Acoustic Micro-Tapping Optical Coherence Elastography to Quantify Corneal Collagen Cross-Linking: An Ex Vivo Human Study.

Purpose: To evaluate changes in the anisotropic elastic properties of ex vivo human cornea treated with ultraviolet cross-linking (CXL) using noncontact acoustic micro-tapping optical coherence elastography (AµT-OCE). Design: Acoustic micro-tapping OCE was performed on normal and CXL human donor cornea in an ex vivo laboratory study. Subjects: Normal human donor cornea (n = 22) divided into 4 subgroups. All samples were stored in optisol. Methods: Elastic properties (in-plane Young's, E, and out-of-plane, G, shear modulus) of normal and ultraviolet CXL-treated human corneas were quantified using noncontact AµT-OCE. A nearly incompressible transverse isotropic model was used to reconstruct moduli from AµT-OCE data. Independently, cornea elastic moduli were also measured with destructive mechanical tests (tensile extensometry and shear rheometry). Main Outcome Measures: Corneal elastic moduli (in-plane Young's modulus, E, in-plane, µ, and out-of-plane, G, shear moduli) can be evaluated in both normal and CXL treated tissues, as well as monitored during the CXL procedure using noncontact AµT-OCE. Results: Cross-linking induced a significant increase in both in-plane and out-of-plane elastic moduli in human cornea. The statistical mean in the paired study (presurgery and postsurgery, n = 7) of the in-plane Young's modulus, E = 3 µ , increased from 19 MPa to 43 MPa, while the out-of-plane shear modulus, G, increased from 188 kPa to 673 kPa. Mechanical tests in a separate subgroup support CXL-induced cornea moduli changes and generally agree with noncontact AµT-OCE measurements. Conclusions: The human cornea is a highly anisotropic material where in-plane mechanical properties are very different from those out-of-plane. Noncontact AµT-OCE can measure changes in the anisotropic elastic properties in human cornea as a result of ultraviolet CXL.

Probing elastic anisotropy of human skin in vivo with light using non-contact acoustic micro-tapping OCE and polarization sensitive OCT.

Skin broadly protects the human body from undesired factors such as ultraviolet radiation and abrasion and helps conserve body temperature and hydration. Skin's elasticity and its level of anisotropy are key to its aesthetics and function. Currently, however, treatment success is often speculative and subjective, and is rarely based on skin's elastic properties because there is no fast and accurate non-contact method for imaging of skin's elasticity. Here we report on a non-contact and non-invasive method to image and characterize skin's elastic anisotropy. It combines acoustic micro-tapping optical coherence elastography (AµT-OCE) with a nearly incompressible transversely isotropic (NITI) model to quantify skin's elastic moduli. In addition, skin sites were imaged with polarization sensitive optical coherence tomography (PS-OCT) to help define fiber orientation. Forearm skin areas were investigated in five volunteers. Results clearly demonstrate elastic anisotropy of skin in all subjects. AµT-OCE has distinct advantages over competitive techniques because it provides objective, quantitative characterization of skin's elasticity without contact, which opens the door for broad translation into clinical use. Finally, we demonstrate that a combination of multiple OCT modalities (structural OCT, OCT angiography, PS-OCT and AµT-OCE) may provide rich information about skin and can be used to characterize scar.

Real-time interleaved spectroscopic photoacoustic and ultrasound (PAUS) scanning with simultaneous fluence compensation and motion correction.

For over two decades photoacoustic imaging has been tested clinically, but successful human trials have been limited. To enable quantitative clinical spectroscopy, the fundamental issues of wavelength-dependent fluence variations and inter-wavelength motion must be overcome. Here we propose a real-time, spectroscopic photoacoustic/ultrasound (PAUS) imaging approach using a compact, 1-kHz rate wavelength-tunable laser. Instead of illuminating tissue over a large area, the fiber-optic delivery system surrounding an US array sequentially scans a narrow laser beam, with partial PA image reconstruction for each laser pulse. The final image is then formed by coherently summing partial images. This scheme enables (i) automatic compensation for wavelength-dependent fluence variations in spectroscopic PA imaging and (ii) motion correction of spectroscopic PA frames using US speckle tracking in real-time systems. The 50-Hz video rate PAUS system is demonstrated in vivo using a murine model of labelled drug delivery.

