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.

Estimation of the full shape of the crystalline lens from OCT: validation using stretched donor lenses.

Quantifying human crystalline lens geometry as a function of age and accommodation is important for improved cataract and presbyopia treatments. In previous works we presented eigenlenses as a basis of 3-D functions to represent the full shape of the crystalline lens ex vivo. Also, we presented the application of eigenlenses to estimate the full shape of the lens in vivo from 3-D optical coherence tomography (OCT) images, where only the central part of the lens -visible through the pupil- is available. The current work presents a validation of the use of eigenlenses to estimate in vivo the full shape of dis-accommodated lenses. We used 14 ex vivo crystalline lenses from donor eyes (11-54 y/o) mounted in a lens stretcher, and measured the geometry and the power of the lenses using a combined OCT and ray tracing aberrometry system. Ex vivo, the full extent of the lens is accessible from OCT because the incident light is not blocked by the iris. We measured in non-stretched (fully accommodated) and stretched (mimicking in vivo dis-accommodated lenses) conditions. Then, we simulated computationally in vivo conditions on the obtained ex vivo lenses geometry (assuming that just the portion of the lens within a given pupil is available), and estimated the full shape using eigenlenses. The mean absolute error (MAE) between estimated and measured lens' diameters and volumes were MAE = 0.26 ± 0.18 mm and MAE = 7.0 ± 4.5 mm3, respectively. Furthermore, we concluded that the estimation error between measured and estimated lenses did not depend on the accommodative state (change in power due to stretching), and thus eigenlenses are also useful for the full shape estimation of in vivo dis-accommodated lenses.

Poster Session: Experimental assessment of scleral anisotropy using multi-meridian air-coupled ultrasonic optical coherence elastography.

Scleral biomechanics plays a key role in the understanding of myopia progression. In this study, we characterized the elastic properties of sclera using an air-coupled ultrasonic (ACUS) optical coherence elastography (OCE) system. New Zealand rabbit eyes (n=7) were measured (<24hr postmortem) in four scleral locations: superior/inferior temporal (ST, IT), and superior/inferior nasal (SN, IN) maintaining an intraocular pressure of 15 mmHg. Elastic waves were induced in the sclera, and wave propagation velocity and shear modulus were measured along two directions: circumferential (superior-inferior) and meridional (nasal-temporal). Wave velocity in scleral tissue ranged from 6 to 24 m/s and shear modulus from 11 to 150 kPa. Velocity was significantly higher (p<.001) in the circumferential vs. meridional directions in the following locations: ST:15.83±2.85 vs 9.43±1.68 m/s, IT:15.00±3.98 vs 8.93±1.53 m/s; SN:16.79±4.30 vs 9.27±1.47 m/s; and IN:13.92±3.85 vs 8.57±1.46 m/s. The average shear modulus in the circumferential was also significantly higher (p<.001) than in the meridional direction for all locations: 65.37±6.04 vs 22.55±1.36 kPa. These results show that the rabbit sclera is mechanically anisotropic with higher rigidity in the circumferential direction compared to the meridional direction. ACUS-OCE is a promising non-invasive method to quantify the biomechanical changes in scleral tissue for future studies involving myopia treatments.

Multiple Optical Elastography Techniques Reveal the Regulation of Corneal Stiffness by Collagen XII.

Purpose: Collagen XII plays a role in regulating the structure and mechanical properties of the cornea. In this work, several optical elastography techniques were used to investigate the effect of collagen XII deficiency on the stiffness of the murine cornea. Methods: A three-prong optical elastography approach was used to investigate the mechanical properties of the cornea. Brillouin microscopy, air-coupled ultrasonic optical coherence elastography (OCE) and heartbeat OCE were used to assess the mechanical properties of wild type (WT) and collagen XII-deficient (Col12a1-/-) murine corneas. The Brillouin frequency shift, elastic wave speed, and compressive strain were all measured as a function of intraocular pressure (IOP). Results: All three optical elastography modalities measured a significantly decreased stiffness in the Col12a1-/- compared to the WT (P < 0.01 for all three modalities). The optical coherence elastography techniques showed that mean stiffness increased as a function of IOP; however, Brillouin microscopy showed no discernable trend in Brillouin frequency shift as a function of IOP. Conclusions: Our approach suggests that the absence of collagen XII significantly softens the cornea. Although both optical coherence elastography techniques showed an expected increase in corneal stiffness as a function of IOP, Brillouin microscopy did not show such a relationship, suggesting that the Brillouin longitudinal modulus may not be affected by changes in IOP. Future work will focus on multimodal biomechanical models, evaluating the effects of other collagen types on corneal stiffness, and in vivo measurements.

