Search

Opto-acoustic imaging involves using light to produce sound waves for visualizing blood in biological tissue. By using multiple optical wavelengths, diagnostic images of blood oxygen saturation and total hemoglobin are generated using endogenous optical contrast, without injection of any external contrast agent and without using any ionizing radiation. The technology has been used in recent clinical studies for diagnosis of breast cancer to help distinguish benign from malignant lesions, potentially reducing the need for biopsy through improved diagnostic imaging accuracy. To enable this application, techniques for mapping oxygen saturation differences within tissue are necessary. Using biologically relevant opto-acoustic phantoms, we analyze the ability of an opto-acoustic imaging system to display colorized parametric maps that are generated using a statistical mapping approach. To mimic breast tissue, a material with closely matching properties for optical absorption, optical scattering, acoustic attenuation, and speed of sound is used. The phantoms include two vessels filled with whole blood at oxygen saturation levels determined using a sensor-based approach. A flow system with gas-mixer and membrane oxygenator adjusts the oxygen saturation of each vessel independently. Datasets are collected with an investigational Imagio® breast imaging system. We examine the ability to distinguish vessels as the oxygen saturation level and imaging depth are varied. At depth of 15 mm and hematocrit of 42%, a sufficient level of contrast to distinguish between two 1.6-mm diameter vessels was measured for an oxygen saturation difference of ∼4.6 % . In addition, an oxygenated vessel was visible at a depth of 48 mm using an optical wavelength of 1064 nm, and a deoxygenated vessel was visible to a depth of 42 mm with 757 nm. The results provide insight toward using color mapped opto-acoustic images for diagnosing breast cancer.

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 (

A new technique based on time-resolved detection of laser-induced stress transients is proposed to visualize distributions of absorbed laser fluence in turbid and layered biological tissues.

In three-dimensional (3D) functional optoacoustic tomography (OAT), wavelength-dependent optical attenuation and nonuniform incident optical fluence limit imaging depth and field of view and can hinder accurate estimation of functional quantities, such as the vascular blood oxygenation. These limitations hinder OAT of large objects, such as a human female breast.We aim to develop a measurement-data-driven method for normalization of the optical fluence distribution and to investigate blood vasculature detectability and accuracy for estimating vascular blood oxygenation.The proposed method is based on reasonable assumptions regarding breast anatomy and optical properties. The nonuniform incident optical fluence is estimated based on the illumination geometry in the OAT system, and the depth-dependent optical attenuation is approximated using Beer-Lambert law.Numerical studies demonstrated that the proposed method significantly enhanced blood vessel detectability and improved estimation accuracy of the vascular blood oxygenation from multiwavelength OAT measurements, compared with direct application of spectral linear unmixing without optical fluence compensation. Experimental results showed that the proposed method revealed previously invisible structures in regions deeper than 15 mm and/or near the chest wall.The proposed method provides a straightforward and computationally inexpensive approximation of wavelength-dependent effective optical attenuation and, thus, enables mitigation of the spectral coloring effect in functional 3D OAT imaging.

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.

Opto-acoustic imaging involves using light to produce sound waves for visualizing blood in biological tissue. By using multiple optical wavelengths, diagnostic images of blood oxygen saturation and total hemoglobin are generated using endogenous optical contrast, without injection of any external contrast agent and without using any ionizing radiation. The technology has been used in recent clinical studies for diagnosis of breast cancer to help distinguish benign from malignant lesions, potentially reducing the need for biopsy through improved diagnostic imaging accuracy. To enable this application, techniques for mapping oxygen saturation differences within tissue are necessary. Using biologically relevant opto-acoustic phantoms, we analyze the ability of an opto-acoustic imaging system to display colorized parametric maps that are generated using a statistical mapping approach. To mimic breast tissue, a material with closely matching properties for optical absorption, optical scattering, acoustic attenuation, and speed of sound is used. The phantoms include two vessels filled with whole blood at oxygen saturation levels determined using a sensor-based approach. A flow system with gas-mixer and membrane oxygenator adjusts the oxygen saturation of each vessel independently. Datasets are collected with an investigational Imagio® breast imaging system. We examine the ability to distinguish vessels as the oxygen saturation level and imaging depth are varied. At depth of 15 mm and hematocrit of 42%, a sufficient level of contrast to distinguish between two 1.6-mm diameter vessels was measured for an oxygen saturation difference of ∼4.6%. In addition, an oxygenated vessel was visible at a depth of 48 mm using an optical wavelength of 1064 nm, and a deoxygenated vessel was visible to a depth of 42 mm with 757 nm. The results provide insight toward using color mapped opto-acoustic images for diagnosing breast cancer.

