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Optoacoustic Imaging is based on the thermal expansion of tissue caused by a temperature rise due to absorption of short laser pulses. At constant laser fluence, optoacoustic image contrast is proportional to differences in optical absorption and the thermoacoustic efficiency, expressed by the Grneisen parameter, Γ. Γ is proportional to the thermal expansion coefficient, the sound velocity squared and the inverse heat capacity at constant pressure. In thermal therapies, these parameters may be modified in the treated area. In this work experiments were performed to examine the influence of these parameters on image contrast. A Laser Optoacoustic Imaging System (LOIS, Fairway Medical Technologies, Houston, Texas) was used to image tissue phantoms comprised of cylindrical Polyvinyl Chloride Plastisol (PVCP) optical absorbing targets imbedded in either gelatin or PVCP as the background medium. Varying concentrations of Black Plastic Color (BPC) and titanium dioxide (TiO2)were added to targets and background to yield desired tissue relevant optical absorption and effective scattering coefficients, respectively. In thermal therapy experiments, ex-vivo bovine liver was heated with laser fibres (805nm laser at 5 W for 600s) to create regions of tissue coagulation. Lesions formed in the liver tissue were visible using the LOIS system with reasonable correspondence to the actual region of tissue coagulation. In the phantom experiments, contrast could be seen with low optical absorbing targets (μaof 0.50cm−1down to0.13cm−1)embedded in a gelatin background (μa=0.13cm−1andμs′=4.2cm−1). Therefore, the data suggest that small objects (

The goal of quantitative optoacoustic tomography (qOAT) is to reconstruct a distribution of absolute chromophore concentrations and/or functional properties from measurements of the optically induced pressure (ultrasound signals) acquired at multiple excitation wavelengths. Estimating the distribution of hemoglobin, an endogenous OAT chromophore, is important because the oxygen saturation distribution of the blood vessels is a well-known indicator of aggressive growth of a cancerous tumor. In a number of studies, a spectral linear unmixing method has been applied to two-dimensional slices of tissue acquired with OAT at multiple wavelengths, leading to promising results at moderate penetration depths of ≤ 2 cm. In the three-dimensional (3D) OAT of the breast, such functional images cannot be accurately reconstructed via the spectral linear unmixing method due to unknown spatial distribution of the optical fluence in a relatively large size of the volume of interest (≥ 4 cm). Optical attenuation in biological tissue depends on the optical wavelength, and the optical fluence is exponentially attenuated with increasing imaging depth. Thus, the accuracy of the estimated distribution decreases with depth. To overcome this challenge, we investigated a spectral linear unmixing method with a simplified optical fluence normalization based on measurements of background absorbed optical energy in the breast. We compare estimates of blood oxygen saturations from two-wavelength clinical OAT breast images and demonstrate acceptable accuracy of ~10% while lack of compensation for the optical fluence distribution can lead to values outside the physiological range. We also quantitatively compare the accuracy of oxygen saturation estimates using numerical simulation of photon transport in realistic 3D OAT breast phantoms at dual wavelengths of 757 and 850 nm with inverse ratio of the optical absorption by deoxy- (Hb) and oxy-hemoglobin (HbO2) and three wavelengths of 757, 800, and 850 nm with inclusion of isosbestic point of the optical absorption in Hb/HbO2.

Due to a demonstrated capability to assess tumor angiogenesis and hypoxia in mammalian systems, there is great interest in applying optoacoustic tomography (OAT) to the study and screening of breast cancer. In order to translate OAT to clinical applications, in silico studies are crucial for studying imaging system parameters that might be impossible to assess via direct experimentation. Previous numerical phantoms have proven to be too unrealistic for rigorous testing of modern image reconstruction methods and clinically relevant signal detection tasks. Recently, the U.S. Food and Drug Administration has released software to generate realistic three-dimensional numerical realizations of the human female breast as part of the Virtual Imaging Clinical Trials for Regulatory Evaluation (VICTRE) project. By careful selection of physical attributes and material coefficients, the VICTRE breast phantom can be customized for particular imaging tasks, but no such customization has been given for OAT. We propose a general framework of in silico studies for OAT breast imaging using the VICTRE breast phantom. We will create an ensemble of OAT breast phantoms, using appropriate optical and acoustic parameters, that have typical sizes and tissue densities. Various lesions will be created and embedded based on clinical scenarios. We will define and perform several signal detection tasks by which the system performance may be compared. Generation of such an ensemble requires substantial computation but once produced, it can be utilized in other numerical simulation studies of the configuration of OAT imaging systems customized for diverse tasks. We will make this ensemble of phantoms publicly available online. The proposed framework will permit standardization of the assessment of 3D OAT data-acquisition parameters and image reconstruction methods.