In vivo assessment of corneal biomechanics under a localized cross-linking treatment using confocal air-coupled optical coherence elastography.

The localized application of the riboflavin/UV-A collagen cross-linking (UV-CXL) corneal treatment has been proposed to concentrate the stiffening process only in the compromised regions of the cornea by limiting the epithelium removal and irradiation area. However, current clinical screening devices dedicated to measuring corneal biomechanics cannot provide maps nor spatial-dependent changes of elasticity in corneas when treated locally with UV-CXL. In this study, we leverage our previously reported confocal air-coupled ultrasonic optical coherence elastography (ACUS-OCE) probe to study local changes of corneal elasticity in three cases: untreated, half-CXL-treated, and full-CXL-treated in vivo rabbit corneas (n = 8). We found a significant increase of the shear modulus in the half-treated (>450%) and full-treated (>650%) corneal regions when compared to the non-treated cases. Therefore, the ACUS-OCE technology possesses a great potential in detecting spatially-dependent mechanical properties of the cornea at multiple meridians and generating elastography maps that are clinically relevant for patient-specific treatment planning and monitoring of UV-CXL procedures.

Introduction to optical coherence elastography: tutorial.

Optical coherence elastography (OCE) has seen rapid growth since its introduction in 1998. The past few decades have seen tremendous advancements in the development of OCE technology and a wide range of applications, including the first clinical applications. This tutorial introduces the basics of solid mechanics, which form the foundation of all elastography methods. We then describe how OCE measurements of tissue motion can be used to quantify tissue biomechanical parameters. We also detail various types of excitation methods, imaging systems, acquisition schemes, and data processing algorithms and how various parameters associated with each step of OCE imaging can affect the final quantitation of biomechanical properties. Finally, we discuss the future of OCE, its potential, and the next steps required for OCE to become an established medical imaging technology.

Wave-based optical coherence elastography: The 10-year perspective.

After 10 years of progress and innovation, optical coherence elastography (OCE) based on the propagation of mechanical waves has become one of the major and the most studied OCE branches, producing a fundamental impact in the quantitative and nondestructive biomechanical characterization of tissues. Preceding previous progress made in ultrasound and magnetic resonance elastography; wave-based OCE has pushed to the limit the advance of three major pillars: (1) implementation of novel wave excitation methods in tissues, (2) understanding new types of mechanical waves in complex boundary conditions by proposing advance analytical and numerical models, and (3) the development of novel estimators capable of retrieving quantitative 2D/3D biomechanical information of tissues. This remarkable progress promoted a major advance in answering basic science questions and the improvement of medical disease diagnosis and treatment monitoring in several types of tissues leading, ultimately, to the first attempts of clinical trials and translational research aiming to have wave-based OCE working in clinical environments. This paper summarizes the fundamental up-to-date principles and categories of wave-based OCE, revises the timeline and the state-of-the-art techniques and applications lying in those categories, and concludes with a discussion on the current challenges and future directions, including clinical translation research.

Micro Air-Pulse Spatial Deformation Spreading Characterizes Degree of Anisotropy in Tissues.

In optical coherence elastography (OCE), air-pulse stimulation has been widely used to produce propagation of mechanical waves for elastic characterization of tissues. In this paper, we propose the use of spatial deformation spreading (SDS) on the surface of samples produced by air-pulse stimulation for the OCE of transverse isotropic tissues. Experiments in isotropic tissue-mimicking phantoms and anisotropic chicken tibialis muscle were conducted using a spectral-domain optical coherence tomography system synchronized with a confocal air-pulse stimulation. SDS measurements were compared with wave speeds values calculated at different propagation angles. We found an approximately linear relationship between shear wave speed and SDS in isotropic phantoms, which was confirmed with predictions made by the numerical integration of a wave propagation model. Experimental measurements in chicken muscle show a good agreement between SDS and surface wave speed taken along and across the axis of symmetry of the tissues, also called degree of anisotropy. In summary, these results demonstrated the capabilities of SDS produced by the air-pulse technique in measuring the shear elastic anisotropy of transverse isotropic tissues.

