely performed only in a limited number of patients with remote metastases. We propose to use tissue stiffness as a marker of the presence of molecular mutations in CRC samples. For this purpose, we applied compression optical coherence elastography (C-OCE) to calculate stiffness values in regions corresponding to specific CRC morphological patterns (n = 54). In parallel to estimating stiffness, molecular analysis from the same zones was performed to establish their relationships. As a result, a high correlation between the presence of KRAS/NRAS/BRAF driver mutations and high stiffness values was revealed regardless of CRC morphological pattern type. Further, we proposed threshold stiffness values for label-free targeted detection of molecular alterations in CRC tissues: for KRAS, NRAS, or BRAF driver mutation-above 803 kPa (sensitivity-91%; specificity-80%; diagnostic accuracy-85%), and only for KRAS driver mutation-above 850 kPa (sensitivity-90%; specificity-88%; diagnostic accuracy-89%). To conclude, C-OCE estimation of tissue stiffness can be used as a clinical diagnostic tool for preliminary screening of genetic burden in CRC tissues.

Phase-Resolved Optical Coherence Elastography: An Insight into Tissue Displacement Estimation.

Robust methods to compute tissue displacements in optical coherence elastography (OCE) data are paramount, as they play a significant role in the accuracy of tissue elastic properties estimation. In this study, the accuracy of different phase estimators was evaluated on simulated OCE data, where the displacements can be accurately set, and on real data. Displacement (∆d) estimates were computed from (i) the original interferogram data (Δφori) and two phase-invariant mathematical manipulations of the interferogram: (ii) its first-order derivative (Δφd) and (iii) its integral (Δφint). We observed a dependence of the phase difference estimation accuracy on the initial depth location of the scatterer and the magnitude of the tissue displacement. However, by combining the three phase-difference estimates (Δdav), the error in phase difference estimation could be minimized. By using Δdav, the median root-mean-square error associated with displacement prediction in simulated OCE data was reduced by 85% and 70% in data with and without noise, respectively, in relation to the traditional estimate. Furthermore, a modest improvement in the minimum detectable displacement in real OCE data was also observed, particularly in data with low signal-to-noise ratios. The feasibility of using Δdav to estimate agarose phantoms' Young's modulus is illustrated.

Supershear surface waves reveal prestress and anisotropy of soft materials.

Surface waves play important roles in many fundamental and applied areas from seismic detection to material characterizations. Supershear surface waves with propagation speeds greater than bulk shear waves have recently been reported, but their properties are not well understood. Here we describe theoretical and experimental results on supershear surface waves in rubbery materials. We find that supershear surface waves can be supported in viscoelastic materials with no restriction on the shear quality factor. Interestingly, the effect of prestress on the speed of the supershear surface wave is opposite to that of the Rayleigh surface wave. Furthermore, anisotropy of material affects the supershear wave much more strongly than the Rayleigh surface wave. We offer heuristic interpretation as well as theoretical verification of our experimental observations. Our work points to the potential applications of supershear waves for characterizing the bulk mechanical properties of soft solid from the free surface.

Quantitative Evaluation of In Vivo Corneal Biomechanical Properties after SMILE and FLEx Surgery by Acoustic Radiation Force Optical Coherence Elastography.

The purpose of this study is to quantitatively evaluate the differences in corneal biomechanics after SMILE and FLEx surgery using an acoustic radiation force optical coherence elastography system (ARF-OCE) and to analyze the effect of the corneal cap on the integrity of corneal biomechanical properties. A custom ring array ultrasound transducer is used to excite corneal tissue to produce Lamb waves. Depth-resolved elastic modulus images of the in vivo cornea after refractive surgery were obtained based on the phase velocity of the Lamb wave. After refractive surgery, the average elastic modulus of the corneal flap decreased (71.7 ± 24.6 kPa), while the elastic modulus of the corneal cap increased (219.5 ± 54.9 kPa). The average elastic modulus of residual stromal bed (RSB) was increased after surgery, and the value after FLEx (305.8 ± 48.5 kPa) was significantly higher than that of SMILE (221.3 ± 43.2 kPa). Compared with FLEx, SMILE preserved most of the anterior stroma with less change in corneal biomechanics, which indicated that SMILE has an advantage in preserving the integrity of the corneal biomechanical properties. Therefore, the biomechanical properties of the cornea obtained by the ARF-OCE system may be one of the essential indicators for evaluating the safety of refractive surgery.