Optoacoustic imaging, based on the differences in optical contrast of blood hemoglobin and oxyhemoglobin, is uniquely suited for the detection of breast vasculature and tumor microvasculature with the inherent capability to differentiate hypoxic from the normally oxygenated tissue. We describe technological details of the clinical ultrasound (US) system with optoacoustic (OA) imaging capabilities developed specifically for diagnostic imaging of breast cancer. The combined OA/US system provides co-registered and fused images of breast morphology based upon gray scale US with the functional parameters of total hemoglobin and blood oxygen saturation in the tumor angiogenesis related microvasculature based upon OA images. The system component that enabled clinical utility of functional OA imaging is the hand-held probe that utilizes a linear array of ultrasonic transducers sensitive within an ultrawide-band of acoustic frequencies from 0.1 MHz to 12 MHz when loaded to the high-impedance input of the low-noise analog preamplifier. The fiberoptic light delivery system integrated into a dual modality probe through a patented design allowed acquisition of OA images while minimizing typical artefacts associated with pulsed laser illumination of skin and the probe components in the US detection path. We report technical advances of the OA/US imaging system that enabled its demonstrated clinical viability. The prototype system performance was validated in well-defined tissue phantoms. Then a commercial prototype system named Imagio™ was produced and tested in a multicenter clinical trial termed PIONEER. We present examples of clinical images which demonstrate that the spatio-temporal co-registration of functional and anatomical images permit radiological assessment of the vascular pattern around tumors, microvascular density of tumors as well as the relative values of the total hemoglobin [tHb] and blood oxygen saturation [sO2] in tumors relative to adjacent normal breast tissues. The co-registration technology enables increased accuracy of radiologist assessment of malignancy by confirming, upgrading and/or downgrading US categorization of breast tumors according to Breast Imaging Reporting And Data System (BI-RADS). Microscopic histologic examinations on the biopsied tissue of the imaged tumors served as a gold standard in verifying the functional and anatomic interpretations of the OA/US image feature analysis. Keywords: Optoacoustic, Photoacoustic, Ultrasound, Functional-anatomical imaging, Breast cancer, Diagnostics, Dual modality

Guest editors introduce contributors to the Special Section Celebrating the Exponential Growth of Optoacoustic/Photoacoustic Imaging. We are pleased to introduce the contributions to this JBO Special Section entitled “Celebrating the Exponential Growth of Biomedical Optoacoustic/Photoacoustic Imaging.” This title was chosen to reflect the strong growth of the field over the last two and a half decades. The diversity of papers in this special section bears witness to this, with contributions that encompass numerical modelling, advanced instrumentation, functional imaging, clinical translation, and novel biomedical applications.

Optoacoustic tomography (OAT) is a promising modality for breast imaging that provides high resolution, detection sensitivity and diagnostic specificity for vascularized breast tumors. In OAT systems employing an arc- shaped illuminator, irregular overlaps of light beams can yield a non-uniform illumination throughout the entire volume of the breast. The imbalance in optical fluence leads to intensity loss in the reconstructed OAT images. Additionally, because optical fluence decreases with depth from breast skin surface, i.e., optical attenuation, deep breast tissues are diminished in the reconstructed images. For qualitative enhancement in 3D OAT imaging, we propose an image processing method to estimate, and compensate for, both the non-uniform incident optical fluence and the optical attenuation. We approximate the non-uniform illumination via maximum intensity extraction for polar angles in a spherical coordinate system. The location of the breast surface is estimated by detecting blood vessels nearest to the breast skin layer that appear with relatively high intensities in the reconstructed image. The breast depth is computed as the minimum distance between each voxel and the detected breast surface. The depth-dependent optical attenuation in the breast is estimated using the Beer– Lambert law down to the maximum penetration depth determined from an analysis of noise and artifacts in the reconstructed image. At each polar angle, the reciprocals of the estimated attenuation is used to compensate for the loss in intensity. The results are that previously invisible structures near the chest wall are revealed, and visible penetration depth was increased by 67% over the conventional, non-compensated volumes.

Optoacoustic (OA) microscopy using an all-optical system based on the probe beam deflection technique (PBDT) for detection of laser-induced acoustic signals was investigated as an alternative to conventional piezoelectric transducers. PBDT provides a number of advantages for OA microscopy including (i) efficient coupling of laser excitation energy to the samples being imaged through the probing laser beam, (ii) undistorted coupling of acoustic waves to the detector without the need for separation of the optical and acoustic paths, (iii) high sensitivity and (iv) ultrawide bandwidth. Because of the unimpeded optical path in PBDT, diffraction-limited lateral resolution can be readily achieved. The sensitivity of the current PBDT sensor of 22μV/Pa and its noise equivalent pressure (NEP) of 11.4Pa are comparable with these parameters of the optical micro-ring resonator and commercial piezoelectric ultrasonic transducers. Benefits of the present prototype OA microscope were demonstrated by successfully resolving micron-size details in histological sections of cardiac muscle.

Laser Optoacoustic Ultrasonic Imaging System Assembly (LOUISA-3D) was developed in response to demand of diagnostic radiologists for an advanced screening system for the breast to improve on low sensitivity of x-ray based modalities of mammography and tomosynthesis in the dense and heterogeneous breast and low specificity magnetic resonance imaging. It is our working hypothesis that co-registration of quantitatively accurate functional images of the breast vasculature and microvasculature, and anatomical images of breast morphological structures will provide a clinically viable solution for the breast cancer care. Functional imaging is LOUISA-3D is enabled by the full view 3D optoacoustic images acquired at two rapidly toggling laser wavelengths in the near-infrared spectral range. 3D images of the breast anatomical background is enabled in LOUISA-3D by a sequence of B-mode ultrasound slices acquired with a transducer array rotating around the breast. This creates the possibility to visualize distributions of the total hemoglobin and blood oxygen saturation within specific morphological structures such as tumor angiogenesis microvasculature and larger vasculature in proximity of the tumor. The system has four major components: (i) a pulsed dual wavelength laser with fiberoptic light delivery system, (ii) an imaging module with two arc shaped probes (optoacoustic and ultrasonic) placed in a transparent bowl that rotates around the breast, (iii) a multichannel electronic system with analog preamplifiers and digital data acquisition boards, and (iv) computer for the system control, data processing and image reconstruction. The most important advancement of this latest system design compared with previously reported systems is the full breast illumination accomplished for each rotational step of the optoacoustic transducer array using fiberoptic illuminator rotating around the breast independently from rotation of the detector probe. We report here a pilot case studies on one healthy volunteer and on patient with a suspicious small lesion in the breast. LOUISA3D visualized deoxygenated veins and oxygenated arteries of a healthy volunteer, indicative of its capability to visualize hypoxic microvasculature in cancerous tumors. A small lesion detected on optoacoustic image of a patient was not visible on ultrasound, potentially indicating high system sensitivity of the optoacoustic subsystem to small but aggressively growing cancerous lesions with high density angiogenesis microvasculature. The main breast vasculature (0.5-1 mm) was visible at depth of up to 40-mm with 0.3-mm resolution. The results of LOUISA-3D pilot clinical validation demonstrated the system readiness for statistically significant clinical feasibility study.