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.

This lecture will discuss history of optoacoustic imaging from pioneering works that set the basic principles of the technology to the first in vivo images, to the most recent advances, and finally to the future medical imaging modalities and their applications in the main stream medicine and surgery. We also present the design features and technical parameters of the optoacoustic imaging systems required for clinically viable devices.

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.

Opto-acoustic imaging involves using light to produce sound waves for visualizing blood in biological tissue. By using two different optical wavelengths, diagnostic images of blood oxygen saturation can be generated using endogenous optical contrast, without injection of any external contrast agent and without using any ionizing radiation. The technology has been used in recent clinical studies for diagnosis of breast cancer to help distinguish benign from malignant lesions, potentially reducing the need for biopsy through improved diagnostic imaging accuracy. To enable this application, techniques that can accurately map and effectively display small differences in oxygen saturation are necessary. We analyze the ability of an opto-acoustic imaging system to display a colorized parametric map for oxygen saturation of blood using biologically-relevant opto-acoustic phantoms. The relationship between colorized image output and known oxygen saturation values is examined. To mimic breast tissue, a material with closely matching properties for optical absorption, optical scattering, acoustic attenuation and speed of sound is used. The phantoms include two vessels filled with whole blood at oxygen saturation levels determined using a gold-standard sensor-based approach. A flow system with gas-mixer and membrane oxygenator adjusts the oxygen saturation of each vessel independently. Data is collected with an investigational Imagio breast imaging system. An opto- acoustic relative color map is generated using a novel statistical mapping approach. In addition, we propose a technique to characterize the ability to distinguish small differences in oxygen saturation as the oxygenation level is varied. When applied to the phantom, with reference vessel at 99% saturation, hematocrit of 42% and depth of 1.5cm, a contrast distinction threshold was reached when an adjusted vessel achieved a difference of approximately 4.6% saturation compared to the reference.

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.

A novel protocol for the seedless synthesis of gold nanorods (AuNRs) using dopamine as a reductant has been developed. We report that the concentration of CTAB can be reduced to 22 mM and that the AuNRs' longitudinal surface plasmon resonance (LSPR) can be tuned from 700 to 1050 nm. The size of the AuNRs can also be tuned from 7 × 30 nm to 20 × 100 nm. The amphiphilicity and the cationic structure of the protonated dopamine enable it to interact favorably with the CTAB bilayer and lead to a high-yield synthesis of AuNRs (80–95%). LSPR peaks, size, and aspect ratio of the synthesized AuNRs can be tuned by adjusting the concentration and ratio of silver ions, CTAB, and dopamine. In addition, this reaction is much faster than previously reported methods requiring only 30 minutes to complete.

One area of particular relevance to optoacoustic imaging is the enhancement of malignant tumor contrast relative to background normal tissue. Although optoacoustic imaging has been shown to be superior to the commonly employed clinical imaging modalities in terms of contrast, optoacoustic contrast agents offer the possibility of both visualizing and treating currently invisible pathological entities. It is likely that operation of a variety of imaging and monitoring devices utilizing optoacoustic principles may be enhanced with application of contrast agents based on metal nanoparticles (NPs) possessing plasmon resonance absorption. Gold and silver NPs will be homogeneously heated with the nanosecond pulses of Q-switched lasers commonly used in optoacoustic imaging and sensing. Solid gold and silver nanorods (NRs) not only possess the strongest optical absorption, the peak of this absorption can be conveniently tuned by making them longer, while keeping their diameter constant.

