Confocal Shear Wave Acoustic Radiation Force Optical Coherence Elastography for Imaging and Quantification of the In Vivo Posterior Eye.

Retinal diseases, such as age-related macular degeneration (AMD), are the leading cause of blindness in the elderly population. Since no known cures are currently present, it is crucial to diagnose the condition in its early stages so that disease progression is monitored. Recent advances show that the mechanical elasticity of the posterior eye changes with the onset of AMD. In this work, we present a quantitative method of mapping the mechanical elasticity of the posterior eye using confocal shear wave acoustic radiation force optical coherence elastography (SW-ARF-OCE). This technique has been developed and validated with both an ex-vivo porcine tissue model and a customized in-vivo rabbit model, which both showed the quantified elasticity variations between different layers. This study verifies the feasibility of using this technology for the quantification and diagnosis of retinal diseases from the in-vivo posterior eye.

High-Speed Integrated Endoscopic Photoacoustic and Ultrasound Imaging System.

Endoscopic integrated photoacoustic and ultrasound imaging has the potential for early detection of the cancer in the gastrointestinal tract. Currently, slow imaging speed is one of the limitations for clinical translation. Here, we developed a high speed integrated endoscopic PA and US imaging system, which is able to perform PA and US imaging simultaneously up to 50 frames per second. Using this system, the architectural morphology and vasculature of the rectum wall were visualized from a Sprague Dawley rat in-vivo.

Coaxial excitation longitudinal shear wave measurement for quantitative elasticity assessment using phase-resolved optical coherence elastography.

Optical coherence elastography (OCE) is an emerging imaging modality for the assessment of mechanical properties in soft tissues. Transverse shear wave measurements using OCE can quantify the elastic moduli perpendicular to the force direction, however, missing the elastic information along the force direction. In this study, we developed coaxial excitation longitudinal shear wave measurements for quantification of elastic moduli along the force direction using M-scans. Incorporating Rayleigh wave measurements using non-coaxial lateral scans into longitudinal shear wave measurements, directionally dependent elastic properties can be quantified along the force direction and perpendicular to the force direction. Therefore, the reported system has the capability to image elasticity of anisotropic biological tissues.

Acoustic Radiation Force Optical Coherence Elastography of Corneal Tissue.

We report on a real-time acoustic radiation force optical coherence elastography (ARF-OCE) system to map the relative elasticity of corneal tissue. A modulated ARF is used as excitation to vibrate the cornea while OCE serves as detection of tissue response. To show feasibility of detecting mechanical contrast using this method, we performed tissue-equivalent agarose phantom studies with inclusions of a different stiffness. We obtained 3-D elastograms of a healthy cornea and a highly cross-linked cornea. Finally we induced a stiffness change on a small portion of a cornea and observed the differences in displacement.

Spatial mapping of tracheal ciliary beat frequency using real time phase-resolved Doppler spectrally encoded interferometric microscopy.

Ciliary motion in the upper airway is the primary mechanism by which the body transports foreign particulates out of the respiratory system in order to maintain proper respiratory function. The ciliary beating frequency (CBF) is often disrupted with the onset of disease as well as other conditions, such as changes in temperature or in response to drug administration. Current imaging of ciliary motion relies on microscopy and high-speed cameras, which cannot be easily adapted to in-vivo imaging. M-mode optical coherence tomography (OCT) imaging is capable of visualization of ciliary activity, but the field of view is limited. We report on the development of a spectrally encoded interferometric microscopy (SEIM) system using a phase-resolved Doppler (PRD) algorithm to measure and map the ciliary beating frequency within an en face region. This novel high speed, high resolution system allows for visualization of both temporal and spatial ciliary motion patterns as well as propagation of metachronal wave. Rabbit tracheal CBF ranging from 9 to 13 Hz has been observed under different temperature conditions, and the effects of using lidocaine and albuterol have also been measured. This study is the stepping stone to in-vivo studies and the translation of imaging spatial CBF to clinics.

Analysis of chemical consistency and the anti-tumor activity of Huangqi-Ezhu (HQ-EZ) concentrated-granules and decoction.

