Integrated optical coherence tomography and multielement ultrasound transducer probe for shear wave elasticity imaging of moving tissues.

Accurate measurements of microelastic properties of soft tissues in-vivo using optical coherence elastography can be affected by motion artifacts caused by cardiac and respiratory cycles. This problem can be overcome using a multielement ultrasound transducer probe where each ultrasound transducer is capable of generating acoustic radiation force (ARF) and, therefore, creating shear waves in tissue. These shear waves, produced during the phase of cardiac and respiratory cycles when tissues are effectively stationary, are detected at the same observation point using phase-sensitive optical coherence tomography (psOCT). Given the known distance between the ultrasound transducers, the speed of shear wave propagation can be calculated by measuring the difference between arrival times of shear waves. The combined multitransducer ARF/psOCT probe has been designed and tested in phantoms and ex-vivo studies using fresh rabbit heart. The measured values of shear moduli are in good agreement with those reported in literature. Our results suggest that the developed multitransducer ARF/psOCT probe can be useful for many in-vivo applications, including quantifying the microelasticity of cardiac muscle.

Laser-activated perfluorocarbon nanodroplets: a new tool for blood brain barrier opening.

A major obstacle in the monitoring and treatment of neurological diseases is the blood brain barrier (BBB), a semipermeable barrier that prevents the delivery of many therapeutics and imaging contrast agents to the brain. In this work, we explored the possibility of laser-activated perfluorocarbon nanodroplets (PFCnDs) to open the BBB and deliver agents to the brain tissue. Specifically, near infrared (NIR) dye-loaded PFCnDs comprised of a perfluorocarbon (PFC) core with a boiling point above physiological temperature were repeatedly vaporized and recondensed from liquid droplet to gas bubble under pulsed laser excitation. As a result, this pulse-to-pulse repeated behavior enabled the recurring interaction of PFCnDs with the endothelial lining of the BBB, allowing for a BBB opening and extravasation of dye into the brain tissue. The blood brain barrier opening and delivery of agents to tissue was confirmed on the macro and the molecular level by evaluating Evans Blue staining, ultrasound-guided photoacoustic (USPA) imaging, and histological tissue analysis. The demonstrated PFCnD-assisted pulsed laser method for BBB opening, therefore, represents a tool that has the potential to enable non-invasive, cost-effective, and efficient image-guided delivery of contrast and therapeutic agents to the brain.

Real-Time Intravascular Ultrasound and Photoacoustic Imaging.

Combined intravascular ultrasound and intravascular photoacoustic (IVUS/IVPA) imaging is an emerging hybrid modality being explored as a means of improving the characterization of atherosclerotic plaque anatomical and compositional features. While initial demonstrations of the technique have been encouraging, they have been limited by catheter rotation and data acquisition, displaying, and processing rates on the order of several seconds per frame as well as the use of off-line image processing. Herein, we present a complete IVUS/IVPA imaging system and method capable of real-time IVUS/IVPA imaging, with online data acquisition, image processing, and display of both IVUS and IVPA images. The integrated IVUS/IVPA catheter is fully contained within a 1-mm outer diameter torque cable coupled on the proximal end to a custom-designed spindle enabling optical and electrical coupling to system hardware, including a nanosecond-pulsed laser with a controllable pulse repetition frequency capable of greater than 10 kHz, motor and servo drive, a US pulser/receiver, and a 200-MHz digitizer. The system performance is characterized and demonstrated on a vessel-mimicking phantom with an embedded coronary stent intended to provide IVPA contrast within content of an IVUS image.

The dynamic deformation of a layered viscoelastic medium under surface excitation.

In this study the dynamic behavior of a layered viscoelastic medium in response to the harmonic and impulsive acoustic radiation force applied to its surface was investigated both theoretically and experimentally. An analytical solution for a layered viscoelastic compressible medium in frequency and time domains was obtained using the Hankel transform. A special incompressible case was considered to model soft biological tissues. To verify our theoretical model, experiments were performed using tissue-like gel-based phantoms with varying mechanical properties. A 3.5 MHz single-element focused ultrasound transducer was used to apply the radiation force at the surface of the phantoms. A phase-sensitive optical coherence tomography system was used to track the displacements of the phantom surface. Theoretically predicted displacements were compared with experimental measurements. The role of the depth dependence of the elastic properties of a medium in its response to an acoustic pulse at the surface was studied. It was shown that the low-frequency vibrations at the surface are more sensitive to the deep layers than high-frequency ones. Therefore, the proposed model in combination with spectral analysis can be used to evaluate depth-dependent distribution of the mechanical properties based on the measurements of the surface deformation.