Noninvasive determination of optical energy distribution in live biological tissues is an important aspect of any laser treatment or diagnostic procedure. It is particularly important for optical dosimetry in tissue, tissue diagnostics based on optical properties, quantitative molecular and functional imaging in the human body based on optical contrast, laser therapeutic procedures (such as photodynamic therapy, photothermal therapy, and laser treatment of various skin lesions and hair removal), and laser microsurgery. Monitoring of changes in tissue optical properties can also be utilized for monitoring of laser–tissue interactions, noninvasive optical biopsy, the effects of laser ablation or denaturation of tissue, and ablation by high-intensity focused ultrasound (HIFU). The precision of these procedures would improve significantly if laser irradiation conditions could be adjusted in accordance with initial optical properties and with changes in optical properties during the course of the treatment. Therefore, there is a definite need for noninvasive measurement and visualization of the light distribution profile in the laser-irradiated tissue in vivo. Such feedback information helps predict the optimal laser wavelength, pulse duration, laser intensity, and light dose to be delivered so as to obtain diagnostic information or to cause a sufficient effect during treatment with minimal damage to adjacent tissue layers.

We describe the ongoing development and performance of a high-pulse-energy wavelength-cycling laser system for three-dimensional optoacoustic tomography of the breast. Joule-level energies are desired for achieving the required penetration depths while maintaining safe fluence levels. Wavelength cycling provides a pulse sequence which repeatedly alternates between two wavelengths (approximately 756 and 797 nm) that provide differential imaging. This improves co-registration of captured differential images and quantification of blood oxygen saturation. New design features have been developed for and incorporated into a clinical prototype laser system, to improve efficacy and ease of use in the clinic. We describe the benefits of these features for operation with a clinical pilot optoacoustic / ultrasound dual-modality three-dimensional imaging system.

We developed a new and improved Laser Optoacoustic Imaging System, LOIS-3D for preclinical research applications in small animal models. The advancements include (i) a new stabilized imaging module with a more homogeneous illumination of the mouse yielding a better spatial resolution (

The hybrid nature of optoacoustic tomography (OAT) brings together the advantages of both optical imaging and ultrasound imaging, making it a promising tool for breast cancer imaging. It is advocated in the modern imaging science literature to utilize objective, or task-based, measures of system performance to guide the optimization of hardware design and image reconstruction algorithms. In this work, we investigate this approach to assess the performance of OAT breast imaging systems. In particular, we apply principles from signal detection theory to compute the detectability of a simulated tumor at different depths within a breast, for two different system designs. The signal-to-noise ratio of the test statistic computed by a numerical observer is employed as the task-specific summary measure of system performance. A numerical breast model is employed that contains both slowly varying background and vessel structures as the background model, and superimpose a deterministic signal to emulate a tumor. This study demonstrates how signal detection performance of a numerical observer will vary as a function of signal depth and imaging system characteristics. The described methodology can be employed readily to systematically optimize other OAT imaging systems for tumor detection tasks.

An optoacoustic (OA) sensor was designed, fabricated, and used to detect spherical gold nanoparticles (NPs) in diluted suspensions. The sensor, operating in the backward mode, was designed to measure signals from microscopic volumes of nanoparticulate suspensions in water. Thermal nonlinearity was observed in the course of OA signal generation. The irradiation of a microvolume of gold nanoparticles at the wavelength matching the peak of their plasmon resonance absorption gives rise to a multitude of thermomechanical processes, including heating of NPs below the critical temperature of water (374 K). The thermal diffusion from nanoparticles to water takes place; however, formation of vapor nanobubbles is avoided. As a result, a specific acoustic signal is produced exhibiting nonlinear behavior with respect to the incident laser pulse energy. The optoacoustic profile of the laser-induced signal generated in a thin layer of highly diluted suspensions of gold nanospheres was examined, thereby providing a basis for a method for detection of metal nanoparticles with high sensitivity.

This lecture presents the design, technical parameters and results of clinical validation of the 2D and 3D laser optoacoustic ultrasonic imaging systems applied in diagnostic imaging of breast cancer.

Optoacoustic tomography (OAT), also known as photoacoustic tomography, is a rapidly emerging hybrid imaging technique that possesses great potential for a wide range of biomedical imaging applications. In OAT, a laser is employed to illuminate the tissue of interest and acoustic signals are produced via the photoacoustic effect. From these data, an estimate of the distribution of the absorbed optical energy density within the tissue is reconstructed, referred to as the object function. This quantity is defined, in part, by the distribution of light fluence within the tissue that is established by the laser source. When performing three-dimensional imaging of large objects, such as a female human breast, it can be difficult to achieve a relatively uniform coverage of light fluence within the volume of interest when the position of the laser source is fixed. To circumvent this, researchers have proposed illumination schemes in which the relative position of the laser source and ultrasound probe is fixed, and both are rotated together to acquire a tomographic data set. A problem with this rotating-illumination scheme is that the tomographic data are inconsistent; namely, the acoustic data recorded at each tomographic view angle (i.e., probe position) are produced by a distinct object function. In this work, the impact of this data inconsistency on image reconstruction accuracy is investigated systematically. This is accomplished by use of computer-simulation studies and application of mathematical results from the theory of microlocal analysis. These studies specify the set of image discontinuities that can be stably reconstructed with a non-stationary optical illumination set-up. The study also includes a comparison of the ability of iterative and analytic image reconstruction methods to mitigate artifacts attributable to the data inconsistency.

