[Show abstract][Hide abstract] ABSTRACT: Photoacoustic imaging has emerged as a highly promising tool to visualize molecular events with deep tissue penetration. Like most other modalities, however, image contrast under in vivo conditions is far from optimal due to background signals from tissue. Using iron oxide-gold core-shell nanoparticles, we have previously demonstrated the concept of magnetomotive photoacoustic (mmPA) imaging, which is capable of dramatically reducing the influence of background signals and producing high-contrast molecular images. Here, we report two significant advances toward clinical translation of this technology. First, we introduce a new class of compact, uniform, magneto-optically coupled core-shell nanoparticles, prepared through localized copolymerization of polypyrrole (PPy) on an iron oxide nanoparticle surface. The resulting iron oxide-PPy nanoparticles feature high colloidal stability and solve the photoinstability and small-scale synthesis problems previously encountered by the gold coating approach. In parallel, we have developed a new generation of mmPA featuring cyclic magnetic motion and ultrasound speckle tracking (USST), whose imaging capture frame rate is several hundred times faster than the photoacoustic speckle tracking (PAST) method we demonstrated previously. These advances enable robust artifact elimination caused by physiologic motions and demonstrate the application of the mmPA technology for in vivo sensitive tumor imaging.
[Show abstract][Hide abstract] ABSTRACT: Because of depth-dependent light attenuation, bulky, low-repetition-rate lasers are usually used in most photoacoustic (PA) systems to provide sufficient pulse energies to image at depth within the body. However, integrating these lasers with real-time clinical ultrasound (US) scanners has been problematic because of their size and cost. In this paper, an integrated PA/US (PAUS) imaging system is presented operating at frame rates >30 Hz. By employing a portable, low-cost, low-pulse-energy (~2 mJ/pulse), high-repetition-rate (~1 kHz), 1053-nm laser, and a rotating galvo-mirror system enabling rapid laser beam scanning over the imaging area, the approach is demonstrated for potential applications requiring a few centimeters of penetration. In particular, we demonstrate here real-time (30 Hz frame rate) imaging (by combining multiple single-shot sub-images covering the scan region) of an 18-gauge needle inserted into a piece of chicken breast with subsequent delivery of an absorptive agent at more than 1-cm depth to mimic PAUS guidance of an interventional procedure. A signal-to-noise ratio of more than 35 dB is obtained for the needle in an imaging area 2.8 × 2.8 cm (depth × lateral). Higher frame rate operation is envisioned with an optimized scanning scheme.
IEEE Transactions on Ultrasonics Ferroelectrics and Frequency Control 02/2015; 62(2):319-28. DOI:10.1109/TUFFC.2014.006728 · 1.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Investigating the elasticity of ocular tissue (cornea and intraocular lens) could help the understanding and management of pathologies related to biomechanical deficiency. In previous studies, we introduced a setup based on optical coherence tomography for shear wave elastography (SWE) with high resolution and high sensitivity. SWE determines tissue stiffness from the propagation speed of shear waves launched within tissue. We proposed acoustic radiation force to remotely induce shear waves by focusing an ultrasound (US) beam in tissue, similar to several elastography techniques. Minimizing the maximum US pressure is essential in ophthalmology for safety reasons. For this purpose, we propose a pulse compression approach. It utilizes coded US emissions to generate shear waves where the energy is spread over a long emission, and then numerically compressed into a short, localized, and high-energy pulse. We used a 7.5-MHz single-element focused transducer driven by coded excitations where the amplitude is modulated by a linear frequency-swept square wave (1 to 7 kHz). An inverse filter approach was used for compression. We demonstrate the feasibility of performing shear wave elastography measurements in tissue-mimicking phantoms at low US pressures (mechanical index < 0.6). (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License.
[Show abstract][Hide abstract] ABSTRACT: Dynamic elastography using radiation force requires that an ultrasound field be focused during hundreds of microseconds at a pressure of several megapascals. Here, we address the importance of the focal geometry. Although there is usually no control of the elevational focal width in generating a tissue mechanical response, we propose a tunable approach to adapt the focus geometry that can significantly improve radiation force efficiency. Several thin, in-house-made polydimethylsiloxane lenses were designed to modify the focal spot of a spherical transducer. They exhibited low absorption and the focal spot widths were extended up to 8-fold in the elevation direction. Radiation force experiments demonstrated an 8-fold increase in tissue displacements using the same pressure level in a tissue-mimicking phantom with a similar shear wave spectrum, meaning it does not affect elastography resolution. Our results demonstrate that larger tissue responses can be obtained for a given pressure level, or that similar response can be reached at a much lower mechanical index (MI). We envision that this work will impact 3-D elastography using 2-D phased arrays, where such shaping can be achieved electronically with the potential for adaptive optimization.
