Normalization of optical fluence distribution for three-dimensional functional optoacoustic tomography of the breast.

SIGNIFICANCE: 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. AIM: 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. APPROACH: 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. RESULTS: 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. CONCLUSIONS: 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.

Novel Multidisciplinary Salivary Gland Society (MSGS) Questionnaire: An International Consensus.

OBJECTIVES: First, establishment and validation of a novel questionnaire documenting the burden of xerostomia and sialadenitis symptoms, including quality of life. Second, to compare two versions regarding the answering scale (proposed developed answers Q3 vs. 0-10 visual analogue scale Q10) of our newly developed questionnaire, in order to evaluate their comprehension by patients and their reproducibility in time. STUDY DESIGN: The study is a systematic review regarding the evaluation of the existing questionnaire and a cohort study regarding the validation of our new MSGS questionnaire. MATERIALS AND METHODS: A Multidisciplinary Salivary Gland Society (MSGS) questionnaire consisting of 20 questions and two scoring systems was developed to quantify symptoms of dry mouth and sialadenitis. Validation of the questionnaire was carried out on 199 patients with salivary pathologies (digestive, nasal, or age-related xerostomia, post radiation therapy, post radioiodine therapy, Sjögren's syndrome, IgG4 disease, recurrent juvenile parotitis, stones, and strictures) and a control group of 66 healthy volunteers. The coherence of the questionnaire's items, its reliability to distinguish patients from healthy volunteers, its comparison with unstimulated sialometry, and the time to fill both versions were assessed. RESULTS: The novel MSGS questionnaire showed good internal coherence of the items, indicating its pertinence: the scale reliability coefficients amounted to a Cronbach's alpha of 0.92 for Q10 and 0.90 for Q3. The time to complete Q3 and Q10 amounted, respectively, to 5.23 min (±2.3 min) and 5.65 min (±2.64 min) for patients and to 3.94 min (±3.94 min) and 3.75 min (±2.11 min) for healthy volunteers. The difference between Q3 and Q10 was not significant. CONCLUSION: We present a novel self-administered questionnaire quantifying xerostomia and non-tumoral salivary gland pathologies. We recommend the use of the Q10 version, as its scale type is well known in the literature and it translation for international use will be more accurate. Laryngoscope, 132:322-331, 2022.

Optical clearing of skin enhanced with hyaluronic acid for increased contrast of optoacoustic imaging.

Enhanced delivery of optical clearing agents (OCA) through skin may improve sensitivity of optical and optoacoustic (OA) methods of imaging, sensing, and monitoring. This report describes a two-step method for enhancement of light penetration through skin. Here, we demonstrate that topical application of hyaluronic acid (HA) improves skin penetration of hydrophilic and lipophilic OCA and thus enhances their performance. We examined the OC effect of 100% polyethylene and polypropylene glycols (PPGs) and their mixture after pretreatment by HA, and demonstrated significant increase in efficiency of light penetration through skin. Increased light transmission resulted in a significant increase of OA image contrast in vitro. Topical pretreatment of skin for about 30 min with 0.5% HA in aqueous solution offers effective delivery of low molecular weight OCA such as a mixture of PPG-425 and polyethylene glycol (PEG)-400. The developed approach of pretreatment by HA prior to application of clearing agents (PEG and PPG) resulted in a ∼ 47-fold increase in transmission of red and near-infrared light and significantly enhanced contrast of OA images.

Melanin nanoparticles as a novel contrast agent for optoacoustic tomography.