Viscosity monitoring during hemodiluted blood coagulation using optical coherence elastography.

Rapid and accurate clot diagnostic systems are needed for the assessment of hemodiluted blood coagulation. We develop a real-time optical coherence elastography (OCE) system, which measures the attenuation coefficient of a compressional wave induced by a piezoelectric transducer (PZT) in a drop of blood using optical coherence tomography (OCT), for the determination of viscous properties during the dynamic whole blood coagulation process. Changes in the viscous properties increase the attenuation coefficient of the sample. Consequently, dynamic blood coagulation status can be monitored by relating changes of the attenuation coefficient to clinically relevant coagulation metrics, including the initial coagulation time and the clot formation rate. This system was used to characterize the influence of activator kaolin and the influence of hemodilution with either NaCl 0.9% or hydroxyethyl starch (HES) 6% on blood coagulation. The results show that PZT-OCE is sensitive to coagulation abnormalities and is able to characterize blood coagulation status based on viscosity-related attenuation coefficient measurements. PZT-OCE can be used for point-of-care testing for diagnosis of coagulation disorders and monitoring of therapies.

Can We Improve Vaginal Tissue Healing Using Customized Devices: 3D Printing and Biomechanical Changes in Vaginal Tissue.

BACKGROUND: Determining biomechanical changes in vaginal tissue with tissue stretch is critical for understanding the role of mechanotransduction on vaginal tissue healing. Noncontact dynamic optical coherence elastography (OCE) can quantify biomechanical changes in vaginal tissues noninvasively. Improved vaginal tissue healing will reduce postoperative complications from vaginal surgery. AIMS: (1) To complete dimensional assessments (DAs) of the vaginal tract. (2) To elucidate biomechanical properties (BMP) of porcine vaginal tissues (PVT). (3) Compare BMPs of piglet and adult PVTs after placement of customized vaginal dilators (VD) by OCE and uniaxial mechanical testing (MT). METHODS: Pilot study using adult nulliparous pig and piglet PVTs (n = 20 each). DA of PVTs was performed using silicone molding. 3D-printed VDs were used to achieve different Relative Diameter Change (RDC) of the PVTs (no dilatation, and -50%, 0%, 50% RDC). Elastographic testing using OCE and MT. RESULTS: Using OCE, no significant differences (SD) were noted between adult and piglet PVT (p = 0.74) or by stretch direction (p = 0.300). SD was noted with increasing RDC (p = 0.023). Using MT, there were SD in tissue stiffness between adult and piglet PVT (p = 0.048), but no SD as a function of RDC (p = 0.750) or stretch direction (p = 0.592). CONCLUSIONS: This study quantified biomechanical changes in PVT with customized stretching by 3D printed VD using both OCE and MT. This work has implications for the mechanotransduction of vaginal wound healing and noninvasive assessment of vaginal diseases.

Noncontact Elastic Wave Imaging Optical Coherence Elastography for Evaluating Changes in Corneal Elasticity Due to Crosslinking.

The mechanical properties of tissues can provide valuable information about tissue integrity and health and can assist in detecting and monitoring the progression of diseases such as keratoconus. Optical coherence elastography (OCE) is a rapidly emerging technique, which can assess localized mechanical contrast in tissues with micrometer spatial resolution. In this work we present a noncontact method of optical coherence elastography to evaluate the changes in the mechanical properties of the cornea after UV-induced collagen cross-linking. A focused air-pulse induced a low amplitude (µm scale) elastic wave, which then propagated radially and was imaged in three dimensions by a phase-stabilized swept source optical coherence tomography (PhS-SSOCT) system. The elastic wave velocity was translated to Young's modulus in agar phantoms of various concentrations. Additionally, the speed of the elastic wave significantly changed in porcine cornea before and after UV-induced corneal collagen cross-linking (CXL). Moreover, different layers of the cornea, such as the anterior stroma, posterior stroma, and inner region, could be discerned from the phase velocities of the elastic wave. Therefore, because of noncontact excitation and imaging, this method may be useful for in vivo detection of ocular diseases such as keratoconus and evaluation of therapeutic interventions such as CXL.