BACKGROUND: Traditional Chinese medicine decoction and modern concentrated-granules are two kinds of Chinese herbal medicine forms used in clinic at present. The former is extracted by traditional boiling method of a pre-mixed multi-herbal medicine according to the doctor's prescription. The latter is a mixture of extract active ingredients from a single variety of herbs by modern technology. It is not clear whether there is a difference in the content and efficacy of the active components between the two methods. METHODS: The effective components of Huangqi-Ezhu (HQ-EZ) traditional decoction and concentratedgranules were determined by HPLC, and the subcutaneous transplanted tumor model of tumor-bearing mice was established to compare the anti-tumor effect. HQ-EZ traditional decoction and concentrated-granules were given respectively by continuous intragastric administration for 15 days. After the last administration the tumor tissue, liver and kidney were removed completely, and the corresponding indexes were detected. RESULTS: Active components of concentrated-granules and traditional decoction are basically the same. Both of TCM forms have great anti-tumor effect against lung cancer, without toxify to liver and kidney. CONCLUSIONS: The two preparation methods have their own advantages in effective components, and the compatibility of HQ-EZ can inhibit the tumor growth of tumor-bearing mice, and has no liver and kidney toxicity.

Characterization of oviduct ciliary beat frequency using real time phase resolved Doppler spectrally encoded interferometric microscopy.

Ciliary activity, characterized by the coordinated beating of ciliary cells, generates the primary driving force for oviduct tubal transport, which is an essential physiological process for successful pregnancies. Malfunction of the cilium in the fallopian tube, or oviduct, may increase the risk of infertility and tubal pregnancy that can result in maternal death. While many ex-vivo studies have been carried out using bright field microscopy, this technique is not feasible for the in-vivo investigation of oviduct ciliary beating frequency (CBF). Optical coherence tomography (OCT) has been able to provide in-vivo CBF imaging in a mouse model, but its resolution may be insufficient to resolve the spatial and temporal features of the cilium. Our group has recently developed the phase resolved Doppler (PRD) OCT method to visualize ciliary strokes at ultra-high displacement sensitivity. However, the cross-sectional field of view (FOV) may not be ideal for visualizing the surface dynamics of ciliated tissue. In this study, we report on the development of phase resolved Doppler spectrally encoded interferometric microscopy (PRD-SEIM) to visualize the oviduct ciliary activity within an en face FOV. This novel real time imaging system offers micrometer spatial resolution, sub-nanometer displacement sensitivity, and the potential for in-vivo endoscopic adaptation. The feasibility of the approach has been validated through ex-vivo experiments where the porcine oviduct CBF has been measured across different temperature conditions and the application of a drug. CBF ranging from 8 to 12 Hz have been observed at different temperatures, while administration of lidocaine decreased the CBF and deactivated the motile cilia. This study will serve as a stepping stone to in-vivo oviduct ciliary endoscopy and future clinical translations.

In-vivo 3D corneal elasticity using air-coupled ultrasound optical coherence elastography.

Corneal elasticity can resist elastic deformations under intraocular pressure to maintain normal corneal shape, which has a great influence on corneal refractive function. Elastography can measure tissue elasticity and provide a powerful tool for clinical diagnosis. Air-coupled ultrasound optical coherence elastography (OCE) has been used in the quantification of ex-vivo corneal elasticity. However, in-vivo imaging of the cornea remains a challenge. The 3D air-coupled ultrasound OCE with an axial motion artifacts correction algorithm was developed to distinguish the in-vivo cornea vibration from the axial eye motion in anesthetized rabbits and visualize the elastic wave propagation clearly. The elastic wave group velocity of in-vivo rabbit cornea was measured to be 5.96 ± 0.55 m/s, which agrees with other studies. The results show the potential of 3D air-coupled ultrasound OCE with an axial motion artifacts correction algorithm for quantitative in-vivo assessment of corneal elasticity.

Quantitative confocal optical coherence elastography for evaluating biomechanics of optic nerve head using Lamb wave model.

The mechanosensitivity of the optic nerve head (ONH) plays a pivotal role in the pathogenesis of glaucoma. Characterizing elasticity of the ONH over changing physiological pressure may provide a better understanding of how changes in intraocular pressure (IOP) lead to changes in the mechanical environment of the ONH. Optical coherence elastography (OCE) is an emerging technique that can detect tissue biomechanics noninvasively with both high temporal and spatial resolution compared with conventional ultrasonic elastography. We describe a confocal OCE system in measuring ONH elasticity in vitro, utilizing a pressure inflation setup in which IOP is controlled precisely. We further utilize the Lamb wave model to fit the phase dispersion curve during data postprocessing. We present a reconstruction of Young's modulus of the ONH by combining our OCE system with a Lamb wave model for the first time. This approach enables the quantification of Young's modulus of the ONH, which can be fit using a piecewise polynomial to the corresponding IOP.