We describe the synthesis and characterization of melanin-like nanoparticles (MNP) as novel contrast agents for optoacoustic tomography. Good dispersion stability of high concentration MNPs in different biological media was achieved with thiol-terminated methoxy-poly(ethylene glycol), which can be used for further functional conjugation. MNP-PEG were found biocompatible with human MCF-7 and 3T3 cells. Cell toxicity of MNPs was found lower than that of gold nanorods for concentrations that provide equal optical absorbance. Optoacoustic tomography images were obtained with Laser Optoacoustic Imaging System (LOIS-3D) from tubes filled with contrast agents and live mice. Imaging of tubes permitted verification of the system resolution <300 µm and sensitivity Δµa=0.03/cm under safe laser fluence of 20 mJ/cm(2). Water suspensions of MNP demonstrated optoacoustic efficiency that is about equal to that of gold nanorods under conditions of equal optical absorption. We conclude that MNPs have the potential for biomedical imaging applications as optoacoustic contrast agents.

Discrete imaging models for three-dimensional optoacoustic tomography using radially symmetric expansion functions.

Optoacoustic tomography (OAT), also known as photoacoustic tomography, is an emerging computed biomedical imaging modality that exploits optical contrast and ultrasonic detection principles. Iterative image reconstruction algorithms that are based on discrete imaging models are actively being developed for OAT due to their ability to improve image quality by incorporating accurate models of the imaging physics, instrument response, and measurement noise. In this work, we investigate the use of discrete imaging models based on Kaiser-Bessel window functions for iterative image reconstruction in OAT. A closed-form expression for the pressure produced by a Kaiser-Bessel function is calculated, which facilitates accurate computation of the system matrix. Computer-simulation and experimental studies are employed to demonstrate the potential advantages of Kaiser-Bessel function-based iterative image reconstruction in OAT.

Enabling in vivo measurements of nanoparticle concentrations with three-dimensional optoacoustic tomography.

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.

Using optoacoustic imaging for measuring the temperature dependence of Grüneisen parameter in optically absorbing solutions.

Grüneisen parameter is a key temperature-dependent physical characteristic responsible for thermoelastic efficiency of materials. We propose a new methodology for accurate measurements of temperature dependence of Grüneisen parameter in optically absorbing solutions. We use two-dimensional optoacoustic (OA) imaging to improve accuracy of measurements. Our approach eliminates contribution of local optical fluence and absorbance. To validate the proposed methodology, we studied temperature dependence of aqueous cupric sulfate solutions in the range from 22 to 4 °C. Our results for the most diluted salt perfectly matched known temperature dependence for the Grüneisen parameter of water. We also found that Grüneisen-temperature relationship for cupric sulfate exhibits linear trend with respect to the concentration. In addition to accurate measurements of Grüneisen changes with temperature, the developed technique provides a basis for future high precision OA temperature monitoring in live tissues.

Laser OptoAcoustic Tomography: Towards New Technology for Biomedical Diagnostics.

This paper provides a short review of physical principles, technology, biomedical applications and perspectives of the optoacoustic imaging. Ideas that made this rapidly developing field possible include the following: (1) laser pulses may be effectively used to produce acoustic pressure in biological tissues localized to the areas of increased optical absorption, (2) the resulting acoustic (ultrasonic) waves propagate in tissues with minimal distortions and attenuation, (3) 2D and 3D maps (images) of the absorbed optical energy can be reconstructed with high resolution from the detected optoacoustic signals. Modern optoacoustic imaging systems include scanning focused transducers and 2D/3D transducer arrays. The widely accepted 2D arrays are employed either for real-time 2D optoacoustic imaging or for 3D imaging via translational or rotational scanning. A commercial prototype of a 3D OAT system is being developed by TomoWave Labs where major biomedical applications include visualization of specific targeting using exogenous optoacoustic contrast agents and imaging of blood distribution and oxygentaion status can be investigated.

Three-dimensional optoacoustic imaging as a new noninvasive technique to study long-term biodistribution of optical contrast agents in small animal models.

We used a 3-D optoacoustic (OA) tomography system to create maps of optical absorbance of mice tissues contrasted with gold nanorods (GNRs). Nude mice were scanned before and after injection of GNRs at time periods varying from 1 to 192 h. Synthesized GNRs were purified from hexadecyltrimethylammonium bromide and coated with polyethylene glycol (PEG) to obtain GNR-PEG complexes suitable for in vivo applications. Intravenous administration of purified GNR-PEG complexes resulted in enhanced OA contrast of internal organs and blood vessels compared to the same mouse before injection of the contrast agent. Maximum enhancement of the OA images was observed 24 to 48 h postinjection, followed by a slow clearance trend for the remaining part of the studied period (eight days). We demonstrate that OA imaging with two laser wavelengths can be used for noninvasive, long-term studies of biological distribution of contrast agents.