Magnetomotive Optical Coherence Elastography for Magnetic Hyperthermia Dosimetry Based on Dynamic Tissue Biomechanics.

Magnetic nanoparticles (MNPs) have been used in many diagnostic and therapeutic biomedical applications over the past few decades to enhance imaging contrast, steer drugs to targets, and treat tumors via hyperthermia. Optical coherence tomography (OCT) is an optical biomedical imaging modality that relies on the detection of backscattered light to generate high-resolution cross-sectional images of biological tissue. MNPs have been utilized as imaging contrast and perturbative mechanical agents in OCT in techniques called magnetomotive OCT (MM-OCT) and magnetomotive elastography (MM-OCE), respectively. MNPs have also been independently used for magnetic hyperthermia treatments, enabling therapeutic functions such as killing tumor cells. It is well known that the localized tissue heating during hyperthermia treatments result in a change in the biomechanical properties of the tissue. Therefore, we propose a novel dosimetric technique for hyperthermia treatment based on the viscoelasticity change detected by MM-OCE, further enabling the theranostic function of MNPs. In this paper, we first review the basic principles and applications of MM-OCT, MM-OCE, and magnetic hyperthermia, and present new preliminary results supporting the concept of MM-OCE-based hyperthermia dosimetry.

Two-dimensional elastic distribution imaging of the sclera using acoustic radiation force optical coherence elastography.

The scleral elasticity is closely related with many ocular diseases, but the relevant research is still insufficient. Here, we utilized optical coherence elastography to carefully study biomechanical properties of the sclera at different positions and under different intraocular pressures. Meanwhile, elastic wave velocity and Young's modulus of each position were obtained using a phase velocity algorithm. Accordingly, the two-dimensional elasticity distribution image was achieved by mapping the Young's modulus values to the corresponding structure based on the relationship between the position and its Young's modulus. Therefore, elastic information in regions-of-interest can be read and compared directly from the scleral structure, indicating that our method may be a very useful tool to evaluate the elasticity of sclera and provide intuitive and reliable proof for diagnosis and research.

Simultaneous tensile and shear measurement of the human cornea in vivo using S0- and A0-wave optical coherence elastography.

Understanding corneal stiffness is valuable for improving refractive surgery, detecting corneal abnormalities, and assessing intraocular pressure. However, accurately measuring the elastic properties, specifically the tensile and shear moduli that govern mechanical deformation, has been challenging. To tackle this issue, we have developed guided-wave optical coherence elastography that can simultaneously excite and analyze symmetric (S0) and anti-symmetric (A0) elastic waves in the cornea at around 10 kHz frequencies, enabling us to extract tensile and shear properties from measured wave dispersion curves. We verified the technique using elastomer phantoms and ex vivo porcine corneas and investigated the dependence on intraocular pressure using acoustoelastic theory that incorporates corneal tension and a nonlinear constitutive tissue model. In a pilot study involving six healthy human subjects aged 31 to 62, we measured shear moduli (Gzx) of 94±20 kPa (mean±standard deviation) and tensile moduli (Exx) of 4.0±1.1 MPa at central corneas. Our preliminary analysis of age-dependence revealed contrasting trends: -8.3±4.5 kPa/decade for shear and 0.30±0.21 MPa/decade for tensile modulus. This OCE technique has the potential to become a highly useful clinical tool for the quantitative biomechanical assessment of the cornea. STATEMENT OF SIGNIFICANCE: This article reports an innovative elastography technique using two guided elastic waves, demonstrating the measurement of both tensile and shear moduli in human cornea in vivo with unprecedented precision. This technique paves the way for comprehensive investigations into corneal mechanics and holds clinical significance in various aspects of corneal health and disease management.