Quantified elasticity mapping of retinal layers using synchronized acoustic radiation force optical coherence elastography.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly (over the age of 60 years) in western countries. In the early stages of the disease, structural changes may be subtle and cannot be detected. Recently it has been postulated that the mechanical properties of the retina may change with the onset of AMD. In this manuscript, we present a novel, non-invasive means that utilizes synchronized acoustic radiation force optical coherence elastography (ARF-OCE) to measure and estimate the elasticity of cadaver porcine retina. Both regions near the optic nerve and in the peripheral retina were studied. An acoustic force is exerted on the tissue for excitation and the resulting tissue vibrations, often in the nanometer scale, are detected with high-resolution optical methods. Segmentation has been performed to isolate individual layers and the Young's modulus has been estimated for each. The results have been successfully compared and mapped to corresponding histological results using H&E staining. Finally, 64 elastograms of the retina were analyzed, as well as the elastic properties, with stiffness ranging from 1.3 to 25.9 kPa in the ganglion to the photoreceptor sides respectively. ARF-OCE allows for the elasticity mapping of anatomical retinal layers. This imaging approach needs further evaluation but has the potential to allow physicians to gain a better understanding of the elasticity of retinal layers in retinal diseases such as AMD.

In Vivo Elasticity Mapping of Posterior Ocular Layers Using Acoustic Radiation Force Optical Coherence Elastography.

Purpose: We used acoustic radiation force optical coherence elastography (ARF-OCE) to map out the elasticity of retinal layers in healthy and diseased in vivo rabbit models for the first time. Methods: A healthy rabbit eye was proptosed and imaged using ARF-OCE, by measuring the tissue deformation after an acoustic force is applied. A diseased retinal inflammation model was used to observe the contrast before and after disease formation. Retinal histologic analysis was performed to identify layers of the retina corresponding with the optical images. Results: The general trend of the retinal layer elasticity is increasing stiffness from the ganglion side to the photoreceptor side, with the stiffest layer being the sclera. In a healthy rabbit model, the mechanical properties varied from 3 to 16 kPa for the five layers that were identified via optical imaging and histology (3.09 ± 0.46, 3.82 ± 0.88, 4.53 ± 0.74, 6.59 ± 2.27, 16.11 ± 5.13 kPa). In the diseased model, we have induced optical damage in a live rabbit and observed a change in the stiffness trend in its retina. Conclusions: High sensitivity elasticity maps can be obtained using the ARF-OCE system to differentiate different retinal layers. Subtle changes in the mechanical properties during the onset of diseases, such as retinal degeneration, can be measured and aid in early clinical diagnosis. This study validates our imaging system for the characterization of retinal elasticity for the detection of retinal diseases in vivo.

Longitudinal shear wave imaging for elasticity mapping using optical coherence elastography.

Shear wave measurements for the determination of tissue elastic properties have been used in clinical diagnosis and soft tissue assessment. A shear wave propagates as a transverse wave where vibration is perpendicular to the wave propagation direction. Previous transverse shear wave measurements could detect the shear modulus in the lateral region of the force; however, they could not provide the elastic information in the axial region of the force. In this study, we report the imaging and quantification of longitudinal shear wave propagation using optical coherence tomography to measure the elastic properties along the force direction. The experimental validation and finite element simulations show that the longitudinal shear wave propagates along the vibration direction as a plane wave in the near field of a planar source. The wave velocity measurement can quantify the shear moduli in a homogeneous phantom and a side-by-side phantom. Combining the transverse shear wave and longitudinal shear wave measurements, this system has great potential to detect the directionally dependent elastic properties in tissues without a change in the force direction.

Association of Electrochemical Therapy With Optical, Mechanical, and Acoustic Impedance Properties of Porcine Skin.

