Sheng-Wen Huang, Emil Radulescu, Shougang Wang, Karl Thiele, David Prater, Douglas Maxwell, Patrick Rafter, Clement Dupuy, Jeremy Drysdale, Ramon Erkamp
Successful ultrasound data collection strongly relies on the skills of the operator. Among different scans,
echocardiography is especially challenging as the heart is surrounded by ribs and lung tissue. Less experienced users
might acquire compromised images because of suboptimal hand-eye coordination and less awareness of artifacts.
Clearly, there is a need for a tool that can guide and train less experienced users to position the probe optimally. We
propose to help users with hand-eye coordination by displaying lines overlaid on B-mode images. The lines indicate the
edges of blockages (e.g., ribs) and are updated in real time according to movement of the probe relative to the blockages.
They provide information about how probe positioning can be improved. To distinguish between blockage and acoustic
window, we use coherence, an indicator of channel data similarity after applying focusing delays. Specialized
beamforming was developed to estimate coherence. Image processing is applied to coherence maps to detect unblocked
beams and the angle of the lines for display. We built a demonstrator based on a Philips iE33 scanner, from which
beamsummed RF data and video output are transferred to a workstation for processing. The detected lines are overlaid
on B-mode images and fed back to the scanner display to provide users real-time guidance. Using such information in
addition to B-mode images, users will be able to quickly find a suitable acoustic window for optimal image quality, and
improve their skill.
We present a photo-acoustic concave transmitter to generate and subsequently focus high frequency ultrasound. Owing
to a short time-duration of pulse laser beam, high frequency acoustic waves and tight focusing can be easily achieved.
The transmitter consists of a light-absorbing film coated on a concave spherical structure. For detection, we used an
optical microring ultrasound detector capable of covering a broadband and high frequency spectrum of photo-acoustic
source. A spot width of ~44 μm was obtained at the focal plane. As the finite size and the specific shape of the microring
cause a geometrical effect on the detection process, especially for high frequency components, we performed a 2-D
spatial signal processing to remove this effect and extract a pure pressure distribution. The aperture for acoustic focusing
could be optically controlled by changing the size of pulse laser beam.
A photoacoustic correlation spectroscopy (PACS) technique was proposed for the first time. This technique is inspired
by its optical counterpart-the fluorescence correlation spectroscopy (FCS), which is widely used in the characterization
of the dynamics of fluorescent species. The fluorescence intensity is measured in FCS while the acoustic signals are
detected in PACS. To proof of concept, we demonstrated the flow measurement of light-absorbing beads probed by a
pulsed laser. A PACS system with temporal resolution of 0.8 sec was built. Polymer microring resonators were used to
detect the photoacoustic signals, which were then signal processed and used to obtain the autocorrelation curves. Flow
speeds ranging from 249 to 15.1 μm/s with corresponding flow time from 4.42 to 72.5 sec were measured. The
capability of low-speed flow measurement can potentially be used for detecting blood flow in relatively deep capillaries
in biological tissues. Moreover, similar to FCS, PACS may have many potential applications in studying the dynamics of
photoacoustic beads.
Ultrasonic (US) imaging is the most common real-time modality, providing multiple dimensional changes in
morphology for clinical practice. Photoacoustic (PA) imaging has demonstrated great promise as a new functional and
molecular imaging tool. However, absorption in background tissue also generates a PA signal and limits the specific
contrast of molecular contrast agents. To increase the linear range of these agents, the background must be suppressed.
Magnetic nanoparticles provide a new possibility to increase contrast by magnetomotive manipulation during imaging.
A multi-functional imaging system integrating US and PA imaging with magnetic manipulation can take advantage of
each single modality by providing anatomical images and molecular function with greater contrast. However, one key
issue for multi-functional imaging is how to spatially combine and temporarily synchronize US and PA imaging with
magnetomotive instrumentation. In this study, we built a simple system to integrate US and PA imaging with
magnetomotive capability. We evaluated this system by measuring the motion of a phantom including magnetic
nanoparticles (MNPs) using US when these particles were subjected to a time-varying magnetic field.