Feasibility of in vivo intravascular photoacoustic imaging using integrated ultrasound and photoacoustic imaging catheter.

Pilot studies of in vivo combined intravascular ultrasound (IVUS) and intravascular photoacoustic (IVPA) imaging are reported. A recently introduced prototype of an integrated IVUS/IVPA imaging catheter consisting of a single-element ultrasound transducer and a light delivery system based on a single optical fiber was adapted and used for in vivo imaging of a coronary stent deployed in a rabbit's thoracic aorta in the presence of luminal blood. The results suggest that in vivo IVUS/IVPA imaging is feasible using the integrated IVUS/IVPA imaging catheter. The challenges of in vivo combined IVUS/IVPA imaging are discussed, and further improvements on the design of the catheter and the clinical imaging system are proposed.

Estimation of mechanical properties of a viscoelastic medium using a laser-induced microbubble interrogated by an acoustic radiation force.

An approach to assess the mechanical properties of a viscoelastic medium using laser-induced microbubbles is presented. To measure mechanical properties of the medium, dynamics of a laser-induced cavitation microbubble in viscoelastic medium under acoustic radiation force was investigated. An objective lens with a 1.13 numerical aperture and an 8.0 mm working distance was designed to focus a 532 nm wavelength nanosecond pulsed laser beam and to create a microbubble at the desired location. A 3.5 MHz ultrasound transducer was used to generate acoustic radiation force to excite a laser-induced microbubble. Motion of the microbubble was tracked using a 25 MHz imaging transducer. Agreement between a theoretical model of bubble motion in a viscoelastic medium and experimental measurements was demonstrated. Young's modulii reconstructed using the laser-induced microbubble approach were compared with those measured using a direct uniaxial method over the range from 0.8 to 13 kPa. The results indicate good agreement between methods. Thus, the proposed approach can be used to assess the mechanical properties of a viscoelastic medium.

Photoacoustic imaging of prostate brachytherapy seeds.

Brachytherapy seed therapy is an increasingly common way to treat prostate cancer through localized radiation. The current standard of care relies on transrectal ultrasound (TRUS) for imaging guidance during the seed placement procedure. As visualization of individual metallic seeds tends to be difficult or inaccurate under TRUS guidance, guide needles are generally tracked to infer seed placement. In an effort to improve seed visualization and placement accuracy, the use of photoacoustic (PA) imaging, which is highly sensitive to metallic objects in soft tissue, was investigated for this clinical application. The PA imaging properties of bare (i.e., embedded in pure gelatin) and tissue-embedded (at depths of up to 13 mm) seeds were investigated with a multi-wavelength (750 to 1090 nm) PA imaging technique. Results indicate that, much like ultrasonic (US) imaging, an angular dependence (i.e., seed orientation relative to imaging transducer) of the PA signal exists. Despite this shortcoming, however, PA imaging offers improved contrast, over US imaging, of a seed in prostate tissue if sufficient local fluence is achieved. Additionally, although the PA signal of a bare seed is greatest for lower laser wavelengths (e.g., 750 nm), the scattering that results from tissue tends to favor the use of higher wavelengths (e.g., 1064 nm, which is the primary wavelength of Nd:YAG lasers) when the seed is located in tissue. A combined PA and US imaging approach (i.e., PAUS imaging) shows strong potential to visualize both the seed and the surrounding anatomical environment of the prostate during brachytherapy seed placement procedures.

Development of a catheter for combined intravascular ultrasound and photoacoustic imaging.