Highly purified biocompatible gold nanorods for contrasted optoacoustic imaging of small animal models.

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.

Investigation of iterative image reconstruction in three-dimensional optoacoustic tomography.

Iterative image reconstruction algorithms for optoacoustic tomography (OAT), also known as photoacoustic tomography, have the ability to improve image quality over analytic algorithms due to their ability to incorporate accurate models of the imaging physics, instrument response and measurement noise. However, to date, there have been few reported attempts to employ advanced iterative image reconstruction algorithms for improving image quality in three-dimensional (3D) OAT. In this work, we implement and investigate two iterative image reconstruction methods for use with a 3D OAT small animal imager: namely a penalized least-squares (PLS) method employing a quadratic smoothness penalty and a PLS method employing a total variation norm penalty. The reconstruction algorithms employ accurate models of the ultrasonic transducer impulse responses. Experimental data sets are employed to compare the performances of the iterative reconstruction algorithms to that of a 3D filtered backprojection (FBP) algorithm. By the use of quantitative measures of image quality, we demonstrate that the iterative reconstruction algorithms can mitigate image artifacts and preserve spatial resolution more effectively than FBP algorithms. These features suggest that the use of advanced image reconstruction algorithms can improve the effectiveness of 3D OAT while reducing the amount of data required for biomedical applications.

An imaging model incorporating ultrasonic transducer properties for three-dimensional optoacoustic tomography.

Optoacoustic tomography (OAT) is a hybrid imaging modality that combines the advantages of optical and ultrasound imaging. Most existing reconstruction algorithms for OAT assume that the ultrasound transducers employed to record the measurement data are point-like. When transducers with large detecting areas and/or compact measurement geometries are utilized, this assumption can result in conspicuous image blurring and distortions in the reconstructed images. In this work, a new OAT imaging model that incorporates the spatial and temporal responses of an ultrasound transducer is introduced. A discrete form of the imaging model is implemented and its numerical properties are investigated. We demonstrate that use of the imaging model in an iterative reconstruction method can improve the spatial resolution of the optoacoustic images as compared to those reconstructed assuming point-like ultrasound transducers.

Real-time optoacoustic monitoring and three-dimensional mapping of a human arm vasculature.

We present our findings from a real-time laser optoacoustic imaging system (LOIS). The system utilizes a Q-switched Nd:YAG laser; a standard 128-channel ultrasonic linear array probe; custom electronics and custom software to collect, process, and display optoacoustic (OA) images at 10 Hz. We propose that this system be used during preoperative mapping of forearm vessels for hemodialysis treatment. To demonstrate the real-time imaging capabilities of the system, we show OA images of forearm vessels in a volunteer and compare our results to ultrasound images of the same region. Our OA images show blood vessels in high contrast. Manipulations with the probe enable us to locate and track arteries and veins of a forearm in real time. We also demonstrate the ability to combine a series of OA image slices into a volume for spatial representation of the vascular network. Finally, we use frame-by-frame analysis of the recorded OA video to measure dynamic changes of the crossection of the ulnar artery.

Optoacoustic imaging of the prostate: development toward image-guided biopsy.