Photoacoustic tomography is an imaging technique based on the reconstruction of distribution of acoustic pressure,
generated by the absorption of short laser pulses in biological tissues. The detected ultrasound signals can be represented
by the convolution of the structure of objects, the laser pulse, and the impulse response of the ultrasound detectors.
Detector's wideband response is essential for imaging reconstruction of multiscale objects by utilizing a range of
characteristic acoustic wavelengths. Optical detection of ultrasound has the advantage of realizing high-frequency widebandwidth
ultrasound detection. Previously we have demonstrated a polymer microring resonator based ultrasound
detector with flat spectral response from dc to high frequency, over 90 MHz at -3-dB. By using a reconstruction
algorithm to simulate the photoacoustic tomography of microspheres of different sizes, we compared the imaging
performance of the microring resonators and piezoelectric transducers. Due to the broadband response, the former was
able to faithfully detect both the boundaries that are characteristics of high spatial frequencies and the inner structure
consisting primarily of low spatial frequency components. Piezoelectric transducers can only preserve one of the two
aspects, depending on the choice of detector's central frequency. Experimental results demonstrate the benefit of
broadband response of polymer microring resonators.
Ultrasound microscopy uses high frequency (>40 MHz) ultrasound to produce high resolution images. For high
resolution microscopy, broadband ultrasound generation and detection is necessary. Because high frequency ultrasound
experiences significant absorption loss that results in weaker signals, it is desirable to focus the energy for microscopy
applications, which also results in higher lateral resolution. In this work, thermo-elastically generated ultrasound was
brought into a tight focus by shining a ns laser pulse onto a thin metal film-coated concave surface. For ultrasound
detection, we use polymer microring resonators which have high frequency and wide band response. We experimentally
obtained spatial and temporal characteristics of focused ultrasound by optical generation and detection. The 3-dB spot
width of the focused ultrasound is ~50 μm. By frequency filtering over 40~100 MHz, 21 μm width is obtained. The
temporal profile is close to the time-derivative of laser pulse waveform. Frequency domain analysis for the signal shows
that high frequency loss mechanism of our system is dominated by angular directivity of the microring detector. The
issues to improve high frequency response are discussed.
Thin polymer etalons are demonstrated as high-frequency ultrasound sensors for three-dimensional (3-D) high-resolution photoacoustic imaging. The etalon, a Fabry-Perot optical resonator, consists of a thin polymer slab sandwiched between two gold layers. It is probed with a scanning continuous-wave (CW) laser for ultrasound array detection. Detection bandwidth of a 20-µm-diam array element exceeds 50 MHz, and the ultrasound sensitivity is comparable to polyvinylidene fluoride (PVDF) equivalents of similar size. In a typical photoacoustic imaging setup, a pulsed laser beam illuminates the imaging target, where optical energy is absorbed and acoustic waves are generated through the thermoelastic effect. An ultrasound detection array is formed by scanning the probing laser beam on the etalon surface in either a 1-D or a 2-D configuration, which produces 2-D or 3-D images, respectively. Axial and lateral resolutions have been demonstrated to be better than 20 µm. Detailed characterizations of the optical and acoustical properties of the etalon, as well as photoacoustic imaging results, suggest that thin polymer etalon arrays can be used as ultrasound detectors for 3-D high-resolution photoacoustic imaging applications.
