Accurate estimates of corneal mechanical properties may improve diagnosis and treatment of many ophthalmic conditions. Recently, we introduced a nearly incompressible transversely isotropic (NITI) model based on two independent shear moduli determining tensile and out-of-plane shear behavior. Here, we directly compare acoustic micro-tapping OCE (AμT-OCE) modulus estimates with those obtained from mechanical testing on ex-vivo porcine corneas. Both OCE and mechanical testing show tensile behavior governed by a Young’s modulus on the order of MPa and out-of-plane shear behavior by a modulus on the order of tens of kPa, suggesting strong anisotropy in the cornea.
In assuming an isotropic model for soft-tissue, dynamic OCE can produce order of magnitude errors in Young’s modulus estimates relative to static mechanical tests. Considering corneal fiber arrangement, we propose a simplified transverse isotropic (TI) model of the cornea, which depends on moduli λ and μ and the independent modulus G (which affects the propagation of vertically polarized surface waves, such as those measured in OCE). Early theoretical and experimental studies suggest that this TI model of the cornea may greatly improve quantitative estimates of corneal mechanics obtained using dynamic OCE.
This paper summarizes the latest results on acoustic micro-tapping (AμT) -based OCE and provides answers to several important questions related to dynamic elastography, including: what is the maximum spatial resolution that can be achieved in dynamic OCE? How should propagation speed be measured in soft tissue, especially in layered or bounded media? How can tissue elastic properties be properly reconstructed from experimental data? What is the potential for clinical translation, and what barriers remain?
Dynamic optical coherence elastography (OCE) tracks elastic wave propagation speed within tissue, enabling quantitative three-dimensional imaging of the elastic modulus. We show that propagating mechanical waves are mode converted at interfaces, creating a finite region on the order of an acoustic wavelength where there is not a simple one-to-one correspondence between wave speed and elastic modulus. Depending on the details of a boundary’s geometry and elasticity contrast, highly complex propagating fields produced near the boundary can substantially affect both the spatial resolution and contrast of the elasticity image. We demonstrate boundary effects on Rayleigh waves incident on a vertical boundary between media of different shear moduli. Lateral resolution is defined by the width of the transition zone between two media and is the limit at which a physical inclusion can be detected with full contrast. We experimentally demonstrate results using a spectral-domain OCT system on tissue-mimicking phantoms, which are replicated using numerical simulations. It is shown that the spatial resolution in dynamic OCE is determined by the temporal and spatial characteristics (i.e., bandwidth and spatial pulse width) of the propagating mechanical wave. Thus, mechanical resolution in dynamic OCE inherently differs from the optical resolution of the OCT imaging system.
Dynamic elastography is an attractive method to evaluate tissue biomechanical properties. Recently, it was extended from US- and MR-based modalities to optical ones, such as optical coherence tomography for three-dimensional (3-D) imaging of propagating mechanical waves in subsurface regions of soft tissues, such as the eye. The measured group velocity is often used to convert wave speed maps into 3-D images of the elastic modulus distribution based on the assumption of bulk shear waves. However, the specific geometry of OCE measurements in bounded materials such as the cornea and skin calls into question elasticity reconstruction assuming a simple relationship between group velocity and shear modulus. We show that in layered media the bulk shear wave assumption results in highly underestimated shear modulus reconstructions and significant structural artifacts in modulus images. We urge the OCE community to be careful in using the group velocity to evaluate tissue elasticity and to focus on developing robust reconstruction methods to accurately reconstruct images of the shear elastic modulus in bounded media.
Photoacoustic (PA) imaging has had limited clinical applicability for many reasons but one primary barrier to clinical translation is the bulky, expensive, and low repetition-rate laser typically used, resulting in low frame-rate images and a system with a large physical footprint. We have previously demonstrated a fast-scan approach delivering the frame rates required for real-time integrated PA/ultrasound (PAUS) imaging. In this paper, we present a new real-time PAUS system based on a swept-scanning source approach using a compact, recently-developed laser, providing pulse-to-pulse wavelength tuning at kHz rates and a scanning fiber-optic delivery system integrated with a high-frequency (15 MHz) US linear array. An array of fibers spanning the array are arranged on two lateral sides of the transducer and scanned sequentially based on optimized pulse sequences. By coherent compounding of multiple sub-images associated with each fiber light source, PA imaging with sufficient SNR at a frame rate of 50 Hz is achieved. Real-time in vivo multi-spectral imaging of nano-drug delivery to mice is demonstrated. With the same scanner footprint, our compact PAUS system can provide not only conventional high-quality scanned US imaging with all associated modes, but interleaved, multispectral PA imaging at video rates appropriate for real-time clinical applications.