Functional opto-acoustic (OA) imaging was fused with gray-scale ultrasound acquired using a specialized duplex handheld probe. Feasibility Study findings indicated the potential to more accurately characterize breast masses for cancer than conventional diagnostic ultrasound (CDU). The Feasibility Study included OA imagery of 74 breast masses that were collected using the investigational Imagio® breast imaging system. Superior specificity and equal sensitivity to CDU was demonstrated, suggesting that OA fusion imaging may potentially obviate the need for negative biopsies without missing cancers in a certain percentage of breast masses. Preliminary results from a 100 subject Pilot Study are also discussed. A larger Pivotal Study (n=2,097 subjects) is underway to confirm the Feasibility Study and Pilot Study findings.

Iterative image reconstruction algorithms can model complicated imaging physics, compensate for imperfect data acquisition systems, and exploit prior information regarding the object. Hence, they produce higher quality images than do analytical image reconstruction algorithms. However, three-dimensional (3D) iterative image reconstruction is computationally burdensome, which greatly hinders its use with applications requiring a large field-of-view (FOV), such as breast imaging. In this study, an improved GPU-based implementation of a numerical imaging model and its adjoint have been developed for use with general gradient-based iterative image reconstruction algorithms. Both computer simulations and experimental studies are conducted to investigate the efficiency and accuracy of the proposed implementation for optoacoustic tomography (OAT). The results suggest that the proposed implementation is more than five times faster than the previous implementation.

We found and interpreted the universal temperature-dependent optoacoustic (photoacoustic) response (ThOR) in blood; the normalized ThOR is invariant with respect to hematocrit at the hemoglobin’s isosbestic point. The unique compartmentalization of hemoglobin, the primary optical absorber at 805 nm, inside red blood cells (RBCs) explains the effect. We studied the temperature dependence of Gruneisen parameter in blood and aqueous solutions of hemoglobin and for the first time experimentally observed transition through the zero optoacoustic response at temperature T 0 , which was proved to be consistent for various blood samples. On the other hand, the hemoglobin solutions demonstrated linear concentration function of the temperature T 0 . When this function was extrapolated to the average hemoglobin concentration inside erythrocytes, the temperature T 0 was found equivalent to that measured in whole and diluted blood. The obtained universal curve of blood ThOR was validated in both transparent and light scattering media. The discovered universal optoacoustic temperature dependent blood response provides foundation for future development of non-invasive in vivo temperature monitoring in vascularized tissues and blood vessels.

Optoacoustic tomography (OAT) is a promising imaging modality for human breast cancer imaging, with higher resolution and deeper penetration compared to other optical imaging modalities such as diffuse optical tomography or optical coherence tomography. It yields a resolution of 1 mm at depth up to 2 cm. But there is an inherent conflict between the limitations imposed on laser power and the need to adequately penetrate a substantial portion of the breast. To achieve sufficient penetration at every view angle, instead of illuminating the whole breast all at once, sometimes illumination is focused onto a small region of the breast and rotated along with the transducer array to cover the entire object. This paper evaluates the effect of this rotating partial illumination design on OAT image reconstruction. The optical process is simulated by conducting Monte Carlo simulations on a numerical phantom mimicking a real breast, with various specially designed illumination schemes. The acoustic process is simulated by incorporating the transducer's spatial impulse response. Iterative reconstruction is applied to estimate the OAT image. We conclude that rotating partial illumination introduces inconsistency into the system equation, and the degree of inconsistency determines the reconstruction quality.

Optoacoustic (photoacoustic) imaging is being adopted for monitoring tissue temperature during hypothermic and hyperthermic cancer treatments. The technique’s accuracy benefits from the knowledge of speed of sound (SoS) and acoustic coefficient of attenuation (AcA) as they change with temperature in biological tissues, blood, and acoustic lens of an ultrasound probe. In these studies we measured SoS and AcA of different ex vivo tissues and blood components (plasma and erythrocyte concentrates) in the temperature range from 5°C to 60°C. We used the technique based on measurements of time-delay and spectral amplitude of pressure pulses generated by wideband planar acoustic waves propagating through the interrogated medium. Water was used as a reference medium with known acoustic properties. In order to validate our experimental technique, we measured the temperature dependence of SoS and AcA for aqueous NaCl solution of known concentration and obtained the results in agreement with published data. Similar to NaCl solution and pure water, SoS in blood and plasma was monotonously increasing with temperature. However, SoS of erythrocyte concentrates displayed abnormalities at temperatures above 45°C, suggesting potential effects from hemoglobin denaturation and/or hemolysis of erythrocytes. On the contrary to aqueous solutions, the SoS in polyvinyl-chloride (plastisol) – a material frequently used for mimicking optical and acoustic properties of tissues – decreased with temperature. We also measured SoS and AcA in silicon material of an acoustic lens and did not observe temperature-related changes of SoS.