Repetitive optical coherence elastography measurements with blinking nanobombs.

Excitation of dye-loaded perfluorocarbon nanoparticles (nanobombs) can generate highly localized axially propagating longitudinal shear waves (LSW) that can be used to quantify tissue mechanical properties without transversal scanning of the imaging beam. In this study, we used repetitive excitations of dodecafluoropentane (C5) and tetradecafluorohexane (C6) nanobombs by a nanosecond-pulsed laser to produce multiple LSWs from a single spot in a phantom. A 1.5 MHz Fourier-domain mode-locked laser in combination with a phase correction algorithm was used to perform elastography. Multiple nanobomb activations were also monitored by detecting photoacoustic signals. Our results demonstrate that C6 nanobombs can be used for repetitive generation of LSW from a single spot for the purpose of material elasticity assessment. This study opens new avenues for continuous quantification of tissue mechanical properties using single delivery of the nanoparticles.

Confocal air-coupled ultrasonic optical coherence elastography probe for quantitative biomechanics.

We present an air-coupled ultrasonic radiation force probe co-focused with a phase-sensitive optical coherence tomography (OCT) system for quantitative wave-based elastography. A custom-made 1 MHz spherically focused piezoelectric transducer with a concentric 10 mm wide circular opening allowed for confocal micro-excitation of waves and phase-sensitive OCT imaging. Phantom studies demonstrated the capabilities of this probe to produce quasi-harmonic excitation up to 4 kHz for generation of elastic waves. Experimental results in ocular tissues showed highly detailed 2D and 3D elasticity mapping using this approach with great potential for clinical translation.

Dynamic Optical Coherence Elastography of the Anterior Eye: Understanding the Biomechanics of the Limbus.

Purpose: Currently, the biomechanical properties of the corneo-scleral limbus when the eye-globe deforms are largely unknown. The purpose of this study is to evaluate changes in elasticity of the cornea, sclera, and limbus when subjected to different intraocular pressures (IOP) using wave-based optical coherence elastography (OCE). Special attention was given to the elasticity changes of the limbal region with respect to the elasticity variations in the neighboring corneal and scleral regions. Methods: Continuous harmonic elastic waves (800 Hz) were mechanically induced in the sclera near the corneo-sclera limbus of in situ porcine eye-globes (n = 8). Wave propagation was imaged using a phase-sensitive optical coherence tomography system (PhS-OCT). The eyes were subjected to five different IOP-levels (10, 15, 20, 30, and 40 mm Hg), and spatially distributed propagation velocities were calculated along corneal, limbal, and scleral regions. Finite element analysis (FEA) of the same regions under the same excitation conditions were conducted for further validation of results. Results: FEA demonstrated that the stiffness of the heterogeneous cornea-limbus-sclera transition can be characterized by phase velocity measurements of the elastic waves produced at 800 Hz in the anterior eye. Experimental results revealed that the wave speed in the limbus (cL = 6.5 m/s) is between the cornea (cc = 2.9 m/s) and sclera (cs = 10.0 m/s) at a physiological IOP level (15 mm Hg) and rapidly increases as the IOP level is increased, even surpassing the wave speed in the sclera. Finally, the change in elastic wave speed in the limbus (ΔcL∼18.5 m/s) was greater than in the cornea (Δcc ∼12.6 m/s) and sclera (Δcs∼8.1 m/s) for the same change in IOP. Conclusions: We demonstrated that wave-based OCE can be utilized to assess limbus biomechanical properties. Moreover, experimental evidence showed that the corneo-scleral limbus is highly nonlinear compared to the cornea and sclera when the eye-globe is deformed by an increase of IOP. This may suggest that the limbus has enough structural flexibility to stabilize anterior eye shape during IOP changes.

Reverberant 3D optical coherence elastography maps the elasticity of individual corneal layers.

The elasticity mapping of individual layers in the cornea using non-destructive elastography techniques advances diagnosis and monitoring of ocular diseases and treatments in ophthalmology. However, transient Lamb waves, currently used in most dynamic optical coherence and ultrasound elastography techniques, diminish the translation of wave speed into shear/Young's modulus. Here, we present reverberant 3D optical coherence elastography (Rev3D-OCE), a novel approach leveraging the physical properties of diffuse fields in detecting elasticity gradients not only in the lateral direction, but also along the depth axis of the cornea. A Monte Carlo analysis, finite element simulations, and experiments in layered phantoms are conducted to validate the technique and to characterize the axial elastography resolution. Experiments in ex vivo porcine cornea at different intraocular pressures reveal that Rev3D-OCE enables the elastic characterization of single layers that matches the anatomical description of corneal layers with unprecedented contrast in the dynamic OCE field.