IMPORTANCE: The classic management of burn scars and other injuries to the skin has largely relied on soft-tissue transfer to resurface damaged tissue with local tissue transfer or skin graft placement. In situ generation of electrochemical reactions using needle electrodes and an application of current may be a new approach to treat scars and skin. OBJECTIVE: To examine the changes in optical, mechanical, and acoustic impedance properties in porcine skin after electrochemical therapy. DESIGN, SETTING, AND PARTICIPANTS: This preclinical pilot study, performed from August 1, 2015, to November 1, 2016, investigated the effects of localized pH-driven electrochemical therapy of ex vivo porcine skin using 24 skin samples. Platinum-plated needle electrodes were inserted into fresh porcine skin samples. A DC power supply provided a voltage of 4 to 5 V with a 3-minute application time. Specimens were analyzed using optical coherence tomography, optical coherence elastography, and ultrasonography. Ultrasonography was performed under 3 conditions (n = 2 per condition), optical coherence tomography was performed under 2 conditions (n = 2 per condition), and optical coherence elastography was performed under 2 conditions (n = 2 per condition). The remaining samples were used for the positive and negative control groups (n = 10). EXPOSURES: Platinum-plated needle electrodes were inserted into fresh porcine skin samples. A DC power supply provided a voltage of 4 to 5 V with a 3-minute application. MAIN OUTCOMES AND MEASURES: Tissue softening was observed at the anode and cathode sites as a result of electrochemical modification. Volumetric changes were noted using each optical and acoustic technique. RESULTS: A total of 24 ex vivo porcine skin samples were used for this pilot study. Optical coherence tomography measured spatial distribution of superficial tissue changes around each electrode site. At 4 V for 3 minutes, a total volumetric effect of 0.47 mm3 was found at the anode site and 0.51 mm3 at the cathode site. For 5 V for 3 minutes, a total volumetric effect of 0.85 mm3 was found at the anode site and 1.05 mm3 at the cathode site. CONCLUSIONS AND RELEVANCE: Electrochemical therapy is a low-cost technique that is on par with the costs of suture and scalpel. The use of electrochemical therapy to create mechanical and physiologic changes in tissue has the potential to locally remodel the soft-tissue matrix, which ultimately may lead to an inexpensive scar treatment or skin rejuvenation therapy. LEVEL OF EVIDENCE: NA.

Miniature probe for mapping mechanical properties of vascular lesions using acoustic radiation force optical coherence elastography.

Cardiovascular diseases are the leading cause of fatalities in the United States. Atherosclerotic plaques are one of the primary complications that can lead to strokes and heart attacks if left untreated. It is essential to diagnose the disease early and distinguish vulnerable plaques from harmless ones. Many methods focus on the structural or molecular properties of plaques. Mechanical properties have been shown to change drastically when abnormalities develop in arterial tissue. We report the development of an acoustic radiation force optical coherence elastography (ARF-OCE) system that uses an integrated miniature ultrasound and optical coherence tomography (OCT) probe to map the relative elasticity of vascular tissues. We demonstrate the capability of the miniature probe to map the biomechanical properties in phantom and human cadaver carotid arteries.

3D mapping of elastic modulus using shear wave optical micro-elastography.

Elastography provides a powerful tool for histopathological identification and clinical diagnosis based on information from tissue stiffness. Benefiting from high resolution, three-dimensional (3D), and noninvasive optical coherence tomography (OCT), optical micro-elastography has the ability to determine elastic properties with a resolution of ~10 µm in a 3D specimen. The shear wave velocity measurement can be used to quantify the elastic modulus. However, in current methods, shear waves are measured near the surface with an interference of surface waves. In this study, we developed acoustic radiation force (ARF) orthogonal excitation optical coherence elastography (ARFOE-OCE) to visualize shear waves in 3D. This method uses acoustic force perpendicular to the OCT beam to excite shear waves in internal specimens and uses Doppler variance method to visualize shear wave propagation in 3D. The measured propagation of shear waves agrees well with the simulation results obtained from finite element analysis (FEA). Orthogonal acoustic excitation allows this method to measure the shear modulus in a deeper specimen which extends the elasticity measurement range beyond the OCT imaging depth. The results show that the ARFOE-OCE system has the ability to noninvasively determine the 3D elastic map.

Ultrafast optical-ultrasonic system and miniaturized catheter for imaging and characterizing atherosclerotic plaques in vivo.

Atherosclerotic coronary artery disease (CAD) is the number one cause of death worldwide. The majority of CAD-induced deaths are due to the rupture of vulnerable plaques. Accurate assessment of plaques is crucial to optimize treatment and prevent death in patients with CAD. Current diagnostic techniques are often limited by either spatial resolution or penetration depth. Several studies have proved that the combined use of optical and ultrasonic imaging techniques increase diagnostic accuracy of vulnerable plaques. Here, we introduce an ultrafast optical-ultrasonic dual-modality imaging system and flexible miniaturized catheter, which enables the translation of this technology into clinical practice. This system can perform simultaneous optical coherence tomography (OCT)-intravascular ultrasound (IVUS) imaging at 72 frames per second safely in vivo, i.e., visualizing a 72 mm-long artery in 4 seconds. Results obtained in atherosclerotic rabbits in vivo and human coronary artery segments show that this ultrafast technique can rapidly provide volumetric mapping of plaques and clearly identify vulnerable plaques. By providing ultrafast imaging of arteries with high resolution and deep penetration depth simultaneously, this hybrid IVUS-OCT technology opens new and safe opportunities to evaluate in real-time the risk posed by plaques, detect vulnerable plaques, and optimize treatment decisions.