IEEE Transactions on Ultrasonics Ferroelectrics and Frequency Control 12/2014; 61(12):2032-41. DOI:10.1109/TUFFC.2014.006721 · 1.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Quantitative analysis of left ventricular deformation can provide valuable information about the extent of disease as well as the efficacy of treatment. In this work, we develop an adaptive multi-level compactly supported radial basis approach for deformation analysis in 3D+time echocardiography. Our method combines displacement information from shape tracking of myocardial boundaries (derived from B-mode data) with mid-wall displacements from radio-frequency-based ultrasound speckle tracking. We evaluate our methods on open-chest canines (N=8) and show that our combined approach is better correlated to magnetic resonance tagging-derived strains than either individual method. We also are able to identify regions of myocardial infarction (confirmed by postmortem analysis) using radial strain values obtained with our approach.
IEEE Transactions on Medical Imaging 06/2014; 33(6):1275-1289. DOI:10.1109/TMI.2014.2308894 · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Optically activated cavitation in a nanoemulsion contrast agent is proposed for therapeutic applications. With a 56°C boiling point perfluorohexane core and highly absorptive gold nanospheres at the oil-water interface, cavitation nuclei in the core can be efficiently induced with a laser fluence below medical safety limits (70 mJ/cm<sup>2</sup> at 1064 nm). This agent is also sensitive to ultrasound (US) exposure and can induce inertial cavitation at a pressure within the medical diagnostic range. Images from a high-speed camera demonstrate bubble formation in these nanoemulsions. The potential of using this contrast agent for blood clot disruption is demonstrated in an in vitro study. The possibility of simultaneous laser and US excitation to reduce the cavitation threshold for therapeutic applications is also discussed.
[Show abstract][Hide abstract] ABSTRACT: Laser ultrasonic (LU) inspection represents an attractive, non-contact method to evaluate composite materials. Current non-contact systems, however, have relatively low sensitivity compared to contact piezoelectric detection. They are also difficult to adjust, very expensive, and strongly influenced by environmental noise. Here, we demonstrate that most of these drawbacks can be eliminated by combining a new generation of compact, inexpensive fiber lasers with new developments in fiber telecommunication optics and an optimally designed balanced probe scheme. In particular, a new type of a balanced fiber-optic Sagnac interferometer is presented as part of an all-optical LU pump-probe system for non-destructive testing and evaluation of aircraft composites. The performance of the LU system is demonstrated on a composite sample with known defects. Wide-band ultrasound probe signals are generated directly at the sample surface with a pulsed fiber laser delivering nanosecond laser pulses at a repetition rate up to 76 kHz rate with a pulse energy of 0.6 mJ. A balanced fiber-optic Sagnac interferometer is employed to detect pressure signals at the same point on the composite surface. A- and B-scans obtained with the Sagnac interferometer are compared to those made with a contact wide-band polyvinylidene fluoride transducer.
[Show abstract][Hide abstract] ABSTRACT: Due to the high scattering coefficient of tissue over the wavelength range used for photoacoustic (PA) imaging, most studies employ bulky, low repetition rate lasers to provide sufficient pulse energies at depth to image within the body. The size and cost of these lasers has impeded integration of photoacoustics into conventional, routinely-used ultrasound (US) scanners. Here, we present an approach leveraging the capabilities of modern, high repetition rate fiber lasers to produce a clinically translatable system providing integrated US/PA images at frame rates > 30 Hz. The system uses a portable, low-cost, low pulse-energy (1 mJ/pulse), high repetition rate (1 kHz), 1064 nm laser and is designed for integrated US/PA imaging of the peripheral vasculature or any relevant diseased region, such as a tumor. Using a rotating galvo-mirror system, the incident laser beam is quickly scanned over the imaging area. Multiple PA images covering the scan area are integrated to form a single PA image. Additionally, ultrasound firings are integrated into the scan sequence to provide an US image reconstructed over the same frame period. We acquired PA images of a 1.5-mmdiameter cylindrical absorber (absorption coefficient 5 cm-1) embedded in a tissue-mimicking gelatin phantom at 6-cm depth. A 2 cm × 1 cm (depth × lateral) area was reconstructed. We obtained a signal-to-noise ratio of more than 30 dB, comparable to conventional PA methods using high energy, low repetition rate lasers. The current system produces an integrated US/PA frame at a 32 Hz rate, and 100 Hz frame rates are possible with our present approach.