A new method is developed to perform local measurements of fluorophore excited state lifetimes in turbid media without collecting the fluorescence emission. The method is based on a pump-probe approach where a first laser pulse excites the dye and then a second laser pulse is used for photoacoustic probing of the transient absorption. The photoacoustic response generated by the probe pulse is recorded by an ultrasound receiver. Repeating the measurement for increasing pump-probe time delays yields a series of photoacoustic signals that are used to extract the lifetime of the excited state. The method is validated by measuring the lifetime of an oxygen sensitive dye solution at different concentrations of dissolved oxygen. The dye is pumped with a 532-nm pulsed laser and the transient absorption at 740 nm is probed using a second pulsed laser system. The photoacoustic-based results are in close agreement with those obtained from time-dependent fluorescent measurements. The method can be extended to photoacoustic lifetime imaging by using a receiver array instead of a single receiver. Potential applications of this method include tissue oxygen imaging for cancer diagnostics and mapping molecular events such as resonant energy transfer and ion collisions in a biological environment.
Cardiovascular inflammatory activity was imaged in vivo. Inflammation is known to be a major cause of
cardiovascular disease. Photoacoustic (PA) imaging was employed using bio-conjugated gold nanorods (GNR) as a
contrast agent. A mouse model based on vascular endothelium injury by a photochemical reaction of Rose Bengal (RB)
dye to green light laser was used. Following a mid-line laparotomy under an approved animal protocol, anti-ICAM-1
conjugated GNR was injected through the dorsal penile vein followed by RB injection through the same vein. The
inferior vena cava immediately distal to the renal veins of a C57BL/6 mouse was exposed to the green light laser for 10
minutes. The peak absorption of GNR was tuned to be 700 nm to minimize possible background absorption by blood
and RB. The stability of GNR in the blood plasma was tested in vitro. Photoacoustic images were obtained through an
ultrasound gel pouch in the mouse abdomen using a commercial ultrasound probe to evaluate inflammatory changes to
the vascular endothelium, confirmed by histology. Preliminary results demonstrate the feasibility of in vivo
photoacoustic imaging by a commercial ultrasound scanner of inflammation using GNR as a contrast agent.
Diagnostic ultrasound imaging traditionally uses piezoelectric transducers for transmission and reception of ultrasound
pulses. As the elements in the imaging array are reduced in size, however, the sensitivity will inherently decrease. We
have developed a new, optically-based ultrasound sensor using polymer microring resonators. The device consists of a
100μm-diameter polystyrene ring waveguide coupled to an input/output bus waveguide, and is fabricated by nanoimprint
lithography. Acoustic pressure causes change in the waveguide cross-section dimension and strain in the polystyrene
material, resulting in a change in the effective refractive index and a shift in resonant wavelength. The ultrasonic
waveform can be recovered from this modulation of optical output. The dynamic range and sensitivity of each microring
can be tuned appropriately by adjusting the Q during fabrication. Our experiments show a low noise-equivalent pressure
on the order of 1 kPa. Sensitivity has been measured by the application of known static pressure and a calibrated 20 MHz
ultrasound transducer. A simple 1D array is demonstrated using wavelength multiplexing. The angular response is
determined by sensing the optoacoustic excitation of a 49μm polyester microsphere and shows wide-angle sensitivity,
making the sensors useful for beamforming. The frequency response is relatively flat between DC and 40 MHz, and can
be extended further by choice of substrate material, limited only by the electrical bandwidth of the photodetector. The
high sensitivity, bandwidth, and angular response make it a potentially useful sensor platform for applications in
ultrasound imaging, dosimetry, and non-destructive testing.
Here we present an ultrasound detection system with an optical end capable of parallel probe. An erbium-doped fiber
amplifier, driven by a tunable laser, outputs light at 27 dBm. A lens collimates the light to probe a 6-μm thick SU-8
etalon and controls the parallel detection area (total array size). A two-lens system guides the reflected light into a
photodetector and controls the active area (array element size) on the etalon surface. A translation stage carries the
photodetector to detect signals from different array elements. The output of the photodetector is recorded using an
oscilloscope. The system's noise equivalent pressure was estimated to be 6.5 kPa over 10~50 MHz using a calibrated
piezoelectric transducer when the -3 dB parallel detection area was 1.8 mm in diameter. The detection bandwidth was
estimate to exceed 70 MHz using a focused 50 MHz piezoelectric transducer. Using a single probe wavelength, a 1D
array with 41 elements and a 1.06 mm aperture length was formed to image a 49 μm black bead photoacoustically. The
final image shows an object size of about 95 μm in diameter. According to the results, realizing high-frequency 2D
optoacoustic arrays using an etalon is possible.