Optical coherence elastography measures the biomechanical properties of the ex vivo porcine cornea after LASIK.

Significance: The biomechanical impact of refractive surgery has long been an area of investigation. Changes to the cornea structure cause alterations to its mechanical integrity, but few studies have examined its specific mechanical impact. Aim: To quantify how the biomechanical properties of the cornea are altered by laser assisted in situ keratomileusis (LASIK) using optical coherence elastography (OCE) in ex vivo porcine corneas. Approach: Three OCE techniques, wave-based air-coupled ultrasound (ACUS) OCE, heartbeat (Hb) OCE, and compression OCE were used to measure the mechanical properties of paired porcine corneas, where one eye of the pair was left untreated, and the fellow eye underwent LASIK. Changes in stiffness as a function of intraocular pressure (IOP) before and after LASIK were measured using each technique. Results: ACUS-OCE showed that corneal stiffness changed as a function of IOP for both the untreated and the treated groups. The elastic wave speed after LASIK was lower than before LASIK. Hb-OCE and compression OCE showed regional changes in corneal strain after LASIK, where the absolute strain difference between the cornea anterior and posterior increased after LASIK. Conclusions: The results of this study suggest that LASIK may soften the cornea and that these changes are largely localized to the region where the surgery was performed.

Spatial mapping of corneal biomechanical properties using wave-based optical coherence elastography.

Quantifying the mechanical properties of the cornea can provide valuable insights into the occurrence and progression of keratoconus, as well as the effectiveness of corneal crosslinking surgery. This study presents a non-contact and non-invasive wave-based optical coherence elastography system that utilizes air-pulse stimulation to create a two-dimensional map of corneal elasticity. Homogeneous and dual concentration phantoms were measured with the sampling of 25 × 25 points over a 6.6 × 6.6 mm2 area, to verify the measurement capability for elastic mapping and the spatial resolution (0.91 mm). The velocity of elastic waves distribution of porcine corneas before and after corneal crosslinking surgery were further mapped, showing a significant change in biomechanics in crosslinked region. This system features non-invasiveness and high resolution, holding great potential for application in ophthalmic clinics.

Motion-artifact-free single shot two-beam optical coherence elastography system.

Significance: The assessment of the biomechanical properties of the skin using various imaging techniques has been used as a diagnostic tool in dermatology. Optical coherence elastography (OCE) is one of the techniques that allows for the measurement of elastic properties. OCE relies on measuring tissue displacements induced by external sources. Measuring the tissue's mechanical properties in vivo using OCE is often challenging due to bulk tissue movement. Aim: This study aimed to develop an OCE system that allows for minimizing the effects of bulk tissue movements. To achieve this, we designed a two-beam OCE system that simultaneously measures the tissue displacement at two locations on the sample. This allows for cancelling the effect of the tissue bulk movement, which is common to both measurement points. Approach: We used a piezoelectric transducer to generate surface acoustic waves (SAW) in the sample. The velocity of the excited waves, which is proportional to the rigidity of the sample, was measured by calculating the phase delay of the SAW at two locations on the sample. Simultaneous measurement at two locations was achieved by dividing a single light beam into two by focusing on the sample at two different locations. The two beams travel different optical path lengths, and the reflected signals were depth encoded in a single optical coherence tomography scan using a single reference beam. Results: The system was characterized using different tissue-mimicking phantoms and the skin of healthy volunteers at the wrist and the palm. We achieved an approximately 50-fold increase in phase sensitivity measurement. Conclusions: We designed a simple two-beam OCE system that effectively minimizes the effect of tissue movement. We believe that the presented system will find immediate applications in the clinic to monitor the progression of systemic sclerosis disease.

Dynamic optical coherence elastography for skin burn assessment: A preliminary study on mice model.

