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OBJECTIVES Intravascular photoacoustic (IVPA) imaging is being developed to image atherosclerotic plaques, a leading cause of morbidity and mortality in the United States. However, the safety of this imaging modality, which requires repeated irradiation with short laser pulses, has not yet been investigated. This study has two objectives. First, determine in vitro the limit of cumulative fluence that can be applied to cells before death at IVPA relevant wavelengths. Second, evaluate if high single pulse fluences are a potential cause of cell death during IVPA imaging. MATERIALS AND METHODS Experiments were conducted using endothelial cells, macrophages, and smooth muscle cells. The cumulative fluence experiments were conducted at 1064 and 1197 nm, using a high pulse repetition frequency laser. Cells were irradiated with a wide range of cumulative fluences and evaluated for cell death. The thresholds for death were compared to the maximum expected clinical cumulative fluence. To evaluate the effect of single pulse fluences, cells were irradiated at 1064, 1210, and 1720 nm. Light was delivered at a range of pulse energies to emulate the fluences that cells would be exposed to during clinical IVPA imaging. RESULTS At 1064 nm, all three cell types remained viable at cumulative fluences above the maximum expected clinical cumulative fluence, which is calculated based on common IVPA imaging protocols. At 1197 nm, cells were viable near or just below the maximum expected clinical cumulative fluence, with some cell type to cell type variation. All three cell types remained viable after irradiation with high single pulse fluences at all three wavelengths. CONCLUSION The cumulative fluence experiments indicate that safety considerations are likely to put constraints on the amount of irradiation that can be used in IVPA imaging protocols. However, this study also indicates that it will be possible to use IVPA imaging safely, since cumulative fluences could be reduced by as much as two orders of magnitude below the maximum expected clinical cumulative fluence by varying the imaging protocol, albeit at the expense of image quality. The single pulse fluence experiments indicate that cell death from single pulse fluence is not likely during IVPA imaging. Thus, future studies should focus on heat accumulation as the likely mechanism of tissue damage. Lasers Surg. Med. © 2018 Wiley Periodicals, Inc.

We present a preliminary study demonstrating the capability of ultrasound-guided intravascular photoacoustic (IVPA) imaging to visualize the depth-resolved distribution of lipid deposits in atherosclerotic plaques in vivo. Based on the characteristic optical absorption of lipid in the near infrared wavelength range, IVPA imaging at a single, 1720 nm, wavelength was used to provide a spatially resolved direct measurement of lipid content in atherosclerotic arteries. By overlaying an IVPA image with a spatially co-registered intravascular ultrasound (IVUS) image, the combined IVPA/IVUS image was used to visualize the distribution of lipid within the vessel wall. Ultrasound-guided IVPA imaging was performed in vivo in the abdominal aorta of a Watanabe heritable hyperlipidemic (WHHL) rabbit. Subsequently, the excised rabbit aorta filled with a solution of red blood cells (RBC) was then imaged ex vivo, and the histology was obtained in the section adjacent to the imaged cross-section. To demonstrate the potential of future clinical application of IVPA/IVUS imaging, a sample of diseased human right coronary artery (RCA) was also imaged. Both in vivo and ex vivo IVPA images clearly showed the distribution of lipid in the atherosclerotic vessels. In vivo IVPA imaging was able to identify diffuse, lipid-rich plaques in the WHHL rabbit model of atherosclerosis. Furthermore, IVPA imaging at a single wavelength was able to identify the lipid core within the human RCA ex vivo. Our results demonstrate that ultrasound-guided IVPA imaging can identify lipid in atherosclerotic plaques in vivo. Importantly, the IVPA/IVUS images were obtained in presence of luminal blood and no saline flush or balloon occlusion was required. Overall, our studies suggest that ultrasound-guided IVPA imaging can potentially be used for depth-resolved visualization of lipid deposits within the anatomical context of the vessel wall and lumen. Therefore, IVUS/ IVPA imaging may become an important tool for the detection of rupture-prone plaques.

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.