In vision correction surgeries, the corneal stroma is subject to limbal-relaxing incisions which change the focusing power of the cornea, but can damage tissue and put the patient at risk of complication. A non-invasive method to launch a mechanical wave in tissue, referred to as Acoustic Micro-Tapping (AuT), is demonstrated with phase-sensitive spectral domain OCT (SD-OCT) to probe for biomechanical changes in porcine and human cornea samples following arcuate keratotomy (AK). This method uses an air-coupled ultrasound transducer to deliver sufficient displacement on the corneal surface to launch a mechanical wave propagating as a guided mode. Rayleigh-Lamb wave propagation is captured at 100 spatial locations 6 mm across the corneal surface, resulting in a high resolution elastogram. The SD-OCT system operates in the MB mode at a functional frame rate of 47 kHz to detect local wave behavior for analysis of the group velocity, group displacement amplitude, displacement attenuation, phase velocity over the bandwidth of the excitation, mean frequency, and bandwidth. An analysis of mechanical wave behavior shows reduced wave speed up to 20% following an incision through 3/4th of the cornea in porcine tissue samples, indicating a potential reduction in elastic modulus. This technique was performed on porcine and human corneas following PRK incision to demonstrate progress toward clinical translation.
Optical coherence elastography (OCE) holds great promise for quantitative characterization of corneal elasticity including robust measurements of the intraocular pressure (IOP) independent of corneal mechanical properties. To translate this method into a viable clinical tool, however, requires wideband, highly accurate mechanical wave measurements using mechanical stimulation requiring no physical contact with the cornea. We have developed a method of non-contact mechanical stimulation of soft media with precise spatial and temporal shaping. We call it acoustic micro-tapping (AuT) because it employs focused, air-coupled ultrasound (US) to induce significant mechanical displacement at the boundary of a soft material using reflection-based radiation force. Combining it with high-speed, four-dimensional (three space dimensions plus time) phase-sensitive optical coherence tomography (PhS-OCT) creates a non-contact tool for high-resolution and quantitative dynamic elastography of soft tissue at near real-time imaging rates. To demonstrate this approach, we present OCE results on a porcine cornea using a homemade, focused 1 MHz air-coupled piezoelectric transducer with a matching layer to launch an US wave through air onto the sample surface. To provide an acoustic line source approximating a 1-D excitation, the transducer was made from a cylindrical segment of a piezoelectric tube. A high-speed (1.6 MHz A-Scan rate) PhS-OCT system was utilized to measure acoustic wave propagation in the cornea at different intraocular pressures (IOPs). Results from this OCE study demonstrate that an air-coupled US wave reflected from an air/tissue interface provides significant radiation force to generate displacement for elasticity imaging for full mechanical characterization of the cornea.
Recently we used ultrasound from an air-coupled transducer for non-contact excitation of broadband mechanical waves in soft tissue such as cornea. The transient displacement, generated by “Acoustic Micro-Tapping” (AuT), was then measured using phase-sensitive spectral domain OCT (SD-OCT). In addition traditional surface wave speed measurement, we investigated complementary methods to characterize the mechanical properties of the target material. We note that the maximum frequency, as well as the group velocity, of the surface wave is related to both the phase velocity of the material and the spatial width of the acoustic pulse. If the spatial and temporal profile of the excitation is well defined, it may be possible to infer elastic modulus from the frequency profile of a propagating mechanical wave. To assess the effect of the spatial profiles of the AuT excitation on frequency profiles of resulting mechanical waves, acoustic pulses with different spatial width (from 0.1 to 1 mm) were applied to agar phantoms with different shear modulus (from 1 to 100 kPa) to generate mechanical waves, and a SD-OCT system with a functional frame rate of 47 kHz was used to track wave propagation. For validation, simulations with the same acoustic and mechanical properties were performed using a finite element method (FEM) to analyze induced wave propagation. The phantom experiment and simulation exhibited similar increase in the maximum frequency with decreasing excitation width. Both estimates also agreed well with previous theoretical results.