Photonic microring resonators have great potential in the application of highly sensitive label-free biosensors and
detection of high-frequency ultrasound due to high Q-factor resonances. Design consideration, device fabrication
techniques, experimental results are report in this paper.
A quantitative flow measurement method that utilizes a sequence of photoacoustic images is described. The method is based on the use of gold nanorods as a contrast agent for photoacoustic imaging. The peak optical absorption wavelength of a gold nanorod depends on its aspect ratio, which can be altered by laser irradiation (we establish a wash-in flow estimation method of this process). The concentration of nanorods with a particular aspect ratio inside a region of interest is affected by both laser-induced shape changes and replenishment of nanorods at a rate determined by the flow velocity. In this study, the concentration is monitored using a custom-designed, high-frame-rate photoacoustic imaging system. This imaging system consists of fiber bundles for wide area laser irradiation, a laser ultrasonic transducer array, and an ultrasound front-end subsystem that allows acoustic data to be acquired simultaneously from 64 transducer elements. Currently, the frame rate of this system is limited by the pulse-repetition frequency of the laser (i.e., 15 Hz). With this system, experimental results from a chicken breast tissue show that flow velocities from 0.125 to 2 mm/s can be measured with an average error of 31.3%.
Nanoparticles 100 nm in diameter containing indocyanine green (ICG) have been developed as a contrast agent for photoacoustic (PA) imaging based on (photonic explorers for biomedical use by biologically localized embedding PEBBLE) technology using organically modified silicate (ormosil) as a matrix. ICG is an FDA-approved dye with strong optical absorption in the near-infrared (NIR) region, where light can penetrate deepest into biological tissue. A photoacoustic imaging system was used to study image contrast as a function of PEBBLE concentration in phantom objects. ICG-embedded ormosil PEBBLEs showed improved stability in aqueous solution compared with free ICG dye. The particles were conjugated with HER-2 antibody for breast cancer and prostate cancer cell targeting. Initial in vitro characterization shows high contrast and high efficiency for binding to prostate cancer cells. ICG can also be used as a photosensitizer (generating toxic oxygen by illumination) for photodynamic therapy. We have measured the photosensitization capability of ICG-embedded ormosil nanoparticles. This feature can be utilized to combine detection and therapeutic functions in a single agent.
We present a fiber-based optical detection system for high-frequency 3D ultrasound and photoacoustic imaging.
Optically probing the surface of a thin polymer Fabry-Perot etalon defines the acoustic array geometry and element size.
We have previously demonstrated wide bandwidth signal detection (>40 MHz) and element size on the order of 15 &mgr;m.
By integrating an etalon into a photoacoustic imaging system, high-resolution 3D images were obtained. However, the
previous system is limited for clinical applications because the etalon is rigidly attached to a free-space optical scanning
system. To move etalon detector technology toward a practical clinical device, we designed a remote-probe system based
on a fiber bundle. A fiber bundle, composed of 160,000 individual light guides of 8-&mgr;m diameter, delivers the optical
probe to the etalon. Light coupled into a single guide creates an active element on the etalon surface. We successfully
measured the ultrasound signals from 10 MHz and 50 MHz ultrasound transducers using a laser tunable around 1550 nm.
With further progress on reducing the size of the etalon, it will be possible to build a practical device for in vivo high-frequency
3D ultrasound and photoacoustic imaging, especially for intravascular and endoscopic applications.