Combined intravascular ultrasound and photoacoustic imaging (IVUS/IVPA) is an emerging modality for the improved characterization of atherosclerotic plaques including anatomical features of the imaged vessel and tissue composition. Encouraging initial demonstrations of the technique, however, have been limited by slow catheter rotation and data acquisition rates on the order of several seconds per frame, with off-line image processing. Herein, we present both a system and an integrated catheter capable of real-time IVUS/IVPA imaging with online 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 with the electrical signals transmitted at the proximal end using a slip ring rotary joint. Additional components include a pulsed laser operating at 10 kHz pulse repetition frequency, motor and servo drive, an ultrasound pulser/receiver, and a 200 MHz digitizer coupled to a system capable of real-time IVUS/IVPA imaging. The system performance was validated on a vessel-mimicking phantom with an embedded coronary stent intended to provide IVPA contrast within content of an IVUS image.

Noninvasively probing the biomechanical properties of crystalline lens has been challenging due to its unique features such as location inside the eye and being optically and ultrasonically transparent. Here we introduce a method of relying on the spectral analysis of the lens surface response to a mechanical stimulation for the depthdependent assessment of lens biomechanical properties. In this method, acoustic radiation force (ARF) is used to remotely induce the deformation on the surface of the crystalline lens, and a phase-sensitive optical coherence tomography (PhS-OCT) system, co-focused with ARF, utilized to monitor the localized temporal response of ARFinduced deformations on the lens surface. The dominant frequency from the amplitude spectra of the surface response is obtained as the indicator of the depthwise elasticity distribution. Pilot experiments were performed on tissue-mimicking layered phantoms and ex vivo porcine crystalline lens. Results indicate that the frequency response of the sample surface is contributed by the mechanical properties of layers located at different depths and the depthdependent elastic properties can be revealed from the amplitude spectrum. Further study will be focused on combining the experimental measurements with theoretical model and inverse numerical method for depth-resolved elastography of the crystalline lens.

The progressive loss of accommodation of the eye, called presbyopia, affects people with age and can result in a complete loss of accommodation by about age 55 years. It is generally accepted that presbyopia is due to an increase in stiffness of the lens. With increasing age, the stiffness of the crystalline lens nucleus increases faster than that of the cortex. During accommodation, the deformation of different parts of the crystalline lens is different and likely changes with age. However, a direct observation of crystalline lens deformation and strain distribution is difficult because although imaging methods such as OCT or Scheimpflug imaging can distinguish cortex and nucleus, they cannot determine their regional deformation. Here, patterns of laser-induced microbubbles were created in gelatin phantoms and different parts of excised animal crystalline lenses and their displacements in response to external deformation were tracked by ultrasound imaging. In the animal lenses, the deformation of the lens cortex was greater than that of nucleus and this regional difference is greater for a 27-month-old bovine lens than for a 6-month-old porcine lens. This approach enables visualization of localized, regional deformation of crystalline lenses and, if applied to lenses from animal species that undergo accommodation, may help to understand the mechanisms of accommodation and presbyopia, improve diagnostics, and, potentially, aid in the development of new methods of lens modifying presbyopia treatments.

Acoustic Radiation Force (ARF) stimulation is actively used in ultrasound elastography to estimate mechanical properties of tissue. Compared with ultrasound imaging, OCT provides advantage in both spatial resolution and signal-to-noise ratio. Therefore, a combination of ARF and OCT technologies can provide a unique opportunity to measure viscoelastic properties of tissue, especially when the use of high intensity radiation pressure is limited for safety reasons. In this presentation we discuss a newly developed theoretical model of the deformation of a layered viscoelastic medium in response to an acoustic radiation force of short duration. An acoustic impulse was considered as an axisymmetric force generated on the upper surface of the medium. An analytical solution of this problem was obtained using the Hankel transform in frequency domain. It was demonstrated that layers at different depths introduce different frequency responses. To verify the developed model, experiments were performed using tissue-simulating, inhomogeneous phantoms of varying mechanical properties. The Young’s modulus of the phantoms was varied from 5 to 50 kPa. A single-element focused ultrasound transducer (3.5 MHz) was used to apply the radiation force with various durations on the surface of phantoms. Displacements on the phantom surface were measured using a phase-sensitive OCT at 25 kHz repetition frequency. The experimental results were in good agreement with the modeling results. Therefore, the proposed theoretical model can be used to reconstruct the mechanical properties of tissue based on ARF/OCT measurements.