In this report, we demonstrate the feasibility of using optoacoustic tomography (OAT) to evaluate biodistributions of nanoparticles in animal models. The redistribution of single-walled carbon nanotubes (SWCNTs) was visualized in living mice. Nanoparticle concentrations in harvested organs were measured spectroscopically using the intrinsic optical absorption and fluorescence of SWCNTs. Observed increases in optoacoustic signal brightness in tissues were compared with increases in optical absorption coefficients caused by SWCNT accumulation. The methodology presented in this report can further be extended to calibrate the sensitivity of an optoacoustic imaging system for a range of changes in optical absorption coefficient values at specific locations or organs in a mouse body to enable noninvasive measurements of nanoparticle concentrations in vivo. Additionally, qualitative information provided by OAT and quantitative information obtained ex vivo may provide valuable feedback for advancing methods of quantitative analysis with OAT.

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.

Because optoacoustic tomography (OAT) can provide functional information based on hemoglobin contrast, it is a promising imaging modality for breast cancer diagnosis. Developing an effective OAT breast imaging system requires balancing multiple design constraints, which can be expensive and time-consuming. Therefore, computer- simulation studies are often conducted to facilitate this task. However, most existing computer-simulation studies of OAT breast imaging employ simple phantoms such as spheres or cylinders that over-simplify the complex anatomical structures in breasts, thus limiting the value of these studies in guiding real-world system design. In this work, we propose a method to generate realistic numerical breast phantoms for OAT research based on clinical magnetic resonance imaging (MRI) data. The phantoms include a skin layer that defines breast-air boundary, major vessel branches that affect light absorption in the breast, and fatty tissue and fibroglandular tissue whose acoustical heterogeneity perturbs acoustic wave propagation. By assigning realistic optical and acoustic parameters to different tissue types, we establish both optic and acoustic breast phantoms, which will be exported into standard data formats for cross-platform usage.

Cryoablation of prostate cancer is an FDA approved clinical procedure, which involves repetitive rapid cooling of a lesion to lethal temperatures of -40°C and below. The major drawback of the technique is the insufficient control over the fast thermal processes that may result in severe complications (impotence, incontinence, perforation of the rectal wall) and morbidity. The developed optoacoustic imaging technique provides non-invasive real-time temperature mapping of tissue adjacent to prostate and enables more efficient control over the procedure, which is necessary to reduce side effects and accelerate the physician’s learning curve. In these studies we successfully demonstrated real-time transrectal optoacoustic imaging during prostate cryoablation in live canine model focused on optoacoustic thermography of the rectal wall within the depth of 1cm. Our method utilized previously discovered universal thermal dependence of the normalized optoacoustic response of blood. Nanosecond-pulse radiation of Ti-Sapphire laser tuned to the isosbestic point of hemoglobin (802±3 nm) was delivered via fiberoptic illuminators assembled on both sides of the linear array of the 128-channel transrectal ultrasound probe. Temperature readouts at discrete locations inside and nearby prostate were also performed using standard transperineal needle sensors. The effect of homeostasis on optoacoustic imaging in live tissue was examined during cooling and shown to be significant only within the range of ±1.5°C in respect to the body temperature. Accuracy of in vivo optoacoustic temperature measurements was determined as ±2°C for the range of temperature from +35 to -15°C, which is more than sufficient for tracking the essential isotherms in the course of clinical procedures.

We developed a methodology for high yield synthesis of gold nanorods (GNR) with narrow band optical absorption centered at 760 nm. GNR were purified from hexadecyltrimethylammonium bromide (CTAB) and coated with polyethylene glycol (PEG). The molar ratio between GNR and PEG (1÷50000) was optimized to make the conjugate a biocompatible PEG-GNR contrast agent for optoacoustic (OA) imaging. In vitro toxicity studies showed no significant change in survival rates of cultured normal (IEC-6, MDCK) and cancer (SKBR3 and HEPG2) cells after they were incubated with 0.125 to 1.25 nM PEG-GNR solutions. In vivo toxicity studies in nude mice showed no pathological changes in liver after the IV injection of GNR. Significant enhancements of OA contrast in comparison to images of untreated mice were observed 1 hour after the GNR injection in a dose of 20 mg gold per kg of body mass.