Optical coherence elastography (OCE) can provide clinically valuable information based on local measurements of tissue stiffness. Improved light sources and scanning methods in optical coherence tomography (OCT) have led to rapid growth in systems for high-resolution, quantitative elastography using imaged displacements and strains within soft tissue to infer local mechanical properties. We describe in some detail the physical processes underlying tissue mechanical response based on static and dynamic displacement methods. Namely, the assumptions commonly used to interpret displacement and strain measurements in terms of tissue elasticity for static OCE and propagating wave modes in dynamic OCE are discussed with the ultimate focus on OCT system design for ophthalmic applications. Practical OCT motion-tracking methods used to map tissue elasticity are also presented to fully describe technical developments in OCE, particularly noting those focused on the anterior segment of the eye. Clinical issues and future directions are discussed in the hope that OCE techniques will rapidly move forward to translational studies and clinical applications.
Acoustic radiation force (ARF) is commonly used in ultrasound (US)-based elastography to generate shear waves deep within soft tissue. These waves can be detected with different methods, e.g. contact conventional ultrasound imaging probes or contact free magnetic resonance or optical coherence tomography (OCT). For many clinical applications, however, for instance the eye, a totally non-contact system for generation/detection of mechanical waves is needed.
Here, we present a method for efficient non-contact excitation of broadband transverse mechanical waves in soft media. The approach is based on pushing the medium under study with a 1 MHz chirped US wave focused to its surface from air. The US beam reflected from the air/medium interface provides the ARF force to the medium surface launching a transient mechanical wave in the transverse (lateral) direction.
The design and performance of the air-coupled transducer is discussed. The focal zone, peak pressure and acoustic intensity are measured for transducers with different numerical apertures. Time and frequency characteristics of the propagating mechanical waves, generated in soft tissue, are tracked with a phase-sensitive ultra-fast frame rate OCT imaging system. Application of the proposed method for non-contact, non-invasive, sub-mm resolution elasticity measurement in soft tissue is proposed.
A new light and sound sensitive nanoemulsion contrast agent is presented. The agents feature a low boiling point liquid perfluorocarbon core and a broad light spectrum absorbing polypyrrole (PPy) polymer shell. The PPy coated nanoemulsions can reversibly convert from liquid to gas phase upon cavitation of the liquid perfluorocarbon core. Cavitation can be initiated using a sufficiently high intensity acoustic pulse or from heat generation due to light absorption from a laser pulse. The emulsions can be made between 150 and 350 nm in diameter and PPy has a broad optical absorption covering both the visible spectrum and extending into the near-infrared spectrum (peak absorption ~1053 nm).
The size, structure, and optical absorption properties of the PPy coated nanoemulsions were characterized and compared to PPy nanoparticles (no liquid core) using dynamic light scattering, ultraviolet-visible spectrophotometry, transmission electron microscopy, and small angle X-ray scattering. The cavitation threshold and signal intensity were measured as a function of both acoustic pressure and laser fluence. Overlapping simultaneous transmission of an acoustic and laser pulse can significantly reduce the activation energy of the contrast agents to levels lower than optical or acoustic activation alone. We also demonstrate that simultaneous light and sound cavitation of the agents can be used in a new sono-photoacoustic imaging method, which enables greater sensitivity than traditional photoacoustic imaging.
Shear wave OCE (SW-OCE) uses an OCT system to track propagating mechanical waves, providing the information
needed to map the elasticity of the target sample. In this study we demonstrate high speed, 4D imaging to capture
transient mechanical wave propagation. Using a high-speed Fourier domain mode-locked (FDML) swept-source OCT
(SS-OCT) system operating at ~1.62 MHz A-line rate, the equivalent volume rate of mechanical wave imaging is 16
kvps (kilo-volumes per second), and total imaging time for a 6 x 6 x 3 mm volume is only 0.32 s. With a displacement
sensitivity of ~10 nanometers, the proposed 4D imaging technique provides sufficient temporal and spatial resolution for
real-time optical coherence elastography (OCE). Combined with a new air-coupled, high-frequency focused ultrasound
stimulator requiring no contact or coupling media, this near real-time system can provide quantitative information on
localized viscoelastic properties. SW-OCE measurements are demonstrated on tissue-mimicking phantoms and porcine
cornea under various intra-ocular pressures. In addition, elasticity anisotropy in the cornea is observed. Images of the
mechanical wave group velocity, which correlates with tissue elasticity, show velocities ranging from 4-20 m/s
depending on pressure and propagation direction. These initial results strong suggest that 4D imaging for real-time OCE
may enable high-resolution quantitative mapping of tissue biomechanical properties in clinical applications.
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