We demonstrate the feasibility of using the dominant frequency of the sample surface response to a mechanical stimulation as an effective indicator for sensing the depthwise distribution of elastic properties in transparent layered phantom samples simulating the cortex and nucleus of the crystalline lens. Focused ultrasound waves are used to noninvasively interrogate the sample surface. A phase-sensitive optical coherence tomography system is utilized to capture the surface dynamics over time with nanometer scale sensitivity. Spectral analysis is performed on the sample surface response to ultrasound stimulation and the dominant frequency is calculated under particular loading parameters. Pilot experiments were conducted on homogeneous and layered tissue-mimicking phantoms. Results indicate that the mechanical layers located at different depths introduce different frequencies to the sample surface response, which are correlated with the depth-dependent elasticity of the sample. The duration and the frequency of the ultrasound excitation are also investigated for their influences on this spectrum-based detection. This noninvasive method may be potentially applied for localized and rapid assessment of the depth dependence of the mechanical properties of the crystalline lens.

In this study the dynamic behavior of a layered viscoelastic medium in response to the impulsive acoustic radiation force applied to its surface was investigated. To verify our theoretical model, experiments were performed using tissue-like gel-based phantoms of varying mechanical properties. A 3.5 MHz single-element focused transducer was used to apply the radiation force at the surface of the phantoms and a phase-sensitive OCT system was used to track the displacements on the phantom surface. The results of this study demonstrate good agreement between theoretical predictions and experimental measurements. It was demonstrated that layers at different depths introduce responses at different frequencies. Therefore, the proposed model in combination with spectral analysis can be used to evaluate depth dependant distribution of the mechanical properties based the measurements on the tissue surface.

Combined intravascular ultrasound and intravascular photoacoustic (IVUS/IVPA) imaging has been previously established as a viable means for assessing atherosclerotic plaque morphological and compositional characteristics using both endogenous and exogenous contrast. In this study, IVUS/IVPA imaging of atherosclerotic rabbit aortas following systemic injection of gold nanorods (AUNRs) with peak absorbance within the tissue optical window is performed. Ex vivo imaging results reveal a high photoacoustic signal from localized AUNRs in regions with atherosclerotic plaques. Corresponding histological staining further confirms the preferential extravasation of AUNRs in atherosclerotic regions with compromised luminal endothelium and acute inflammation. The ability to detect AUNRs using combined IVUS and photoacoustic imaging in the presence of luminal saline and luminal blood is evaluated using both spectroscopic and single wavelength IVPA imaging techniques. Results demonstrate that AUNR detection within the arterial wall can be achieved using both methods, even in the case of imaging through luminal blood.

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.

The mechanical properties of ex vivo animal lenses from three groups were evaluated: old bovine (25–30 mo old, n = 4), young bovine (6 mo old, n = 4) and young porcine (6 mo old, n = 4) eye globes. We measured the dynamics of laser-induced microbubbles created at different locations within the crystalline lenses. An impulsive acoustic radiation force was applied to the microbubble, and the microbubble displacements were measured using a custom-built high pulse repetition frequency ultrasound system. Based on the measured dynamics of the microbubbles, Young's moduli of bovine and porcine lens tissue in the vicinity of the microbubbles were reconstructed. Age-related changes and location-dependent variations in the Young's modulus of the lenses were observed. Near the center, the old bovine lenses had a Young's modulus approximately fivefold higher than that of young bovine and porcine lenses. The gradient of Young's modulus with respect to radial distance was observed in the lenses from three groups.

Intravascular photoacoustic (IVPA) imaging can characterize atherosclerotic plaque composition on the basis of the optical absorption contrast between different tissue types. Given the high optical absorption of lipid at 1720 nm wavelength, an atherosclerotic rabbit aorta was imaged at this wavelength ex vivo using an integrated intravascular ultrasound (IVUS) and IVPA imaging catheter in the presence of luminal blood. Strong optical absorption of lipid combined with low background signal from other tissues provides a high-contrast, depth-resolved IVPA image of lipid. The ability to image lipid at a single wavelength without removing luminal blood suggests that in vivo detection of lipid in atherosclerotic plaques using combined IVUS/IVPA imaging is possible.

