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Significance: Photoacoustic imaging (PAI) is an emerging technology that holds high promise in a wide range of clinical applications, but standardized methods for system testing are lacking, impeding objective device performance evaluation, calibration, and inter-device comparisons. To address this shortfall, this tutorial offers readers structured guidance in developing tissue-mimicking phantoms for photoacoustic applications with potential extensions to certain acoustic and optical imaging applications., Aim: The tutorial review aims to summarize recommendations on phantom development for PAI applications to harmonize efforts in standardization and system calibration in the field., Approach: The International Photoacoustic Standardization Consortium has conducted a consensus exercise to define recommendations for the development of tissue-mimicking phantoms in PAI., Results: Recommendations on phantom development are summarized in seven defined steps, expanding from (1) general understanding of the imaging modality, definition of (2) relevant terminology and parameters and (3) phantom purposes, recommendation of (4) basic material properties, (5) material characterization methods, and (6) phantom design to (7) reproducibility efforts., Conclusions: The tutorial offers a comprehensive framework for the development of tissue-mimicking phantoms in PAI to streamline efforts in system testing and push forward the advancement and translation of the technology., (© 2024 The Authors.)

Significance: Photoacoustic tomography (PAT) has great potential in monitoring disease progression and treatment response in breast cancer. However, due to variations in breast repositioning, there is a chance of geometric misalignment between images. Further, poor repositioning can affect light fluence distribution and imaging field-of-view, making images different from one another. The net effect is that it becomes challenging to distinguish between image changes due to repositioning effects and those due to true biological variations., Aim: The aim is to develop a three-dimensional image registration framework for geometrically aligning repeated PAT volumetric images, which are potentially affected by repositioning effects such as misalignment, changed radiant exposure conditions, and different fields-of-view., Approach: The proposed framework involves the use of a coordinate-based neural network to represent the displacement field between pairs of PAT volumetric images. A loss function based on normalized cross correlation and Frangi vesselness feature extraction at multiple scales was implemented. We refer to our image registration framework as MUVINN-reg, which stands for multiscale vesselness-based image registration using neural networks. The approach was tested on a longitudinal dataset of healthy volunteer breast PAT images acquired with the hybrid photoacoustic-ultrasound Photoacoustic Mammoscope 3 imaging system. The registration performance was also tested under unfavorable repositioning conditions such as intentional mispositioning, and variation in breast-supporting cup size between measurements., Results: A total of 13 pairs of repeated PAT scans were included in this study. MUVINN-reg showed excellent performance in co-registering each pair of images. The proposed framework was shown to be robust to image intensity shifts and field-of-view changes. Furthermore, MUVINN-reg could align vessels at imaging depths greater than 4 cm., Conclusions: The proposed framework will enable the use of PAT for quantitative and reproducible monitoring of disease progression and treatment response., (© 2024 The Authors.)

Significance: During the development and early testing phases of new photoacoustic (PA) breast imaging systems, several choices need to be made in aspects of system design and measurement sequences. Decision-making can be complex for state-of-the-art systems such as 3D hybrid photoacoustic-ultrasound (PA-US) breast imagers intended for multispectral quantitative imaging. These systems have a large set of design choices and system settings that affect imaging performance in different ways and often require trade-offs. Decisions have to be made carefully as they can strongly influence the imaging performance., Aim: A systematic approach to assess the influence of various choices on the imaging performance in carefully controlled laboratory situations is crucial before starting with human studies. Test objects and phantoms are used for first imaging studies, but most reported structures have a 2D geometry and are not suitable to assess all the image quality characteristics (IQCs) of 3D hybrid PA-US systems., Approach: Our work introduces a suite of five test objects designed for hybrid PA-US systems with a 3D detection aperture. We present the test object designs and production protocols and explain how they can be used to study various performance measures. To demonstrate the utility of the developed objects, measurements are made with an existing tomographic PA system., Results: Two test objects were developed for measurements of the US detectors' impulse responses and light distribution on the breast surface. Three others were developed to assess image quality and quantitative accuracy of the PA and US modes. Three of the five objects were imaged to demonstrate their use., Conclusions: The developed test objects allow one to study influences of various choices in design and system settings. With this, IQCs can be assessed as a function of measurement sequence settings for the PA and US modes in a controlled way. Systematic studies and measurements using these objects will help to optimize various system settings and measurement protocols in laboratory situations before embarking on human studies.