Photoacoustic imaging provides optical contrast with good penetration and high spatial resolution,
making it an attractive tool for noninvasive neural applications. We chose a commercial dye (NK2761)
commonly used for optical imaging of membrane potential to enhance photoacoustic images of the live
lobster nerve cord. The abdominal segment of the nerve cord was excised, stained and positioned in a
custom neural recording system, enabling electrical stimulation and recording of compound action
potentials. Photoacoustic and pulse echo images were also collected using a commercial ultrasound scanner
and a 10-MHz linear probe. A wavelength-tunable pulsed laser source (SureliteTM, 5 ns, ~15 mJ, 30
mJ/cm2) operating at 20 Hz produced photoacoustic waves. Longitudinal photoacoustic scans of a 25-mm
segment of the excised nerve cord, including ganglionic and axonal processes, were collected and displayed
every 7 seconds. Without the contrast agent, an average of 10 scans produced a peak photoacoustic signal 6
dB over background noise. An additional 29 dB was obtained after the nerve was submerged in the dye for
20 minutes. The gain decreased to 23 dB and 14 dB at 810 nm and 910 nm, respectively - consistent with
the dye's optical absorbance measured using a portable spectrometer. The contrast-enhanced photoacoustic
signal had a broad spectrum peaking at 4 MHz, and, after high pass filtering, images approached 200-&mgr;m
spatial resolution. The hybrid imaging system, which provided several hours of electrical stimulation and
recording, represents a robust testbed to develop novel photoacoustic contrast for neural applications.
Recent advances in fabrication techniques have accelerated development of optical generation and detection of
ultrasound, a promising technology to construct high-frequency arrays for high resolution ultrasound imaging. A
two-dimensional (2-D) gold nanostructure has been fabricated to optically generate high frequency ultrasound. The
structure consists of 2-D arrangements of gold nanoparticles, sandwiched between a transparent substrate and a 4.5 &mgr;m
thick PDMS layer. A pulsed laser beam is focused onto the optically absorbing gold nanostructure, and consequently, a
localized volume is heated, and thermal expansion launches an acoustic wave into the overlying layer. The high optical
extinction ratio of the gold nanostructure provides a convenient method to construct an integrated transmit/receive
optoacoustic array. A thin polymer Fabry-Perot etalon is used for optoacoustic detection. The etalon is an active optical
resonator, where the relatively low elasticity of the polymer and the high quality factor of the resonator combine to
provide high ultrasound sensitivity. An integrated device combining the gold nanostructure and the etalon has been
fabricated. Preliminary results demonstrate its promise as an all-optical ultrasound transducer.
We have studied the potential of gold nanorods to target cancer cells and provide contrast for photoacoustic
imaging. The elongated "rod" shape of these nanoparticles provides a mechanism to tune their plasmon peak absorption
wavelength. The absorption peak is shifted to longer wavelengths by increasing the aspect ratio of the rods. Particles 15
nm in diameter and 45 nm long were prepared using a seed mediated growth method. Their plasmon absorption peak
was designed to be at 800 nm for increased penetration depth into biological tissue. They were conjugated with a
specific antibody to target prostate cancer cells. We have applied photoacoustics to image a prostate cell culture targeted
by conjugated gold particles. Images confirm the efficiency of conjugated particle binding to the targeted cell
membranes. Photoacoustic detection of a single cell layer is demonstrated. To evaluate the applicability of the technique
to clinical prostate cancer detection, we have imaged phantom objects mimicking a real tissue with small (2 mm size)
inclusions of nanoparticle gel solution. Our photoacoustic imaging setup is based on a modified commercial ultrasonic
scanner which makes it attractive for fast implementation in cancer diagnosis in clinical application. In addition, the
setup allows for dual mode operation where a photoacoustic image is superimposed on a conventional B-mode
ultrasound image. Dual mode operation is demonstrated by imaging a mouse with gold nanorod gel solution implanted
in its hind limb.