Combined intravascular photoacoustic (IVPA) and intravascular ultrasound (IVUS) imaging has been previously established as a viable means for imaging atherosclerotic plaques using both endogenous and exogenous contrast. In this study, IVUS/IVPA imaging of an atherosclerotic rabbit aorta following injection of gold nanorods (AuNR) with peak absorbance within the tissue optical window was performed. Ex-vivo imaging results revealed high photoacoustic signal from localized AuNR. Corresponding histological cross-sections and digital photographs of the artery lumen confirmed the presence of AuNR preferentially located at atherosclerotic regions and in agreement with IVPA signal. Furthermore, an integrated IVUS/IVPA imaging catheter was used to image the AuNR in the presence of luminal blood. The results suggest that AuNR allow for IVPA imaging of exogenously labeled atherosclerotic plaques with a comparatively low background signal and without the need for arterial flushing.

Successful diagnosis and treatment of atherosclerosis demands imaging modalities that can characterize the composition of atherosclerotic plaques, stage the disease, and guide interventional therapy. In this chapter, combined intravascular photoacoustic (IVPA) and intravascular ultrasound (IVUS) imaging is used to address these issues. Based on the difference in optical absorption spectra, lipid-rich tissues can be differentiated using spectroscopic IVPA imaging. Using gold nanoparticles as contrast agent, events happening at the molecular and cellular levels may be visualized in IVPA images. IVPA imaging can also monitor stent deployment during interventional therapy procedures. Design of integrated IVUS/IVPA catheters is discussed. Based on the structural information provided by IVUS images, IVPA images may add further clinically relevant information, helping the management of atherosclerosis.

The vulnerability of atherosclerotic plaques that are formed in the arterial walls due to atherosclerosis depends on both their distribution and composition. The distribution of the plaques can be imaged using an intravascular ultrasound (IVUS) imaging which is a clinically approved minimally-invasive method. The recently introduced intravascular photoacoustic (IVPA) imaging may be used to obtain the necessary information about the composition of the plaques. Previous studies using excised rabbit arteries have demonstrated that the combined IVUS/IVPA imaging may simultaneously provide the morphology and functional information of plaques. However, for in-vivo IVUS/IVPA imaging, an integrated IVUS/IVPA imaging catheter capable both of delivering light into a vessel lumen with consequent detection of photoacoustic transients and of probing the arterial walls in pulse-echo mode is required. In the current study, an advanced prototype of the integrated IVUS/IVPA imaging catheter based on a 40-MHz single-element ultrasound transducer and a 600-μm-core single optical fiber is introduced. Unlike previously reported prototypes, the current integrated IVUS/IVPA imaging catheter is capable of cross-sectional imaging of vessel walls via mechanical rotation of the catheter. The performance of the integrated IVUS/IVPA catheter was evaluated in tissue-mimicking phantoms with and without the presence of blood in a lumen. The results of our study suggest that the approach used to develop integrated IVUS/IVPA imaging catheter can be successfully translated to the clinical environment for in-vivo combined IVUS/IVPA 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.

The ability to visualize and track temporarily or perma- nently implanted metal devices is important in many applications ranging from diagnosis to therapy. Specifically, reliable imaging of metal needles is required in today's clinical settings. Currently, ultra- sound is utilized to image a needle inserted into tissue in real time. However, the diagnostic value and tracking ability of these images depends highly on the orientation of the needle, and also its proximity to regions of interest in the tissue. We examine the use of photoacous- tic imaging combined with current ultrasound imaging methods to obtain high-contrast images of commonly used needles in the body. Experiments were performed using 21 G and 30 G needles inserted into ex vivo porcine tissue and tissue-mimicking phantoms. The needles and surrounding tissue were imaged using an ultrasound im- aging system interfaced with the pulsed laser source necessary for photoacoustic imaging. The results suggest that photoacoustic imag- ing, combined with ultrasound imaging, is capable of real-time, high- contrast, and high-spatial-resolution visualization of metal implants within anatomical landmarks of the background tissue. © 2010 Society of