Skin burns that include tissue coagulation necrosis imply variations in stiffness. Dynamic phase-sensitive optical coherence elastography (OCE) is used to evaluate the stiffness of burned skin nondestructively in this paper. The homemade dynamic OCE was initially verified through tissue-mimicking phantom experiments regarding Rayleigh wave speed. After being burned with a series of temperatures and durations, the corresponding structure and stiffness variations of mice skin were demonstrated by histological images, optical coherence tomography B-scans, and OCE elastic wave speed maps. The results clearly displayed the variation in elastic properties and stiffness of the scab edge extending in the lateral direction. Statistical analysis revealed that murine skin burned at temperatures exceeding 100°C typically exhibited greater stiffness than skin burned at temperatures below 100°C. The dynamic OCE technique shows potential application for incorporating elasticity properties as a biomechanical extension module to diagnose skin burn injuries.

Acute alcohol consumption modulates corneal biomechanical properties as revealed by optical coherence elastography.

Acute alcohol ingestion has been found to impact visual functions, including eye movement, but its effects on corneal biomechanical properties remain unclear. This study aimed to investigate the influence of acute alcohol consumption on corneal biomechanical properties using optical coherence elastography (OCE). An air-coupled ultrasound transducer induced elastic waves in mice corneas in vivo, and a high-resolution phase-sensitive optical coherence tomography (OCT) system tracked the mechanical waves to quantify the elastic wave speed. In vivo measurements were performed on three groups of age- and gender-matched mice: control, placebo (administered saline), and alcohol (administered ethanol) groups. Longitudinal measurements were conducted over a one-hour period to assess acute temporal changes in wave speeds, which are associated with inherent biomechanical properties of the cornea. The results showed a significant decrease in wave speed for the alcohol group after 10 min of ingestion in comparison to pre-ingestion values (p = 0.0096), whereas the temporal wave speed changes for the placebo group were statistically insignificant (p = 0.076). In contrast, the control group showed no significant changes in elastic wave speed and corneal thickness. Furthermore, a significant difference was observed between the wave speeds of the placebo and alcohol groups at each measurement time point between 10 and 50 min (p < 0.05), though both groups exhibited a similar trend in corneal thickness change. The findings of this study have important implications for clinical assessments and research in corneal disorders, highlighting the potential of OCE as a valuable tool for evaluating such changes.

Quantitative assessment of corneal elasticity distribution after FS-LASIK using optical coherence elastography.

Quantifying corneal elasticity after femtosecond laser-assisted in situ keratomileusis (FS-LASIK) procedure plays an important role in improving surgical safety and quality, since some latent complications may occur ascribing to changes in postoperative corneal biomechanics. Nevertheless, it is suggested that current research has been severely constrained due to the lack of an accurate quantification method to obtain postoperative corneal elasticity distribution. In this paper, an acoustic radiation force optical coherence elastography system combined with the improved phase velocity algorithm was utilized to realize elasticity distribution images of the in vivo rabbit cornea after FS-LASIK under various intraocular pressure levels. As a result, elasticity variations within and between the regions of interest could be identified precisely. This is the first time that elasticity imaging of in vivo cornea after FS-LASIK surgery was demonstrated, and the results suggested that this technology may hold promise in further exploring corneal biomechanical properties after refractive surgery.

High-accuracy optical coherence elastography digital volume correlation methods to measure depth regions with low correlation.

The decreasing correlation of optical coherence tomography (OCT) images with depth is an unavoidable problem for the depth measurement of the digital volume correlation (DVC) based optical coherence elastography (OCE) method. We propose an OCE-DVC method to characterize biological tissue deformation in deeper regions. The method proposes a strategy based on reliability layer guided displacement tracking to achieve the OCE-DVC method for the deformation measurement in deep regions of OCT images. Parallel computing solves the computational burden associated with the OCE-DVC method. The layer-by-layer adaptive data reading methods are used to guarantee the parallel computing of high-resolution OCT images. The proposed method shown in this study nearly doubles the depth of quantitative characterization of displacement and strain. At this depth, the standard deviation of displacement and strain measurements is reduced by nearly 78%. Under nonuniform deformation field, OCE-DVC method tracked the displacement with large strain gradient in depth region.

Storage-induced mechanical changes of porcine lenses assessed with optical coherence elastography and inverse finite element modeling.