In this work, we introduce an improved prototype of the imaging system that combines three-dimensional optoacoustic tomography (3D-OAT) and laser ultrasound tomography slicer (2D-LUT) to obtain coregistered maps of tissue optical absorption and speed of sound (SOS). The imaging scan is performed by a 360 degree rotation of a phantom/mouse with respect to a static arc-shaped array of ultrasonic transducers. A Q-switched laser system is used to establish optoacoustic illumination pattern appropriate for deep tissue imaging with a tunable (730-840 nm) output wavelengths operated at 10 Hz pulse repetition rate. For the LUT slicer scans, the array is pivoted by 90 degrees with respect to the central transducers providing accurate registration of optoacoustic and SOS maps, the latter being reconstructed using waveform inversion with source encoding (WISE) technique. The coregistered OAT-LUT modality is validated by imaging a phantom and a live mouse. SOS maps acquired in the imaging system can be employed by an iterative optoacoustic reconstruction algorithm capable of compensating for acoustic wavefield aberrations. The most promising applications of the imaging system include 3D angiography, cancer research, and longitudinal studies of biological distributions of optoacoustic contrast agents (carbon nanotubes, metal plasmonic nanoparticles, fluorophores, etc.).

Optoacoustic (OA) sensor was designed, fabricated and used to detect spherical gold nanoparticles (NPs) in suspensions at the level of up to a single particle. The sensor operating in the backward mode was designed to measure signals from microscopic volumes of nanoparticulate suspensions in water. Thermal nonlinearity was observed in the course of OA signal generation. The irradiation of the microvolume of gold nanoparticles gives rise to a multitude of thermomechanical processes, including heating of NPs above the vaporization temperature, thermal diffusion from nanoparticles to water and formation of vapor nanobubbles. As a result, a specific acoustic signal is produced exhibiting nonlinear behaviour with respect to the incident laser pulse energy. The optoacoustic profile of the laser-induced signal generated in a thin layer of highly diluted suspensions of gold nanospheres was examined thereby providing a basis for a method for detection of metal nanoparticles with high sensitivity.

A laser optoacoustic imaging system (LOIS) uses time-resolved detection of laser-induced pressure profiles in tissue in order to reconstruct images of the tissue based on distribution of acoustic sources. Laser illumination with short pulses generates distribution of acoustic sources that accurately replicates the distribution of absorbed optical energy. The complex spatial profile of heterogeneous distribution of acoustic sources can be represented in the frequency domain by a wide spectrum of ultrasound ranging from tens of kilohertz to tens of megahertz. Therefore, LOIS requires a unique acoustic detector operating simultaneously within a wide range of ultrasonic frequencies. Physical principles of an array of ultrawide-band ultrasonic transducers used in LOIS designed for imaging tumors in the depth of tissue are described. The performance characteristics of the transducer array were modeled and compared with experiments performed in gel phantoms resembling optical and acoustic properties of human tissue with small tumors. The amplitude and the spectrum of laser-induced ultrasound pulses were measured in order to determine the transducer sensitivity and the level of thermal noises within the entire ultrasonic band of detection. Spatial resolution of optoacoustic images obtained with an array of piezoelectric transducers and its transient directivity pattern within the field of view are described. The detector design considerations essential for obtaining high-quality optoacoustic images are presented.

The phenomenon of plasmon resonance in ellipsoidal nanoparticles with shells is considered. Based on the geometrical sizes of a nanoparticle and its components, the theory is developed which allows the calculation of absorption spectra. Using the Maxwell — Garnett theory, a collective plasmon resonance is considered, which represents a nonlinear dependence of the plasmon frequency on the concentration of nanoparticles.

The spatial distribution of laser radiation intensity in turbid condensed media is studied analytically, numerically, and experimentally by the optoacoustic method. Based on optoacoustic measurements and Monte Carlo numerical simulations, the relation is obtained between the optical characteristics of a scattering medium and the position of the maximum of the spatial distribution of radiation intensity in the medium. It is shown that, when the anisotropy factor exceeds 0.8, this dependence has a universal type in the ranges of absorption and scattering coefficients typical for biological tissues. The method is proposed for measuring the extinction and absorption coefficients in light scattering media from the temporal shape of an optoacoustic pulse detected in relative units. An approximate method for solving a radiation transfer equation is verified, and the regions of application of the P3 and P5 approximation are established.

The dependence of the plasmon resonance frequency of metal ellipsoids of revolution on their eccentricity is calculated. The plasmon resonance shifts to the red with increasing eccentricity and its intensity increases. The resonance intensity increases with decreasing the imaginary part of the dielectric constant of a metal. The plasmon resonance frequency in a suspension of randomly oriented prolate nanoparticles (with a large eccentricity) almost exactly coincides with that in a suspension of oriented particles. These features permit the efficient improvement of the sensitivity and resolving power of optoacoustic tomography by introducing prolate metal nanoparticles into the region of an object under study. The possibility of plasmon resonance narrowing by introducing metal nanoparticles into an amplifying medium is pointed out.