Delineating Corneal Elastic Anisotropy in a Porcine Model Using Noncontact OCT Elastography and Ex Vivo Mechanical Tests.

Purpose: To compare noncontact acoustic microtapping (AµT) OCT elastography (OCE) with destructive mechanical tests to confirm corneal elastic anisotropy. Design: Ex vivo laboratory study with noncontact AµT-OCE followed by mechanical rheometry and extensometry. Participants: Inflated cornea of whole-globe porcine eyes (n = 9). Methods: A noncontact AµT transducer was used to launch propagating mechanical waves in the cornea that were imaged with phase-sensitive OCT at physiologically relevant controlled pressures. Reconstruction of both Young's modulus (E) and out-of-plane shear modulus (G) in the cornea from experimental data was performed using a nearly incompressible transversely isotropic (NITI) medium material model assuming spatial isotropy of corneal tensile properties. Corneal samples were excised and parallel plate rheometry was performed to measure shear modulus, G. Corneal samples were then subjected to strip extensometry to measure the Young's modulus, E. Main Outcome Measures: Strong corneal anisotropy was confirmed with both AµT-OCE and mechanical tests, with the Young's (E) and shear (G) moduli differing by more than an order of magnitude. These results show that AµT-OCE can quantify both moduli simultaneously with a noncontact, noninvasive, clinically translatable technique. Results: Mean of the OCE measured moduli were E = 12 ± 5 MPa and G = 31 ± 11 kPa at 5 mmHg and E = 20 ± 9 MPa and G = 61 ± 29 kPa at 20 mmHg. Tensile testing yielded a mean Young's modulus of 1 MPa - 20 MPa over a strain range of 1% to 7%. Shear storage and loss modulus (G'/G'') measured with rheometry was approximately 82/13 ± 12/4 kPa at 0.2 Hz and 133/29 ± 16/3 kPa at 16 Hz (0.1% strain). Conclusions: The cornea is confirmed to be a strongly anisotropic elastic material that cannot be characterized with a single elastic modulus. The NITI model is the simplest one that accounts for the cornea's incompressibility and in-plane distribution of lamellae. AµT-OCE has been shown to be the only reported noncontact, noninvasive method to measure both elastic moduli. Submillimeter spatial resolution and near real-time operation can be achieved. Quantifying corneal elasticity in vivo will enable significant innovation in ophthalmology, helping to develop personalized biomechanical models of the eye that can predict response to ophthalmic interventions.

Spatially localized sono-photoacoutic activation of phase-change contrast agents.

Sono-photoacoustic (SPA) activation lowers the threshold of phase-change contrast agents by timing a laser shot to coincide with the arrival of an acoustic wave at a region of interest. The combination of photothermal heating from optical absorption and negative pressure from the acoustic wave greatly reduces the droplet's combined vaporization threshold compared to using laser energy or acoustic energy alone. In previous studies, SPA imaging used a broadly illuminated optical pulse combined with plane wave acoustic pulses transmitted from a linear ultrasound array. Acoustic plane waves cover a wide lateral field of view, enabling direct visualization of the contrast agent distribution. In contrast, we demonstrate here that localized SPA activation is possible using electronically steered/focused ultrasound pulses. The focused SPA activation region is defined axially by the number of cycles in the acoustic pulse and laterally by the acoustic beam width. By reducing the spot size and enabling rapid electronic steering, complex activation patterns are possible, which may be particularly useful in therapeutic applications.

Nearly-incompressible transverse isotropy (NITI) of cornea elasticity: model and experiments with acoustic micro-tapping OCE.