Significance: Recovering accurate oxygenation estimations in the breast with quantitative photoacoustic tomography (QPAT) is not straightforward. Accurate light fluence models are required, but the unknown ground truth of the breast makes it difficult to validate them. Phantoms are often used for the validation, but most reported phantoms have a simple architecture. Fluence models developed in these simplistic objects are not accurate for application on the complex tissues of the breast., Aim: We present a sophisticated breast phantom platform for photoacoustic (PA) and ultrasound (US) imaging in general, and specifically for QPAT. The breast phantom is semi-anthropomorphic in distribution of optical and acoustic properties and contains wall-less channels with blood., Approach: 3D printing approaches are used to develop the solid 3D breast phantom from custom polyvinyl chloride plastisol formulations and additives for replicating the tissue optical and acoustic properties. A flow circuit was developed to flush the channels with bovine blood with a controlled oxygen saturation level. To showcase the phantom's functionality, PA measurements were performed on the phantom with two oxygenation levels. Image reconstructions with and without fluence compensation from Monte Carlo simulations were analyzed for the accuracy of oxygen saturation estimations., Results: We present design aspects of the phantom, demonstrate how it is developed, and present its breast-like appearance in PA and US imaging. The oxygen saturations were estimated in two regions of interest with and without using the fluence models. The fluence compensation positively influenced the SO2 estimations in all cases and confirmed that highly accurate fluence models are required to minimize estimation errors., Conclusions: This phantom allows studies to be performed in PA in carefully controlled laboratory settings to validate approaches to recover both qualitative and quantitative features sought after in in-vivo studies. We believe that testing with phantoms of this complexity can streamline the transition of new PA technologies from the laboratory to studies in the clinic.

We present the Twente Photoacoustic Mammoscope 2, a photoacoustic breast imaging system employing a tomographic configuration. It images one breast pendant inside an imaging tank filled with water while a woman lies prone on a bed. A dual-head laser (755 and 1064 nm) illuminates the breast with one beam directed at the nipple and nine beams directed at the sides. Ultrasound signals are detected using 12 arc-shaped arrays, each curving along the pendant breast. Each array comprises 32 piezocomposite elements each with a center frequency of 1 MHz. The imaging tank and the ultrasound arrays rotate around the breast in steps to obtain additional multiple projections. Three-dimensional images are reconstructed using a filtered backprojection algorithm. The system is described in detail, and measurements on a test object are presented. As part of a preliminary study to assess the system's in vivo performance, the breasts of two healthy volunteers were imaged. These images show the breast contour, the nipple, and the vascular anatomy within the breast. In the nipple of one case, multiple high-intensity "hot spots" are observed, which we suspect are associated with the lactiferous ducts terminating in the nipple.

An important problem in minimally invasive photoacoustic (PA) imaging of brachytherapy seeds is reflection artifacts caused by the high signal from the optical fiber/needle tip reflecting off the seed. The presence of these artifacts confounds interpretation of images. In this letter, we demonstrate a recently developed concept called photoacoustic-guided focused ultrasound (PAFUSion) for the first time in the context of interstitial illumination PA imaging to identify and remove reflection artifacts. In this method, ultrasound (US) from the transducer is focused on the region of the optical fiber/needle tip identified in a first step using PA imaging. The image developed from the US diverging from the focus zone at the tip region visualizes only the reflections from seeds and other acoustic inhomogeneities, allowing identification of the reflection artifacts of the first step. These artifacts can then be removed from the PA image. Using PAFUSion, we demonstrate reduction of reflection artifacts and thereby improved interstitial PA visualization of brachytherapy seeds in phantom and