Atherosclerosis is characterized by formation and development of the plaques in the inner layer of the vessel wall. To detect and characterize atherosclerotic plaques, we previously introduced the combined intravascular ultrasound (IVUS) and intravascular photoacoustic (IVPA) imaging capable of assessing plaque morphology and composition. The utility of IVUS/IVPA imaging has been demonstrated by imaging tissue-mimicking phantoms and ex vivo arterial samples using laboratory prototype of the imaging system. However, the clinical realization of a IVUS/IVPA imaging requires an integrated intravascular imaging catheter. In this paper, two designs of IVUS/IVPA imaging catheters--side fire fiber-based and mirror-based catheters--are reported. A commercially available IVUS imaging catheter was utilized for both pulse-echo ultrasound imaging and detection of photoacoustic transients. Laser pulses were delivered by custom-designed fiber-based optical systems. The optical fiber and IVUS imaging catheter were combined into a single device. Both designs were tested and compared using point targets and tissue-mimicking phantoms. The results indicate applicability of the proposed catheters for clinical use.

Intravascular Photoacoustic Imaging.

Intravascular photoacoustic (IVPA) imaging is a catheter-based, minimally invasive, imaging modality capable of providing high-resolution optical absorption map of the arterial wall. Integrated with intravascular ultrasound (IVUS) imaging, combined IVPA and IVUS imaging can be used to detect and characterize atherosclerotic plaques building up in the inner lining of an artery. In this paper, we present and discuss various representative applications of combined IVPA/IVUS imaging of atherosclerosis, including assessment of the composition of atherosclerotic plaques, imaging of macrophages within the plaques, and molecular imaging of biomarkers associated with formation and development of plaques. In addition, imaging of coronary artery stents using IVPA and IVUS imaging is demonstrated. Furthermore, the design of an integrated IVUS/IVPA imaging catheter needed for in vivo clinical applications is discussed.

Pulsed magneto-acoustic imaging.

Nanoparticles are attracting considerable interest as contrast agents for many different imaging modalities. Moreover, imaging the events at the cellular and molecular level is possible by using nanoparticles that have the desired targeting moiety. Unfortunately, ultrasound imaging cannot visualize the nano-structures directly due to its limited spatial resolution and contrast. We present a new technique, pulsed magneto-acoustic imaging, capable of imaging magnetic nanoparticles indirectly. In this method, a high-strength pulsed magnetic field is used to induce motion within the magnetically labeled tissue and ultrasound is used to detect internal tissue motion. Experiments on tissue-mimicking phantoms and ex-vivo animal tissues demonstrated a clear contrast between normal and iron-laden samples labeled with 5 nm magnetic nanoparticles. In addition, the sensitivity of this new imaging technique was investigated for different concentrations of magnetic agents. The results of the study suggest that magnetic nanoparticles can be used as contrast agents in pulsed magneto-acoustic imaging. Furthermore, PMA imaging could become an imaging tool capable of visualizing the cellular and molecular composition of deep-lying structures.

Assessment of shear modulus of tissue using ultrasound radiation force acting on a spherical acoustic inhomogeneity.

An ultrasound-based method to locally assess the shear modulus of a medium is reported. The proposed approach is based on the application of an impulse acoustic radiation force to an inhomogeneity in the medium and subsequent monitoring of the spatio-temporal response. In our experimental studies, a short pulse produced by a 1.5-MHz highly focused ultrasound transducer was used to initiate the motion of a rigid sphere embedded into an elastic medium. Another 25 MHz focused ultrasound transducer operating in pulse-echo mode was used to track the displacement of the sphere. The experiments were performed in gel phantoms with varying shear modulus to demonstrate the relationship between the displacement of the sphere and shear modulus of the surrounding medium. Because the magnitude of acoustic force applied to sphere depends on the acoustic material properties and, therefore, cannot be used to assess the absolute value of shear modulus, the temporal behavior of the displacement of the sphere was analyzed. The results of this study indicate that there is a strong correlation between the shear modulus of a medium and spatio-temporal characteristics of the motion of the rigid sphere embedded in this medium.

Plasmonic intravascular photoacoustic imaging for detection of macrophages in atherosclerotic plaques.

To detect macrophages in atherosclerotic plaques, plasmonic gold nanoparticles are introduced as a contrast agent for intravascular photoacoustic imaging. The phantom and ex vivo tissue studies show that the individual spherical nanoparticles, resonant at 530 nm wavelength, produce a weak photoacoustic signal at 680 nm wavelength while photoacoustic signal from nanoparticles internalized by macrophages is very strong due to the plasmon resonance coupling effect. These results suggest that intravascular photoacoustic imaging can assess the macrophage-mediated aggregation of nanoparticles and therefore identify the presence and the location of nanoparticles associated with macrophage-rich atherosclerotic plaques.