The cornea provides the largest refractive power for the human visual system. Its stiffness, along with intraocular pressure (IOP), are linked to several pathologies, including keratoconus and glaucoma. Although mechanical tests can quantify corneal elasticity ex vivo, they cannot be used clinically. Dynamic optical coherence elastography (OCE), which launches and tracks shear waves to estimate stiffness, provides an attractive non-contact probe of corneal elasticity. To date, however, OCE studies report corneal moduli around tens of kPa, orders-of-magnitude less than those (few MPa) obtained by tensile/inflation testing. This large discrepancy impedes OCE's clinical adoption. Based on corneal microstructure, we introduce and fully characterize a nearly-incompressible transversely isotropic (NITI) model depicting corneal biomechanics. We show that the cornea must be described by at least two shear moduli, contrary to current single-modulus models, decoupling tensile and shear responses. We measure both as a function of IOP in ex vivo porcine cornea, obtaining values consistent with both tensile and shear tests. At pressures above 30 mmHg, the model begins to fail, consistent with non-linear changes in cornea at high IOP.

Spatial resolution in dynamic optical coherence elastography.

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.

Does group velocity always reflect elastic modulus in shear wave elastography?

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.

Super-shear evanescent waves for non-contact elastography of soft tissues.

We describe surface wave propagation in soft elastic media at speeds exceeding the bulk shear wave speed. By linking these waves to the elastodynamic Green's function, we derive a simple relationship to quantify the elasticity of a soft medium from the speed of this supershear evanescent wave (SEW). We experimentally probe SEW propagation in tissue-mimicking phantoms, human cornea ex vivo, and skin in vivo using a high-speed optical coherence elastography system. Measurements confirm the predicted relationship between SEW and bulk shear wave speeds, agreeing well with both theoretical and numerical models. These results suggest that SEW measurements may be a robust method to quantify elasticity in soft media, particularly in complex, bounded materials where dispersive Rayleigh-Lamb modes complicate measurements.

Computational Fluid Dynamics Modeling of the Burr Orbital Motion in Rotational Atherectomy with Particle Image Velocimetry Validation.

Rotational atherectomy (RA) uses a high-speed rotating burr introduced via a catheter through the artery to remove hardened atherosclerotic plaque. Current clinical RA technique lacks consensus on burr size and rotational speed. The rotating burr orbits inside the artery due to the fluid force of the blood. Different from a common RA technique of upsizing burrs for larger luminal gain, a small burr can orbit to treat a large lumen. A 3D computational fluid dynamics (CFD) model was developed to simulate the burr motion and study the fluid flow and force in RA. A particle image velocimetry experiment was conducted to measure and validate the flow field including the radial and axial velocities and a pair of counter-rotating vortices near the burr equator in CFD. The hydraulic force on the burr and the contact force between the burr and the arterial wall were estimated by CFD. The contact force can be reduced by using smaller burr and lower rotational speed. Utilizing the small burr orbital motion has the potential to be an improved RA technique.

Design and Testing of a Single-Element Ultrasound Viscoelastography System for Point-of-Care Edema Quantification.

Management of fluid overload in patients with end-stage renal disease represents a unique challenge to clinical practice because of the lack of accurate and objective measurement methods. Currently, peripheral edema is subjectively assessed by palpation of the patient's extremities, ostensibly a qualitative indication of tissue viscoelastic properties. New robust quantitative estimates of tissue fluid content would allow clinicians to better guide treatment, minimizing reactive treatment decision making. Ultrasound viscoelastography (UVE) can be used to estimate strain in viscoelastic tissue, deriving material properties that can help guide treatment. We are developing and testing a simple, low-cost UVE system using a single-element imaging transducer that is simpler and less computationally demanding than array-based systems. This benchtop validation study tested the feasibility of using the UVE system by measuring the mechanical properties of a tissue-mimicking material under large strains. We generated depth-dependent creep curves and viscoelastic parameter maps of time constants and elastic moduli for the Kelvin model of viscoelasticity. During testing, the UVE system performed well, with mean UVE-measured strain matching standard mechanical testing with maximum absolute errors ≤4%. Motion tracking revealed high correlation and signal-to-noise ratios, indicating that the system is reliable.