The effectiveness of an imaging technique is often based on the ability to image quantitatively both morphological and physiological functions of the tissue. Here we present several ultrasound-based imaging techniques capable of visualizing both structural and functional properties of living tissue. Each imaging system utilizes custom-made, targeted nanoparticles developed to probe specific molecular events. Therefore, images of these nanoparticles display molecular processes in the body. Furthermore, the developed nanoparticle contrast agents can also be used for image-guided molecular therapy. For each imaging system, the basic physics and principles behind each approach are described. Experimental aspects of each imaging system including fabrication of integrated imaging probes and associated imaging hardware, and design of targeted contrast agents are discussed. Finally, biomedical and clinical applications of the developed imaging approaches ranging from microscopic to macroscopic imaging of cardiovascular diseases, cancer detection, diagnosis, therapy and therapy monitoring are demonstrated and discussed.

Coronary atherosclerosis is a complex disease accompanied by the development of plaques in the arterial wall. Since the vulnerability of the plaques depends on their composition, the appropriate treatment of the arteriosclerosis requires a reliable characterization of the plaques' geometry and content. The intravascular ultrasound (IVUS) imaging is capable of providing structural details of the plaques as well as some functional information. In turn, more functional information about the same plaques can be obtained from intravascular photoacoustic (IVPA) images since the optical properties of the plaque's components differ from that of their environment. The combined IVUS/IVPA imaging is capable of simultaneously detecting and differentiating the plaques, thus determining their vulnerability. The potential of combined IVUS/IVPA imaging has already been demonstrated in phantoms and ex-vivo experiments. However, for in-vivo or clinical imaging, an integrated IVUS/IVPA catheter is required. In this paper, we introduce two prototypes of integrated IVUS/IVPA catheters for in-vivo imaging based on a commercially available single-element IVUS imaging catheter. The light delivery systems are developed using multimode optical fibers with custom-designed distal tips. Both prototypes were tested and compared using an arterial mimicking phantom. The advantages and limitations of both designs are discussed. Overall, the results of our studies suggest that both designs of integrated IVUS/IVPA catheter have a potential for in-vivo IVPA/IVUS imaging of atherosclerotic plaques.

A new metallodielectric nanoparticle consisting of a silica core and silver outer cage was developed for the purpose of enhancing photoacoustic imaging contrast in pancreatic tissue. These nanocages were injected into an ex vivo porcine pancreas and imaged using a combined photoacoustic and ultrasound (PAUS) assembly. This custom-designed PAUS assembly delivered 800 nm light through a fiber optical light delivery system integrated with 128 element linear array transducer operating at 7.5 MHz center frequency. Imaging results prove that the nanocage contrast agents have the ability to enhance photoacoustic imaging contrast. Furthermore, the value of the combined PAUS imaging modality was demonstrated as the location of nanocages against background native tissue was evident. Future applications of these nanocage contrast agents could include targeting them to pancreatic cancer for enhancement of photoacoustic imaging for diagnosis and therapy.

There is a need for an imaging technique that can reliably identify and characterize the vulnerability of atherosclerotic plaques. Catheter-based intravascular ultrasound (IVUS) is one of the imaging tools of the clinical evaluation of atherosclerosis. However, histopathological information obtained with IVUS imaging is limited. We present and discuss the applicability of a combined intravascular photoacoustic (IVPA) and intravascular ultrasound (IVUS) imaging approach to assess both vessel structure and tissue composition thus identifying rupture-prone atherosclerotic plaques. Photoacoustic (or optoacoustic and, generally, thermoacoustic) imaging relies on the absorption of electromagnetic energy, such as light, and the subsequent emission of an acoustic wave. Therefore, the amplitude and temporal characteristics of the photoacoustic signal is primarily determined by optical absorption properties of different types of tissues and can be used to differentiate the lipid, fibrous and fibro-cellular components of an inflammatory lesion. Simultaneous IVUS and IVPA imaging studies were conducted using 40 MHz clinical IVUS imaging catheter interfaced with a pulsed laser system. The performance of the IVPA/IVUS imaging was assessed using phantoms with point targets and vessel-mimicking phantoms. To detect the lipids in the plaque, ex-vivo IVPA imaging studies of a normal and an atherosclerotic rabbit aorta were performed at a 532 nm wavelength. To assess plaque composition, multi-wavelength (680–950 nm) spectroscopic IVPA imaging studies were carried out. Finally, molecular and cellular IVPA imaging was demonstrated using plasmonic nanoparticles. Overall, our studies suggest that plaque detection and characterization can be improved using the combined IVPA/IVUS imaging.