Combined ultrasound and photoacoustic imaging to detect and stage deep vein thrombosis: phantom and ex vivo studies.

Treatment of deep venous thrombosis (DVT)--a primary cause of potentially fatal pulmonary embolism (PE)--depends on the age of the thrombus. The existing clinical imaging methods are capable of visualizing a thrombus but cannot determine the age of the blood clot. Therefore, there is a need for an imaging technique to reliably diagnose and adequately stage DVT. To stage DVT (i.e., to determine the age of the thrombus, and therefore, to differentiate acute from chronic DVT), we explored photoacoustic imaging, a technique capable of noninvasive measurements of the optical absorption in tissue. Indeed, optical absorption of the blood clot changes with age, since maturation of DVT is associated with significant cellular and molecular reorganization. The ultrasound and photoacoustic imaging studies were performed using DVT-mimicking phantoms and phantoms with embedded acute and chronic thrombi obtained from an animal model of DVT. The location and structure of the clots were visualized using ultrasound imaging, while the composition, and therefore age, of thrombi were related to the magnitude and spatiotemporal characteristics of the photoacoustic signal. Overall, the results of our study suggest that combined ultrasound and photoacoustic imaging of thrombi may be capable of simultaneous detection and staging of DVT.

Quantitative ultrasound method to detect and monitor laser-induced cavitation bubbles.

An ultrasound technique to measure the spatial and temporal behavior of the laser-induced cavitation bubble is introduced. The cavitation bubbles were formed in water and in gels using a nanosecond pulsed Nd:YAG laser operating at 532 nm. A focused, single-element, 25-MHz ultrasound transducer was employed both to detect the acoustic emission generated by plasma expansion and to acoustically probe the bubble at different stages of its evolution. The arrival time of the passive acoustic emission was used to estimate the location of the cavitation bubble's origin and the time of flight of the ultrasound pulse-echo signal was used to define its spatial extent. The results of ultrasound estimations of the bubble size were compared and found to be in agreement with both the direct optical measurements of the stationary bubble and the theoretical estimates of bubble dynamics derived from the well-known Rayleigh model of a cavity collapse. The results of this study indicate that the proposed quantitative ultrasound technique, capable of detecting and accurately measuring laser-induced cavitation bubbles in water and in a tissue-like medium, could be used in various biomedical and clinical applications.

Adaptive beamforming for photoacoustic imaging.

An adaptive photoacoustic image reconstruction technique that combines coherence factor (CF) weighting and the minimum variance (MV) method is introduced. The backprojection method is widely used to reconstruct photoacoustic tomography images. Owing to the scattering of light, the quality of the photoacoustic imaging can be degraded. CF, an adaptive weighting technique, is known to improve the lateral resolution of photoacoustic images. In addition, an MV adaptive beamforming method can further improve the image quality by suppressing signals from off-axis directions. Experimental studies are performed to quantify the spatial resolution and contrast of the adaptive photoacoustic beamforming methods.

Ultrasound measurements of cavitation bubble radius for femtosecond laser-induced breakdown in water.

A recently developed ultrasound technique is evaluated by measuring the behavior of a cavitation bubble that is induced in water by a femtosecond laser pulse. The passive acoustic emission during optical breakdown is used to estimate the location of the cavitation bubble's origin. In turn, the position of the bubble wall is defined based on the active ultrasonic pulse-echo signal. The results suggest that the developed ultrasound technique can be used for quantitative measurements of femtosecond laser-induced microbubbles.

Motion of a solid sphere in a viscoelastic medium in response to applied acoustic radiation force: Theoretical analysis and experimental verification.

The motion of a rigid sphere in a viscoelastic medium in response to an acoustic radiation force of short duration was investigated. Theoretical and numerical studies were carried out first. To verify the developed model, experiments were performed using rigid spheres of various diameters and densities embedded into tissue-like, gel-based phantoms of varying mechanical properties. A 1.5 MHz, single-element, focused transducer was used to apply the desired radiation force. Another single-element, focused transducer operating at 25 MHz was used to track the displacements of the sphere. The results of this study demonstrate good agreement between theoretical predictions and experimental measurements. The developed theoretical model accurately describes the displacement of the solid spheres in a viscoelastic medium in response to the acoustic radiation force.