Longitudinal shear waves for elastic characterization of tissues in optical coherence elastography.

In dynamic optical coherence elastography (OCE), surface acoustic waves are the predominant perturbations. They constrain the quantification of elastic modulus to the direction of wave propagation only along the surface of tissues, and disregard elasticity gradients along depth. Longitudinal shear waves (LSW), on the other hand, can be generated at the surface of the tissue and propagate through depth with desirable properties for OCE: (1) LSW travel at the shear wave speed and can discriminate elasticity gradients along depth, and (2) the displacement of LSW is longitudinally polarized along the direction of propagation; therefore, it can be measured by a phase-sensitive optical coherence tomography system. In this study, we explore the capabilities of LSW generated by a circular glass plate in contact with a sample using numerical simulations and tissue-mimicking phantom experiments. Results demonstrate the potential of LSW in detecting an elasticity gradient along axial and lateral directions simultaneously. Finally, LSW are used for the elastography of ex vivo mouse brain and demonstrate important implications in in vivo and in situ measurements of local elasticity changes in brain and how they might correlate with the onset and progression of degenerative brain diseases.

Shear wave propagation in viscoelastic media: validation of an approximate forward model.

Many approaches to elastography incorporate shear waves; in some systems these are produced by acoustic radiation force (ARF) push pulses. Understanding the shape and decay of propagating shear waves in lossy tissues is key to obtaining accurate estimates of tissue properties, and so analytical models have been proposed. In this paper, we reconsider a previous analytical model with the goal of obtaining a computationally straightforward and efficient equation for the propagation of shear waves from a focal push pulse. Next, this model is compared with an experimental optical coherence tomography (OCT) system and with finite element models, in two viscoelastic materials that mimic tissue. We find that the three different cases-analytical model, finite element model, and experimental results-demonstrate reasonable agreement within the subtle differences present in their respective conditions. These results support the use of an efficient form of the Hankel transform for both lossless (elastic) and lossy (viscoelastic) media, and for both short (impulsive) and longer (extended) push pulses that can model a range of experimental conditions.

In vivo estimation of the Young's modulus in normal human dermis.

Skin elastic properties change during a cutaneous disorder or in the aging process. Deep knowledge of skin layers helps monitoring and diagnosing structural changes. High frequency ultrasound (HF-US) has been recently introduced to diagnose and evaluate some dermatological disorders in the clinical practice. US elastography adds elasticity information of the analyzed tissue. In particular, harmonic elastography estimates the speed of shear waves produced by external vibration sources, in order to relate the shear wave speed to the Young's modulus. In the epidermis and dermis layers, shear waves are not generated; in contrast, surface acoustic waves (SAWs) exist as they propagate in the top of the tissue. This study uses crawling wave sonoelastography for the estimation of SAWs in human thigh dermis in vivo. Experiments were performed in ten volunteers in the range of 200 - 500 Hz. As other studies suggest, SAW speed needs to be compensated to reach shear wave speed, for calculating the Young's modulus. Thus, the SAW speed estimated was corrected when it propagates in solidUS gel interface. Specifically, the elasticity modulus found was $18.35 \pm 1.04$ KPa for a vibration frequency of 200 Hz. Results suggest that the elasticity modulus can be estimated in vivo using crawling wave HF-US for skin application and shows potential for future application in skin disorders.

Measurement of surface acoustic waves in high-frequency ultrasound: Preliminary results.

Skin lesions change elastic properties near the surface. In the last decades, several non-invasive elastography techniques have been developed for detecting the mechanical properties of tissue. In particular, harmonic elastography is characterized for inducing shear wave propagation by an external vibrator in order to estimate shear modulus. However, near the boundary region, propagation is governed by surface acoustic waves (SAW). This paper combines crawling waves elastography with a high-frequency ultrasound (HFUS) system for the estimation of the SAW-to-shear compensation factor when ultrasound (US) gel is used as coupling interface. Experiments explore the SAWspeed in a homogeneous phantom with a solid-water interface in order to corroborate theoretical findings. Subsequently, experiments in a solid-US gel interface are conducted in order to find the correct compensation factor. Preliminary results suggest that SAW propagation can be detected using HFUS, and shear velocity maps can be generated by applying the estimated empirical correction factor. This study will potentially avoid the underestimation of shear modulus when using SAW-based HFUS elastography which is promising for the better diagnosis of skin diseases.