Highly proliferative cancer cells over express molecular markers such as epidermal growth factor receptor (EGFR). When specifically targeted gold nanoparticles bind to EGFR they tend to cluster on the cell membrane leading to an optical red-shift in the plasmon resonance frequency and an increase in absorption in the red region. These changes in optical properties provide the opportunity for photoacoustic imaging to differentiate cancer cells from surrounding benign cells - the contrast in photoacoustic imaging is based on the optical absorption properties. The imaging experiments were performed using ex-vivo tumor models. The results of our study indicate that photoacoustic imaging is capable of highly sensitive and selective detection of cancer cells by utilizing the plasmon resonance coupling effect of EGFR targeted gold nanoparticles.

An ultrasound-based method to detect and characterize the laser-induced microbubbles was developed. This method is based on temporal measurement of passive acoustic emission from cavity during laser-tissue interaction and simultaneous active pulse-echo ultrasound probing of the cavitation bubble. These measurements were used to estimate the location of the nanosecond laser induced cavity and to monitor the spatial and temporal behavior of the microbubble. The measurements agreed with estimates derived from a well-known Rayleigh model of the cavity collapse. Overall, the studies indicate that the developed ultrasound technique can be used to detect and accurately measure laser-induced microbubbles in tissue.

There is a need for a clinical imaging technique to reliably diagnose and adequately age deep vein thrombosis (DVT). Maturation of DVT is associated with the reorganization and possibly significant changes in the optical absorption of the blood clot. In this paper, we explore photoacoustic imaging to age DVT. Photoacoustic imaging is a technique capable of remote measurements of optical absorption of tissue. Theoretical and experimental studies were performed using DVT-mimicking phantoms. The results of our study suggest that combined ultrasound and photoacoustic imaging of thrombi can provide information about the structure and age of deep vein thrombosis.

An advanced in-vivo imaging technology; namely, combined ultrasound, elasticity and photoacoustic imaging, capable of visualizing both structural and functional properties of living tissue, is presented. This hybrid imaging technology is based on the fusion of the complementary imaging modalities and takes full advantage of the many synergistic features of these systems. To highlight fundamental differences and similarities between the imaging systems and to appreciate advantages and limitations of each imaging system, the basic physics of each imaging system is described. The experimental aspects of combined imaging including hardware, signal and image processing algorithms, etc. are presented. Noise and primary artifacts associated with each imaging modality and combined imaging system are analyzed, and techniques to increase and optimize contrast-to-noise and signal-to-noise ratios in the images are discussed. Finally, biomedical and clinical applications of the combined ultrasound, elasticity and photoacoustic imaging ranging from macroscopic to microscopic imaging of pathology are demonstrated and discussed

Combination of three complementary imaging technologies - ultrasound imaging, elastography, and optoacoustic imaging - is suggested for detection and diagnostics of tissue pathology including cancer. The fusion of these ultrasound-based techniques results in a novel imaging system capable of simultaneous imaging of the anatomy (ultrasound imaging), cancer-induced angiogenesis (optoacoustic imaging) and changes in mechanical properties (elasticity imaging) of tissue to uniquely identify and differentiate pathology at various stages. To evaluate our approach, analytical and numerical studies were performed using heterogeneous phantoms where ultrasonic, optical and viscoelastic properties of the materials were chosen to closely mimic soft tissue. The results of this study suggest that combined ultrasound-based imaging is possible and can provide more accurate, reliable and earlier detection and diagnosis of tissue pathology. In addition, monitoring of cancer treatment and guidance of tissue biopsy are possible with a combined imaging system.