A high frame rate photoacoustic imaging system is described. Applications of this system to perfusion measurements are also presented as a demonstration of its potential usage. The system consists of an ultrasound front-end sub-system for acquisition of acoustic array data. The ultrasound front-end sub-system is also known as the DiPhAS (digital phased array system) which is capable of simultaneously acquiring radio frequency data from 64 transducer channels at a rate up to 40 MSamples/sec per channel. In this study, an ultrasonic linear array with a 5 MHz center frequency was employed as part of the integrated photoacoustic probe. The photoacoustic probe also had two linear light guides mounted on the sides of the ultrasonic array for broad laser irradiation from a Q-switched Nd:YAG pulsed laser. After the acquired ultrasound array data were transferred to a personal computer via a high speed digital I/Q card, dynamic focusing and image reconstruction were done off-line. The 64-channel array data can be acquired and transferred every 4 milliseconds, thus making the frame rate of the system up to 250 Hz. The actual frame rate of the current system is limited by the pulse repetition frequency of the laser at 15 Hz. To demonstrate capabilities of the system, photoacoustic perfusion measurements with gold nanorods were performed. A previously proposed time-intensity based flow estimation technique utilizing the shape transitions of gold nanorods under laser irradiation was employed. Good estimation results were achieved and potential of this high frame rate photoacoustic imaging system is clearly demonstrated.
A time-intensity based method for photoacoustic blood flow measurements was proposed in last year's meeting. The method made use of the strong photoacoustic response of gold nanospheres and the "wash-out" characteristics of the nanospheres were analyzed. In this paper, we develop a new quantitative technique for measuring blood flows based on the "wash-in" characteristics of the nanoparticles. In particular, the technique makes use of the shape dependence of the optical absorption of gold nanorods (i.e., cylindrical nanoparticles) and the transitions in their shape induced by pulsed laser irradiation. The photon-induced shape transition of gold nanorods involves mainly a rod-to-sphere conversion and a shift in the peak optical absorption wavelength. The application of a series of laser pulses with the same laser energy will induce shape changes in gold nanorods as they flow through a region of interest, with quantitative flow information being derived from the photoacoustic signals from the irradiated gold nanorods measured as a function of time. To demonstrate the feasibility of the technique, an Nd:YAG laser operating at 1064 nm was used for irradiation and a ultrasonic transducer with a center frequency of 1 MHz was used for acoustic detection. Excellent agreement between the measured velocities and the actual velocities was demonstrated, with a linear regression correlation coefficient higher than 0.9. Compared to the wash-out analysis, the wash-in analysis is more suitable for measuring flows in microcirculation.
An optoacoustic detector denotes the detection of acoustic signals by optical devices. Recent advances in fabrication techniques and the availability of high power tunable laser sources have greatly accelerated the development of efficient optoacoustic detectors. The unique advantages of optoacoustic technology are of special interest in applications that require high resolution imaging. For these applications optoacoustic technology enables high frequency transducer arrays with element size on the order of 10 μm. Laser generated ultrasound (photoacoustic effect) has been studied since the early observations of A.G. Bell (1880) of audible sound generated by light absorption . Modern studies have demonstrated the use of the photoacoustic effect to form a versatile imaging modality for medical and biological applications. A short laser pulse illuminates a tissue creating rapid thermal expansion and acoustic emission. Detection of the resulting acoustic field by an array enables the imaging of the tissue optical absorption using ultrasonic imaging methods. We present an integrated imaging system that employs photoacoustic sound generation and 2D optoacoustic reception. The optoacoustic receiver consists of a thin polymer Fabry-Perot etalon. The etalon is an optical resonator of a high quality factor (Q = 750). The relatively low elasticity modulus of the polymer and the high Q-factor of the resonator combine to yield high ultrasound sensitivity. The etalon thickness (10 μm) was optimized for wide bandwidth (typically above 50 MHz). An optical scanning and focusing system is used to create a large aperture and high density 2D ultrasonic receiver array. High resolution 3D images of phantom targets and biological tissue samples were obtained.
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