Optoacoustic (photoacoustic) temperature imaging could provide improved spatial resolution and temperature sensitivity as compared to other techniques of non-invasive thermometry used during thermal therapies for safe and efficient treatment of lesions. However, accuracy of the reported optoacoustic methods is compromised by biological variability and heterogeneous composition of tissues. We report our findings on the universal character of the normalized temperature dependent optoacoustic response (ThOR) in blood, which is invariant with respect to hematocrit at the isosbestic point of hemoglobin. The phenomenon is caused by the unique homeostatic compartmentalization of blood hemoglobin exclusively inside erythrocytes. On the contrary, the normalized ThOR in aqueous solutions of hemoglobin showed linear variation with respect to its concentration and was identical to that of blood when extrapolated to the hemoglobin concentration inside erythrocytes. To substantiate the conclusions, we analyzed optoacoustic images acquired from the samples of whole and diluted blood as well as hemoglobin solutions during gradual cooling from +37 to −15 °C. Our experimental methodology allowed direct observation and accurate measurement of the temperature of zero optoacoustic response, manifested as the sample's image faded into background and then reappeared in the reversed (negative) contrast. These findings provide a framework necessary for accurate correlation of measured normalized optoacoustic image intensity and local temperature in vascularized tissues independent of tissue composition.

We present results from a recent study involving the Imagio TM breast imaging system, which produces fused real-time two-dimensional color-coded opto-acoustic (OA) images that are co-registered and temporally inter- leaved with real-time gray scale ultrasound using a specialized duplex handheld probe. The use of dual optical wavelengths provides functional blood map images of breast tissue and tumors displayed with high contrast based on total hemoglobin and oxygen saturation of the blood. This provides functional diagnostic information pertaining to tumor metabolism. OA also shows morphologic information about tumor neo-vascularity that is complementary to the morphological information obtained with conventional gray scale ultrasound. This fusion technology conveniently enables real-time analysis of the functional opto-acoustic features of lesions detected by readers familiar with anatomical gray scale ultrasound. We demonstrate co-registered opto-acoustic and ultrasonic images of malignant and benign tumors from a recent clinical study that provide new insight into the function of tumors in-vivo. Results from the Feasibility Study show preliminary evidence that the technology may have the capability to improve characterization of benign and malignant breast masses over conventional diagnostic breast ultrasound alone and to improve overall accuracy of breast mass diagnosis. In particular, OA improved speci city over that of conventional diagnostic ultrasound, which could potentially reduce the number of negative biopsies performed without missing cancers.

Optoacoustic microscopy (OAM) is an emerging technology combining the beneficial features of optical contrast and ultrasound resolution, to form a hybrid imaging technique capable of multi-scale, high-contrast and high-resolution imaging through optically scattering biological tissues. In the past 15 years, two system modifications have been developed for optoacoustic / photoacoustic microscopy: acoustic-resolution AR-OAM and optical-resolution OR-OAM. Typically, acoustic resolution systems can image deeper tissues structures, however, with resolution at least an order of magnitude worse than the systems of optical-resolution. It would be attractive for variety of biomedical applications to attain high (submicron) resolution at a depth exceeding the present limit of the optical resolution optoacoustic microscopy. Here we introduce a novel, all-optical method for OAM, in which not only thermal energy deposition, but also optoacoustic signal detection is achieved optically. In our design the probe laser beam was used as an ultrawide-band ultrasonic transducer. In this method the acoustic pressure wave amplitude is proportional to the angle of deflection of the probing CW laser beam incident on a balanced dual photodiode. Such laser beam deflection (LBD) method overcomes the limitations of conventional piezoelectric ultrasound transducers and optical interferometers. LBD method allows one to use high numerical aperture objectives for better focusing, avoid distortions associated with the system elements that separate optical and acoustic paths, and provides better sensitivity than any optical interferometer. It also provides a non-contact method that is insensitive to optical and acoustic artifacts typical of backward mode of optoacoustic imaging. The LBD sensitivity depends on a large number of system parameters such as probe beam power, spot size, interaction length, optical refraction index of the coupling medium, laser wavelength, photodiode sensitivity, proximity to the optoacoustic source, and thus, can be optimized. The basic setup of OR-LBD-OAM shows high sensitivity competitive with commercial ultrasonic transducers. We report first images of biological cells and tissues obtained using this technique.

In this work we introduce an improved prototype of three-dimensional imaging system that combines optoacoustic tomography (OAT) and laser ultrasound tomography (LUT) to obtain coregistered maps of tissue optical absorption and speed of sound (SoS). The OAT scan is performed by a 360 degree rotation of a mouse with respect to an arc-shaped array of ultrasonic transducers. A Q-switched laser system is used to establish optoacoustic illumination pattern appropriate for deep tissue imaging with a tunable (730-840 nm) output wavelengths operated at 10 Hz pulse repetition rate. A 532 nm wavelength output, being mostly absorbed within a narrow superficial layer of skin, is used to outline the visualized biological object. Broadband laser ultrasound emitters are arranged in another arc pattern and are positioned opposite and orthogonal to the array of transducers. This imaging geometry allows reconstruction of volumes that depict SoS distributions from the measured time of flight data. The reconstructed LUT images can subsequently be employed by an optoacoustic reconstruction algorithm to compensate for acoustic wavefield aberration and thereby improve accuracy of the reconstructed images of the absorbed optical energy. The coregistered OAT-LUT imaging is validated in a phantom and live mouse using a single-slice system prototype.

A new experimental approach for measurements of temperature dependence of the Gruneisen parameter in optically absorbing solutions is proposed. Two-dimensional optoacoustic (OA) imaging is used to improve accuracy of signal amplitude measurements and spatial localization of the studied samples. We estimated OA response of optically absorbing solutions measuring median intensity of OA images within the region of interest (ROI) as a function of temperature. We showed that when normalized to its value at a particular temperature, OA image intensity becomes an accurate metric reflecting temperature changes of Gruneisen parameter regardless of local optical fluence and absorbance, assuming those remain constant with temperature. Using the proposed method we studied temperature dependence of aqueous solutions of nickel and cupric sulfate in the range from 4 to 40°C. Obtained results were compared with temperature dependence for the Gruneisen parameter of DI-water, which we measured by using carbon ink colloid. We also found that Gruneisen-temperature relationship for nickel sulfate exhibits linear trend with respect to the concentration, and is independent of coupling medium and laser excitation wavelength.In the future, the developed methodology could be adopted for important applications of in vivo optoacoustic temperature monitoring.