Measurements of mechanical properties of tissue can be used in many applications ranging from disease diagnosis to treatment planning and monitoring. In this paper, we present a technique to measure mechanical properties of the tissue undergoing laser surgery during which the cavitation bubble is introduced. Utilizing the laser‐induced microbubble, the mechanical properties of the tissue were assessed by measuring displacement and oscillations of the bubble under applied acoustic radiation force. The bubbles were produced using a nanosecond pulsed laser operating at 532 nm. Using the lens (0.92 numerical aperture, 11.5‐mm focal length), the laser beam was focused inside the gelatin to create microbubbles ranging from 80‐ to 250‐cm diameter. The bubbles were then interrogated using acoustic pulses of different durations and amplitudes. First, the size of each laser‐induced microbubble was estimated by measuring the laser‐produced shock wave and pulse‐echo ultrasound signals. Then, a 1.5‐MHz transducer gene...

Lasers are used in many biomedical and clinical applications, ranging from diagnosis to therapy. In eye microsurgery, for example, a pulsed laser beam produces a localized surgical effect through the formation of a cavitation microbubble as a result of tissue photodisruption occurring in the focal zone. However, to insure successful presurgical planning, surgical procedure, and postoperative stages of pathology treatment, the mechanical properties of the tissue must be analyzed before selective laser intervention. Since microbubbles are already produced during laser surgery, we have developed an integrated approach utilizing these laser‐induced microbubbles as reporters of tissue viscoelasticity. Specifically, we have derived a general model of gas bubble dynamics in viscoelastic media to describe both translation and oscillations of the microbubble exposed to the acoustic radiation force. Furthermore, an ultrasound method based on temporal measurement of passive acoustic emission from cavity during laser...

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.

The effective management of cancer requires early yet reliable detection, localization, and diagnosis. Therefore, there is a definite and urgent clinical need for an imaging technique that is widely available, is simple to perform, is safe, and that can detect and adequately diagnose cancer. In this paper we present a hybrid imaging technology based on fusion of complementary imaging modalities ultrasound, optoacoustics, and elastography to take full advantage of the many synergistic features of these modalities and thus to significantly improve sensitivity and specificity of cancer imaging. To evaluate our approach, numerical and experimental studies were performed using heterogeneous phantoms where ultrasonic, optical, and viscoelastic properties of the materials were chosen to closely mimic soft tissue. The results of this study suggest that combined ultrasound‐based imaging is possible and can provide more accurate, reliable and earlier detection and diagnosis of tissue pathology. In addition, monitoring of cancer treatment and guidance of tissue biopsy are possible with combined imaging system. Practical and experimental aspects of combined imaging will be discussed with emphasis on data capture and signal/image processing algorithms. The paper will conclude with a discussion of the advantages, limitations, and potential clinical applications of the combined imaging technique.

Assessment of molecular signatures of tumors in addition to their anatomy and morphology is desired for effective diagnostic and therapeutic procedures. Development of in vivo imaging techniques that can identify and monitor molecular composition of tumors remains an important challenge in pre-clinical research and medical practice. Here we present a molecular photoacoustic imaging technique that can visualize the presence and activity of an important cancer biomarker – epidermal growth factor receptor (EGFR), utilizing the effect of plasmon resonance coupling between molecular targeted gold nanoparticles. Specifically, spectral analysis of photoacoustic images revealed profound changes in the optical absorption of systemically delivered EGFR-targeted gold nanospheres due to their molecular interactions with tumor cells overexpressing EGFR. In contrast, no changes in optical properties and, therefore, photoacoustic signal, were observed after systemic delivery of non-targeted gold nanoparticles to the tumors. The results indicate that multi-wavelength photoacoustic imaging augmented with molecularly targeted gold nanoparticles has the ability to monitor molecular specific interactions between nanoparticles and cell-surface receptors, allowing visualization of the presence and functional activity of tumor cells. Furthermore, the approach can be used for other cancer cell-surface receptors such as human epidermal growth factor receptor 2 (HER2). Therefore, ultrasound-guided molecular photoacoustic imaging can potentially aid in tumor diagnosis, selection of customized patient-specific treatment, and monitor the therapeutic progression and outcome in vivo.