Comparative study of shear wave-based elastography techniques in optical coherence tomography.

We compare five optical coherence elastography techniques able to estimate the shear speed of waves generated by one and two sources of excitation. The first two techniques make use of one piezoelectric actuator in order to produce a continuous shear wave propagation or a tone-burst propagation (TBP) of 400 Hz over a gelatin tissue-mimicking phantom. The remaining techniques utilize a second actuator located on the opposite side of the region of interest in order to create three types of interference patterns: crawling waves, swept crawling waves, and standing waves, depending on the selection of the frequency difference between the two actuators. We evaluated accuracy, contrast to noise ratio, resolution, and acquisition time for each technique during experiments. Numerical simulations were also performed in order to support the experimental findings. Results suggest that in the presence of strong internal reflections, single source methods are more accurate and less variable when compared to the two-actuator methods. In particular, TBP reports the best performance with an accuracy error < 4.1 % . Finally, the TBP was tested in a fresh chicken tibialis anterior muscle with a localized thermally ablated lesion in order to evaluate its performance in biological tissue.

Reverberant shear wave fields and estimation of tissue properties.

The determination of shear wave speed is an important subject in the field of elastography, since elevated shear wave speeds can be directly linked to increased stiffness of tissues. MRI and ultrasound scanners are frequently used to detect shear waves and a variety of estimators are applied to calculate the underlying shear wave speed. The estimators can be relatively simple if plane wave behavior is assumed with a known direction of propagation. However, multiple reflections from organ boundaries and internal inhomogeneities and mode conversions can create a complicated field in time and space. Thus, we explore the mathematics of multiple component shear wave fields and derive the basic properties, from which efficient estimators can be obtained. We approach this problem from the historic perspective of reverberant fields, a conceptual framework used in architectural acoustics and related fields. The framework can be recast for the alternative case of shear waves in a bounded elastic media, and the expected value of displacement patterns in shear reverberant fields are derived, along with some practical estimators of shear wave speed. These are applied to finite element models and phantoms to illustrate the characteristics of reverberant fields and provide preliminary confirmation of the overall framework.

Crawling wave optical coherence elastography.

Elastography is a technique that measures and maps the local elastic property of biological tissues. Aiming for detection of micron-scale inclusions, various optical elastography, especially optical coherence elastography (OCE), techniques have been investigated over the past decade. The challenges of current optical elastography methods include the decrease in elastographic resolution as compared with its parent imaging resolution, the detection sensitivity and accuracy, and the cost of the overall system. Here we report for the first time, we believe, on an elastography technique-crawling wave optical coherence elastography (CRW-OCE)-which significantly lowers the requirements on the imaging speed and opens the path to high-resolution and high-sensitivity OCE at relatively low cost. Methods of crawling wave excitation, data acquisition, and crawling wave tracking are presented.

A 3D assessment tool for accurate volume measurement for monitoring the evolution of cutaneous leishmaniasis wounds.

Clinical assessment and outcome metrics are serious weaknesses identified on the systematic reviews of cutaneous Leishmaniasis wounds. Methods with high accuracy and low-variability are required to standarize study outcomes in clinical trials. This work presents a precise, complete and noncontact 3D assessment tool for monitoring the evolution of cutaneous Leishmaniasis (CL) wounds based on a 3D laser scanner and computer vision algorithms. A 3D mesh of the wound is obtained by a commercial 3D laser scanner. Then, a semi-automatic segmentation using active contours is performed to separate the ulcer from the healthy skin. Finally, metrics of volume, area, perimeter and depth are obtained from the mesh. Traditional manual 3D and 3D measurements are obtained as a gold standard. Experiments applied to phantoms and real CL wounds suggest that the proposed 3D assessment tool provides higher accuracy (error <2%) and precision rates (error <4%) than conventional manual methods (precision error < 35%). This 3D assessment tool provides high accuracy metrics which deserve more formal prospective study.