In this work, we investigate a novel reconstruction method for laser-induced ultrasound computed tomography (USCT) breast imaging that circumvents limitations of existing methods that rely on ray-tracing. There is currently great interest in developing hybrid imaging systems that combine optoacoustic tomography (OAT) and USCT. There are two primary motivations for this: (1) the speed-of-sound (SOS) distribution reconstructed by USCT can provide complementary diagnostic information; and (2) the reconstructed SOS distribution can be incorporated in the OAT reconstruction algorithm to improve OAT image quality. However, image reconstruction in USCT remains challenging. The majority of existing approaches for USCT breast imaging involve ray-tracing to establish the imaging operator. This process is cumbersome and can lead to inaccuracies in the reconstructed SOS images in the presence of multiple ray-paths and/or shadow zones. To circumvent these problems, we implemented a partial differential equation-based Eulerian approach to USCT that was proposed in the mathematics literature but never investigated for medical imaging applications. This method operates by directly inverting the Eikonal equation without ray-tracing. A numerical implementation of this method was developed and compared to existing reconstruction methods for USCT breast imaging. We demonstrated the ability of the new method to reconstruct SOS maps from TOF data obtained by a hybrid OAT/USCT imager built by our team.

Ultrasound endoscopy has been proven effective in identifying and staging relatively advanced tumors in esophageal or colon wall lining. When combined with optoacoustic imaging modality, the endoscopy examination may prove beneficial in detecting also early stage tumors as well as more accurate staging of advanced tumors based on functional - anatomical maps. Here we present a prototype of a dual-modality optoacoustic – laser ultrasound (OA-LUS) endoscopy system with enhanced imaging capabilities. The system consists of a rotating 90° off-axis parabolic reflector which is acoustically coupled to a flat 8-element transducer array. A parabolic mirror serves dual purpose of directing light towards a sample and reflecting incoming optically generated ultrasound signals towards a detector. LUS modality is enabled by placing an optically absorbing and acoustically transparent polymeric membrane in the path of laser light to generate broadband and non-reverberating transient ultrasound waves propagating towards the sample. Focused system detects ultrasound signals and reconstructs the image similar to optoacoustic mode. Presence of a delay between optically generated and reflected acoustic signals allows concurrent image acquisition in OA and LUS modalities.

Time-resolved piezoelectric detection of wide-band ultrasonic transients induced by laser pulses in absorbing medium was studied. An optoacoustic transducer was developed for measuring the profiles of ultrasonic transients propagating in backward direction out of the laser-irradiated medium. For this purpose, an optical fiber for delivery of laser pulses to the surface of absorbing medium and a wide-band lithium niobate acoustic transducer were incorporated in one compact system, optoacoustic front surface transducer (OAFST). The transducer possesses temporal resolution (rise time) of 3.5 ns, low effective thermal noise pressure (10 Pa), and high sensitivity of piezoelectric detection (10 μV/Pa) over the ultrasonic frequency range from 1 to 100 MHz. Nd:YAG laser pulses at 355 nm were employed to generate distribution of acoustic sources in water solutions of potassium chromate with various concentrations. A temporal course of ultrasonic transients launched into an optically and acoustically transparent me...

Current imaging modalities fail to detect small tumors in the breast. Opto-acoustic tomography is a novel technique for early cancer detection with promising diagnostic capability. The experimental limit of sensitivity and maximal depth of the laser opto-acoustic detection for small model tumors located within bulk phantom tissue were studied. Two phantoms with optical properties similar to that of breast tissue in the near infrared spectral range were used in these studies: turbid gelatin slabs with the thickness of 100 mm and chicken breast muscle slabs with the thickness of up to 80 mm. Gelatin spheres with enhanced absorption coefficient relative to the background absorption and liver tissue were used to simulate small tumors. The experiments demonstrated the capability of laser optoacoustic imaging to detect and localize phantom tumors with the diameter of 2 mm at a depth of up to 60 mm within the gelatin phantoms and 3/spl times/2/spl times/0.6-mm piece of liver tissue within 80-mm chicken breast tissue. Theoretical studies on sensitivity of opto-acoustic detection at various diameters, depths of location, and absorption coefficients of small tumors were performed using the experimental data. Our results suggest that the opto-acoustic imaging may occupy a significant niche in early detection of cancer in the breast and other organs.

A review of our recent works advancing three-dimensional optoacoustic tomography systems and their applications in preclinical imaging using small animal models and clinical application in diagnostic imaging of breast cancer is presented.