Conference on Photons Plus Ultrasound: Imaging and Sensing; 03/2014
[Show abstract][Hide abstract] ABSTRACT: Ultrasound-induced inertial cavitation is a mechanical process used for site-localized therapies such as non-invasive surgery. Initiating cavitation in tissue requires very high intensity focused ultrasound (HIFU) and low-frequencies. Hence, some applications like thrombolysis require targeted contrast agents to reduce peak intensities and the potential for secondary effects. A new type of theranostic nanoemulsion has been developed as a combined ultrasound (US)/photoacoustic(PA) agent for molecular imaging and therapy. It includes a nanoscale emulsion core encapsulated with a layer of gold nanospheres at the water/ oil interface. Its optical absorption exhibits a spectrum broadened up to 1100 nm, opening the possibility that 1064 nm light can excite cavitation nuclei. If optically-excited nuclei are produced at the same time that a low-frequency US wave is at peak negative pressure, then highly localized therapies based on acoustic cavitation may be enabled at very low US pressures. We have demonstrated this concept using a low-cost, low energy, portable 1064 nm fiber laser in conjunction with a 1.24 MHz US transducer for simultaneous laser/US excitation of nanoemulsions. Active cavitation detection from backscattered signals indicated that cavitation can be initiated at very low acoustic pressures (less than 1 MPa) when laser excitation coincides with the rarefaction phase of the acoustic wave, and that no cavitation is produced when light is delivered during the compressive phase. US can sustain cavitation activity during long acoustic bursts and stimulate diffusion of the emulsion, thus increasing treatment speed. An in vitro clot model has been used to demonstrate combined US and laser excitation of the nanoemulsion for efficient thrombolysis.
Conference on Photons Plus Ultrasound: Imaging and Sensing; 03/2014
[Show abstract][Hide abstract] ABSTRACT: Optical coherence tomography (OCT) provides high spatial resolution and sensitivity that are ideal for imaging the cornea and lens. Quantifying the biomechanical properties of these tissues could add clinically valuable information. Thus, we propose a dynamic elastography method combining OCT detection and a mechanical actuator to map the shear modulus of soft tissues. We used a piezoelectric actuator driven in the kHz range and we used phase-sensitive OCT (PhS-OCT) to track the resulting shear waves at an equivalent frame rate of 47 kHz. We mapped the shear wave speed of anesthetized mice cornea using monochromatic excitations. We found a significant difference between a group of knock-out (3.92 +/- 0.35 m/s, N=4) and wild-type mice (5.04 +/- 0.51 m/s, N=3). These preliminary results demonstrate the feasibility of using PhS-OCT to perform in vivo shear wave elastography of the cornea. We then implemented a shear pulse compression approach on ex vivo human cornea. For that purpose, frequency- modulated excitations were used and the resulting displacement field was digitally compressed in a short broadband pulse with a 7 dB gain in signal-to-noise ratio (SNR).
Proceedings of SPIE - The International Society for Optical Engineering 02/2014; 8934. DOI:10.1117/12.2040033 · 0.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report on the use of phase-sensitive optical coherence tomography (PhS-OCT) to detect and track temporal and spatial shear wave propagation within tissue, induced by ultrasound radiation force. Kilohertz-range shear waves are remotely generated in samples using focused ultrasound emission and their propagation is tracked using PhS-OCT. Cross-sectional maps of the local shear modulus are reconstructed from local estimates of shear wave speed in tissue-mimicking phantoms. We demonstrate the feasibility of combining ultrasound radiation force and PhS-OCT to perform high-resolution mapping of the shear modulus.
[Show abstract][Hide abstract] ABSTRACT: Shear wave elastography measures the stiffness of soft tissues from the speed of propagating shear waves induced in tissue. Optical coherence tomography (OCT) is a promising detection modality given its high sensitivity and spatial resolution, making it suitable for elastic characterization of skin, peripheral vasculature or ocular tissues. For clinical applications, it would be valuable to use a non-contact shear source. Thus, we propose acoustic radiation force as a remote shear source combined with OCT for visualization. A single-element focused transducer (central frequency 7.5 MHz) was used to apply a maximal pressure of ~3 MPa for 100 μs in agar phantoms. It induced shear waves with an amplitude of several hundreds of nanometers and a broadband spectrum in the kilohertz range. Phasesensitive OCT was used to track shear waves at an equivalent frame rate of 47 kHz. We reconstructed shear modulus maps in a heterogeneous phantom. In addition, we use 3-ms long coded excitation to increase the displacement signal-to-noise ratio. We applied digital pulse compression to the resulting displacement field to obtain a gain of ~15 dB compared to standard pulse excitation while maintaining the US pressure level and the shear wave spatial and temporal resolution. This is a promising result for shear wave generation at low US pressures (~ 1 MPa).