The objective of this study is to demonstrate in vivo the feasibility of optoacoustic temperature imaging during cryotherapy of prostate cancer. We developed a preclinical prototype optoacoustic temperature imager that included pulsed optical excitation at a wavelength of 805 nm, a modified clinical transrectal ultrasound probe, a parallel data acquisition system, image processing and visualization software. Cryotherapy of a canine prostate was performed in vivo using a commercial clinical system, Cryocare® CS, with an integrated ultrasound imaging. The universal temperature-dependent optoacoustic response of blood was employed to convert reconstructed optoacoustic images to temperature maps. Optoacoustic imaging of temperature during prostate cryotherapy was performed in the longitudinal view over a region of 30 mm (long) × 10 mm (deep) that covered the rectum, the Denonvilliers fascia, and the posterior portion of the treated gland. The transrectal optoacoustic images showed high-contrast vascularized regions, which were used for quantitative estimation of local temperature profiles. The constructed temperature maps and their temporal dynamics were consistent with the arrangement of the cryoprobe and readouts of the thermal needle sensors. The temporal profiles of the readouts from the thermal needle sensors and the temporal profile estimated from the normalized optoacoustic intensity of the selected vascularized region showed significant resemblance, except for the initial overshoot, that may be explained as a result of the physiological thermoregulatory compensation. The temperature was mapped with errors not exceeding ±2 °C (standard deviation) consistent with the clinical requirements for monitoring cryotherapy of the prostate. In vivo results showed that the optoacoustic temperature imaging is a promising non-invasive technique for real-time imaging of tissue temperature during cryotherapy of prostate cancer, which can be combined with transrectal ultrasound-the current standard for guiding clinical cryotherapy procedure.

Photoacoustic tomography (PAT) also referred to as optoacoustic tomography (OAT) is a hybrid imaging modality that employs nonionizing optical radiation and ultrasonic detection. Here, we describe the application of a new class of optical contrast agents based on mesoscopic hollow gold nanospheres (HAuNS) to PAT. HAuNS are approximately 40 nm in diameter with a hollow interior and consist of a thin gold wall. They display strong resonance absorption tuned to the near-infrared (NIR) range, with an absorption peak at 800 nm, whose photoacoustic efficiency is significantly greater than that of blood. Following surface conjugation with thiolated poly(ethylene glycol), the pegylated HAuNS (PEG-HAuNS) had distribution and elimination half-lives of 1.38 +/- 0.38 and 71.82 +/- 30.46 h, respectively. Compared with PAT images based on the intrinsic optical contrast in nude mice, the PAT images acquired within 2 h after intravenous administration of PEG-HAuNS showed the brain vasculature with greater clarity and detail. The image depicted brain blood vessels as small as approximately 100 mum in diameter using PEG-HAuNS as contrast agents. Preliminary results showed no acute toxicity to the liver, spleen, or kidneys in mice following a single imaging dose of PEG-HAuNS. Our results indicate that PEG-HAuNS are promising contrast agents for PAT, with high spatial resolution and enhanced sensitivity.

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.

Aims: Clusters of nanoparticles may significantly improve the sensitivity of diagnostics and the safety and efficacy of therapeutic nanotechnologies in medicine. We report methods for the formation of nanoparticle clusters and for monitoring their accumulation in cancer cells. Methods: The accumulation of gold nanoparticles in tumor cells was studied using flow cytometry, optical scattering and fluorescent, atomic force, photothermal and scanning electron microscopy. Results: Incubation of cells at 37°C for 30 min or more with 10–30-nm nanoparticles resulted in the formation of clusters of nanoparticles as large as 20 nanoparticles or more. Conclusions: Specific targeting using a monoclonal antibody as a vector increases the concentration of nanoparticles on the surface of target cells compared with nonspecific nanoparticle accumulation. In turn, an increased concentration of nanoparticles on the target surface yields larger nanoparticle clusters inside the cells due to endocytosis. Photothermal and scattering microscopy were found to be the most sensitive methods for imaging nanoparticle clusters in living cells. Biomedical applications of nanoparticles (NPs) involve their interactions with living cells through various mechanisms. These interactions may result in the formation of NP clusters (NPCs) on the

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 and other type of biomedical research. The system (LOUIS-3DM) combines a multiwavelength optoacoustic tomography (OAT) and laser-induced ultrasound tomography (LUT) to obtain coregistered maps of tissue optical absorption and speed of sound, 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 distributions of optoacoustic contrast agents.

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.