A three-dimensional mouse imaging system combining optoacoustic tomography and laser ultrasound (LOUIS-3DM) has been developed. It features broadband laser ultrasound emitters positioned opposite an array of transducers. This imaging geometry allows reconstruction of images that either depicts the speed of sound distribution from measured time of flight data, or acoustic attenuation from the measured signal amplitude. We have investigated the performance of two laser ultrasound source designs, both easily adapta ble to a commercial imaging system: small diameter source (600 µm) generated off a flat surface, and larger diameter (3 mm) spherical source. Laser energy requirements are modest, well below 1 mJ per pulse for either design. Their performance at normal incidence is comparable both in amplitude and frequency response. However, off-axis generation differs dramatically and the shortcomings of th e simple flat emitter design are eviden t. We show that, in order to achieve optimal performance through proper illumination of the detector array, spherical wave front characteristics are desired. Keywords: Broadband ultrasound, laser ultrasonics, wave front propagation, delta-source, spherical wave generation, wide-directivity source. INTRODUCTION We have developed a three-dimensional mouse imaging system (LOUIS-3DM) combining optoacoustic (OA) tomography

We developed the ¯rst prototype of dual-modality imager combining optoacoustic t omography (OAT) and laserultrasound tomography (UST) using computer models followed by experimental va lidation. The system designedfor preclinical biomedical research can concurrently yield images depicting both the abs orbed optical energydensity and acoustic properties (speed of sound) of an object. In our design of the UST imager, we seek toreplace conventional electrical generation of ultrasound waves by laser-induced ultra sound (LU). While earlierstudies yielded encouraging results [Manohar, et al., Appl. Phys. Lett, 131911, 2 007], they were limited totwo-dimensional (2D) geometries. In this work, we conduct computer-simulation st udies to investigate di®erentdesigns for the 3D LU UST imager. The number and location of the laser ultrasound emitters, which areconstrained to reside on the cylindrical surface opposite to the arc of detectors, are optimized. In addition tothe system parameters, an iterative image reconstruction algorithm was o ptimized. We demonstrate that highquality volumetric maps of the speed of sound can be reconstructed when only 32 emitt ers and 128 receivingtransducers are employed to record time-of-°ight data at 360 tomographic view ang les. The implications of theproposed system for small animal and breast-cancer imaging are discussed.Keywords: Laser ultrasound tomography, optoacoustic tomography, iterative ima ge reconstruction

In this work, we introduce a novel three-dimensional imaging system for in vivo high-resolution anatomical and functional whole-body visualization of small animal models developed for preclinical or other type of biomedical research. The system (LOUIS-3DM) combines a multi-wavelength optoacoustic and ultrawide-band laser ultrasound tomographies to obtain coregistered maps of tissue optical absorption and acoustic properties, displayed within the skin outline of the studied animal. The most promising applications of the LOUIS-3DM include 3D angiography, cancer research, and longitudinal studies of biological distribution of optoacoustic contrast agents (carbon nanotubes, metal plasmonic nanoparticles, etc.).

Two-dimensional optoacoustic imaging with a hand-held probe operated in backward mode is being developed for diagnostic imaging of breast cancer to evaluate the feasibility of a dual-modality optoacoustic plus ultrasonic system that maps functional information of anatomical tissue structures with ultrasonic resolution. Tissue is illuminated at 757nm and 1064nm for optical contrast between hypoxic blood of breast carcinomas and normally oxygenated blood in benign masses. The system is optimized and calibrated in phantoms for a pilot clinical study of patients with breast masses suspected for malignancy. Capability of the non-invasive system to improve detection and diagnosis of breast tumors is discussed.

Alexandrite laser ablation of enamel enhanced by an indocyanine green dye was studied. A microjet system was employed to deliver precisely measured small amounts of absorbing dye solution to the site of irradiation. A sequence of physical phenomena involved in dye-enhanced laser ablation of dental enamel was revealed when laser pulse profiles were compared with the profiles of laser-induced pressure, laser-induced plasma, and ablation plume kinetics. To understand photomechanical effects on the enamel ablation, the absolute values of pressure waves were measured by a calibrated wide-band acoustic transducer. Absolute amplitude and temporal profile of pressure waves, plasma emission, ablation plume kinetics, ablation efficiency, and crater quality under free-running and and Q-switched ablation of enamel were studied. It was found that there is an optimal dye solution volume (100-200 nL) when the maximum ablation efficiency (30 μm/pulse) can be obtained. It was shown that the ablation efficiency under Q-switched laser irradiation is approximately one order of magnitude lower than that under free-running ablation. It was shown that Q-switched enamel ablation with dye solution is caused by the powerful recoil pressure wave with an amplitude 3-6.5 kbar. In contrast, dye-enhanced free-running enamel ablation is caused by plasma-mediated evaporation of enamel and accompanied by recoil pressure waves of lower amplitude (0.5-1 kbar) that is below mechanical damage threshold in enamel. Uneven crater walls after Q-switched ablation were observed by scanning electron microscopy (SEM). Free-running ablation makes precise craters with smooth and even crater walls.

Plasma mediated ablation of collagen gels and porcine cornea was studied at various laser pulse durations in the range of 1 ns-300 fs at 1053-nm wavelength. It was found that pulsed laser ablation of transparent and weakly absorbing gels is always mediated by plasma. On the other hand, ablation of strongly absorbing tissues is mediated by plasma in the ultrashort-pulse range only. Ablation threshold along with plasma optical breakdown threshold decreases with increasing tissue absorbance for subnanosecond pulses. In contrast, the ablation threshold was found to be practically independent of tissue linear absorption for femtosecond laser pulses. The mechanism of optical breakdown at the tissue surface was theoretically investigated. In the nanosecond range of laser pulse duration, optical breakdown proceeds via avalanche ionization initiated by heating of electrons contributed by strongly absorbing impurities at the tissue surface. In the ultrashortpulse range, optical breakdown is initiated by multiphoton ionization of the irradiated medium (six photons in case of tissue irradiated at 1053-nm wavelength), and is less sensitive to linear absorption. High-quality ablation craters with no thermal or mechanical damage to surrounding material were obtained with subpicosecond laser pulses. Experimental results suggest that subpicosecond plasma mediated ablation can be employed as a tool for precise laser microsurgery of various tissues.