Proceedings of SPIE - The International Society for Optical Engineering 01/2014; 8946. DOI:10.1117/12.2038019 · 0.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A composite contrast agent, a nanoemulsion bead with assembled gold nanospheres at the interface, is proposed to improve the specific contrast of photoacoustic molecular imaging. A phase transition in the bead's core is induced by absorption of a nanosecond laser pulse with a fairly low laser fluence (∼3.5 mJ/cm(2)), creating a transient microbubble through dramatically enhanced thermal expansion. This generates nonlinear photoacoustic signals with more than 10 times larger amplitude compared to that of a linear agent with the same optical absorption. By applying a differential scheme similar to ultrasound pulse inversion, more than 40 dB contrast enhancement is demonstrated with suppression of background signals.
[Show abstract][Hide abstract] ABSTRACT: Assessing the biomechanical properties of soft tissue provides clinically valuable information to supplement conventional structural imaging. In the previous studies, we introduced a dynamic elastography technique based on phase-sensitive optical coherence tomography (PhS-OCT) to characterize submillimetric structures such as skin layers or ocular tissues. Here, we propose to implement a pulse compression technique for shear wave elastography. We performed shear wave pulse compression in tissue-mimicking phantoms. Using a mechanical actuator to generate broadband frequency-modulated vibrations (1 to 5 kHz), induced displacements were detected at an equivalent frame rate of 47 kHz using a PhS-OCT. The recorded signal was digitally compressed to a broadband pulse. Stiffness maps were then reconstructed from spatially localized estimates of the local shear wave speed. We demonstrate that a simple pulse compression scheme can increase shear wave detection signal-to-noise ratio (>12 dB gain) and reduce artifacts in reconstructing stiffness maps of heterogeneous media.
[Show abstract][Hide abstract] ABSTRACT: We propose an integrated method combining low-frequency mechanics with optical imaging to map the shear modulus within the biological tissue. Induced shear wave propagating in tissue is tracked in space and time using phase-sensitive optical coherence tomography (PhS-OCT). Local estimates of the shear-wave speed obtained from tracking results can image the local shear modulus. A PhS-OCT system remotely records depth-resolved, dynamic mechanical waves at an equivalent frame rate of ∼47 kHz with the high spatial resolution. The proposed method was validated by examining tissue-mimicking phantoms made of agar and light scattering material. Results demonstrate that the shear wave imaging can accurately map the elastic moduli of these phantoms.
[Show abstract][Hide abstract] ABSTRACT: A computationally efficient method for phase aberration correction in ultrasound imaging is presented. The method is based on time delay estimation via minimization of the sum of absolute differences between radio frequency samples of adjacent array elements. Effects of averaging estimated aberration pat- terns over scan angles, and truncation to a single bit wordlength are examined. Phase distortions due to near-field inhomogeneities are simulated using silicone rubber aberrators. Performance of the method is tested using experimental data. Simulation studies addressing different factors affecting efficiency of the method, such as the number of iterations, window length, and the number of scan angles used for averaging, are presented. Images of a standard resolution phantom are reconstructed and used for qualitative testing.
[Show abstract][Hide abstract] ABSTRACT: The advantages of photoacoustic (PA) imaging, including low cost, non-ionizing operation, and sub-mm spatial resolution at centimeters depth, make it a promising modality to probe nanoparticle-targeted abnormalities in real time at cellular and molecular levels. However, detecting rare cell types in a heterogeneous background with strong optical scattering and absorption remains a big challenge. For example, differentiating circulating tumor cells in vivo (typically fewer than 10 cells/mL for an active tumor) among billions of erythrocytes in the blood is nearly impossible. In this paper, a newly developed technique, magnetomotive photoacoustic (mmPA) imaging, which can greatly increase the sensitivity and specificity of sensing targeted cells or molecular interactions, is reviewed. Its primary advantage is suppression of background signals through magnetic enrichment/manipulation with simultaneous PA detection of magnetic contrast agent targeted objects. Results from phantom and in vitro studies demonstrate the capability of mmPA imaging to differentiate regions targeted with magnetic nanoparticles from the background, and to trap and sensitively detect targeted cells at a concentration of a single cell per milliliter in a flow system mimicking a human peripheral artery. This technique provides an example of the ways in which molecular imaging can potentially enable robust molecular diagnosis and treatment, and accelerate the translation of molecular medicine into the clinic.
[Show abstract][Hide abstract] ABSTRACT: In recent years, conjugated polymers have attracted considerable attention from the imaging community as a new class of contrast agent due to their intriguing structural, chemical, and optical properties. Their size and emission wavelength tunability, brightness, photostability, and low toxicity have been demonstrated in a wide range of in vitro sensing and cellular imaging applications, and have just begun to show impact in in vivo settings. In this Perspective, we summarize recent advances in engineering conjugated polymers as imaging contrast agents, their emerging applications in molecular imaging (referred to as in vivo uses in this paper), as well as our perspectives on future research.