Introduction: In an effort of gaining a better understanding of the lens mechanics, ex vivo lenses samples are often used. Yet, ex vivo tissue might undergo important postmortem changes depending on the unavoidable preservation method employed. The purpose of this study was to assess how various storage conditions and the removal of the lens capsule affect the mechanical properties of ex vivo porcine lens samples. Methods: A total of 81 freshly enucleated porcine eyes were obtained and divided into six groups and preserved differently. In the first three groups, the lens within the intact eye was preserved for 24 h by: (i) freezing at -80°C (n = 12), (ii) freezing at -20°C (n = 12), and (iii) refrigeration at +8°C (n = 12). In the remaining groups, the lenses were immediately extracted and treated as follows: (iv) kept intact, no storage (n = 12), (v) decapsulated, no storage (n = 21), and (vi) immersed in Minimum Essential Medium (MEM) at +8°C (n = 12) for 24 h. Frozen lenses were thawed at room temperature. Each lens was compressed between two glass lamella and subjected, first to a period of relaxation during which the compression force was recorded and second to an oscillating micro-compression while the deformation was recorded with a total of 256 subsequent B-scans via optical coherence tomography. The corresponding axial strain was retrieved via phase-sensitive image processing and subsequently used as input for an inverse finite element analysis (iFEA) to retrieve the visco-hyperelastic material properties of the lenses. Results: After freezing at temperatures of -80°C and -20°C, the cortical strains increased by 14% (p = 0.01) and 34% (p < 0.001), and the nuclear strains decreased by 17% (p = 0.014) and 36% (p < 0.001), compared to the lenses tested immediately after postmortem, respectively. According to iFEA, this resulted from an increased ratio of the nuclear: cortical E-modulus (4.06 and 7.06) in -80°C and -20°C frozen lenses compared to fresh lenses (3.3). Decapsulation had the largest effect on the material constant C10, showing an increase both in the nucleus and cortex. Preservation of the intact eye in the refrigerator induced the least mechanical alterations in the lens, compared to the intact fresh condition. Discussion: Combining iFEA with optical coherence elastography allowed us to identify important changes in the lens mechanics induced after different preserving ex vivo methods.

Optical coherence elastography with osmotically induced strains: Preliminary demonstration for express detection of cartilage degradation.

Optical coherence elastography (OCE) demonstrated impressive abilities for diagnosing tissue types/states using differences in their biomechanics. Usually, OCE visualizes tissue deformation induced by some additional stimulus (e.g., contact compression or auxiliary elastic-wave excitation). We propose a new variant of OCE with osmotically induced straining (OIS-OCE) and demonstrate its application to assess various stages of proteoglycan content degradation in cartilage. The information-bearing signatures in OIS-OCE are the magnitude and rate of strains caused by the application of osmotically active solutions onto the sample surface. OCE examination of the induced strains does not require special tissue preparation, the osmotic stimulation is highly reproducible, and strains are observed in noncontact mode. Several minutes suffice to obtain a conclusion. These features are promising for intraoperative method usage when express assessment of tissue state is required during surgical operations. The "waterfall" images demonstrate the development of cumulative osmotic strains in control and degraded cartilage samples.

Noncontact elasticity measurement of hydrogels in a culture dish using reverberant optical coherence elastography.

Estimating the elasticity of hydrogel phantoms in a cell culture plane is important for understanding the cell behavior in response to various types of mechanical stimuli. Hence, a noncontact tool for measuring the elastic properties of hydrogel phantoms in such three-dimensional cell cultures is required. A well-known method to determine the mechanical properties of hydrogels is the transient wave method. However, due to the multiple reflections of waves from the boundaries, a bigger cell culture plane or multiple directional filters may be required. In this study, we utilized reverberant shear wave elastography, which is based on the autocorrelation principle, to evaluate the shear wave speed in hydrogel samples within a culture dish. Numerical simulations were performed first to confirm the validity of the reverberant elastography method. Subsequently, we used this method to measure the wave speeds in hydrogel phantoms with different concentrations. Shear rheology tests were also performed, and their results were found to be in good agreement with the measured shear wave speeds. The proposed method could be useful for measuring the elasticity of tissues in tissue engineering applications in an inexpensive and noncontact manner.