Optoacoustic (OA) tomography has demonstrated utility in identifying blood-rich malignancies in breast tissue. We describe the development and characterization of a laser OA imaging system for the prostate (LOIS-P). The system consists of a fiber-coupled Q-switched laser operating at 757 nm, a commercial 128-channel ultrasonic probe, a digital signal processor, and software that uses the filtered radial back-projection algorithm for image reconstruction. The system is used to reconstruct OA images of a blood-rich lesion induced in vivo in a canine prostate. OA images obtained in vivo are compared to images acquired using ultrasound, the current gold standard for guiding biopsy of the prostate. Although key structural features such as the urethra could be identified with both imaging techniques, a bloody lesion representing a highly vascularized tumor could only be clearly identified in OA images. The advantages and limitations of both forward and backward illumination modes are also evaluated by collecting OA images of phantoms simulating blood vessels within tissue. System resolution is estimated to be 0.2 mm in the radial direction of the acoustic array. The minimum detectable pressure signal is 1.83 Pa. Our results encourage further development toward a dual-modality OA/ultrasonic system for prostate imaging and image-guided biopsy.

Feasibility of optoacoustic visualization of high-intensity focused ultrasound-induced thermal lesions in live tissue.

A 3-D optoacoustic imaging system was used to visualize thermal lesions produced in vivo using high-intensity focused ultrasound (HIFU). A 7.5-MHz, surgical, focused transducer with a radius of curvature of 35 mm and an aperture diameter of 23 mm was used to generate HIFU. A pulsed laser, which could operate at 755 nm and 1064 nm, was used to illuminate excised tissue and mice using a bifurcated fiber bundle resulting in two wide beams of light. Tomographic images were obtained while the specimens were rotated within a sphere outlined by a concave arc-shaped array of 64 piezo-composite transducers. These images were then combined to reconstruct 3-D volume images (voxel resolution 0.5 mm), which were acquired before and after HIFU exposure. In vivo optoacoustic images acquired at 1064 nm provided visualization of HIFU lesions. The lesion was indicated by a negative optoacoustic contrast. The molecular nature of such contrast may possibly be associated with reduction of the optical absorption due to reduced concentration of blood, tissue dehydration, denaturation of proteins and porphyrins, and reduction of thermoacoustic efficiency in the thermally treated tissue. These preliminary results demonstrate the potential of optoacoustic imaging to assess and monitor the progress of HIFU therapy.

Photoacoustic imaging of living mouse brain vasculature using hollow gold nanospheres.

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.

Measurement of the spectral directivity of optoacoustic and ultrasonic transducers with a laser ultrasonic source.

Comprehensive characterization of wideband ultrasonic transducers and specifically optoacoustic detectors is achieved through the analysis of their frequency response as a function of the incident angle. The tests are performed under well-defined, repeatable operating conditions. Backillumination of a blackened, acoustically matched planar surface with a short laser pulse creates an acoustic impulse which is used as a wideband ultrasonic source. Upon illumination with a short laser pulse, the bandwidth of our source shows a -6 dB point of 12 MHz and a low-frequency roll-off around 300 kHz. Using proprietary software, we examine thoroughly the planarity of the emitted wave front within a specified amplitude cutoff and phase incoherence. Analysis of the angular dependence of the frequency response yields invaluable directivity information about the detector under study: a necessary component toward accurate optoacoustic image reconstruction and quantitative tomography. The laser ultrasonic source we developed is the main feature of our directivity measurement setup. Due to its simplicity, it can easily be adapted to various calibration devices. This paper focuses on the development and characterization of the flatness and the bandwidth of our wideband ultrasonic source.

Whole-body three-dimensional optoacoustic tomography system for small animals.

We develop a system for three-dimensional whole-body optoacoustic tomography of small animals for applications in preclinical research. The tomographic images are obtained while the objects of study (phantoms or mice) are rotated within a sphere outlined by a concave arc-shaped array of 64 piezocomposite transducers. Two pulsed lasers operating in the near-IR spectral range (755 and 1064 nm) with an average pulsed energy of about 100 mJ, a repetition rate of 10 Hz, and a pulse duration of 15 to 75 ns are used as optical illumination sources. During the scan, the mouse is illuminated orthogonally to the array with two wide beams of light from a bifurcated fiber bundle. The system is capable of generating images of individual organs and blood vessels through the entire body of a mouse with spatial resolution of approximately 0.5 mm.