In the search for improved imaging modalities for detection and diagnosis of breast cancer, a high negative prediction value is also important. Photoacoustic (optoacoustic) imaging is a relatively new technique that has high potential for visualizing breast malignancies, but little is known about the photoacoustic appearance of benign lesions. In this work, we investigate the visibility of benign breast cysts in forward-mode photoacoustic mammography using 1064-nm light, as currently applied in the Twente photoacoustic mammoscope. Results from (Monte Carlo and k-wave) simulations and phantom measurements were used to interpret results from patient measurements. There was a strong agreement among the results from simulations, phantom, and patient measurements. Depending on the absorption contrast between cyst and breast tissue, cysts were visible as either one or two confined high-contrast areas representing the front and the back of the cyst, respectively. This edge enhancement is most likely the consequence of the local sudden change in the absorbed energy density and Grüneisen coefficients. Although the current forward-mode single-wavelength photoacoustic mammoscope cannot always unambiguously discriminate cysts from malignancies, this study reveals specific features of cysts compared to malignancies, which can be exploited for discrimination of the two abnormalities in future modifications of the imager.

Recently, we presented an add-on to a photoacoustic (PA) computed tomography imager that permits the simultaneous imaging of ultrasound (US) transmission parameters such as the speed of sound (SOS), without additional measurements or instruments. This method uses strong absorbers positioned outside the object in the path of light for producing laser-induced US to interrogate the object in a conventional PA imager. Here, we investigate the feasibility of using this approach, first with PA to pin-point the location of photothermal therapeutic agents and then with serial SOS tomograms to image and monitor the resulting local temperature changes when the agents are excited with continuous wave (CW) light. As the object we used an agar-based tissue-mimicking cylinder carrying beads embedded with different concentrations of gold nanospheres. PA and SOS tomograms were simultaneously acquired as the gold nanospheres were photothermally heated using a 532-nm CW laser. In a first approximation, using the relation between SOS of water and temperature, the SOS tomograms were converted into temperature maps. The experimental results were verified using simulations: Monte Carlo modeling of light propagation through a turbid medium and using the obtained absorbed energy densities in heat diffusion modeling for spatial temperature distribution.

We introduce a needle probe based on photoacoustics (PA) to extend the scope of optical needle methods in guiding biopsies. Pulsed light is coupled to an optical fiber in a needle to be inserted in tissue, and PA signals are detected using an ultrasound imager used for needle guidance. This PA needle samples large volumes and possesses an imaging component so that sites forward and off-axis of the fiber are surveyed. This allows navigation of those regions for optical characterization and direct biopsy in a subsequent step. The concept is explored on simple phantoms and biological specimens.

The pathological status of the sentinel lymph node is important for accurate melanoma staging, ascertaining prognosis and planning treatment. The standard procedure involves biopsy of the node and histopathological assessment of its status. Drawbacks of this examination include a finite sampling of the node with the likelihood of missing metastases, and a significant time-lag before histopathological results are available to the surgeon. We studied the applicability of photoacoustic computed tomographic imaging as an intraoperative modality for examining the status of resected human sentinel lymph nodes. We first applied the technique to image ex vivo pig lymph nodes carrying metastases-simulating melanoma cells using multiple wavelengths. The experience gained was applied to image a suspect human lymph node. We validated the photoacoustic imaging results by comparing a reconstructed slice with a histopathological section through the node. Our results suggest that photoacoustics has the potential to develop into an intraoperative imaging method to detect melanoma metastases in sentinel lymph nodes.

A popular phantom in photoacoustic imaging is poly(vinyl alcohol) (PVA) hydrogel fabricated by freezing and thawing (F-T) aqueous solutions of PVA. The material possesses acoustic and optical properties similar to those of tissue. Earlier work characterized PVA gels in small test specimens where temperature distributions during F-T are relatively homogeneous. In this work, in breast-sized samples we observed substantial temperature differences between the shallow regions and the interior during the F-T procedure. We investigated whether spatial variations were also present in the acoustic and optical properties. The speed of sound, acoustic attenuation, and optical reduced scattering coefficients were measured on specimens sampled at various locations in a large phantom. In general, the properties matched values quoted for breast tissue. But while acoustic properties were relatively homogeneous, the reduced scattering was substantially different at the surface compared with the interior. We correlated these variations with gel microstructure inspected using scanning electron microscopy. Interestingly, the phantom's reduced scattering spatial distribution matches the optical properties of the standard two-layer breast model used in x ray dosimetry. We conclude that large PVA samples prepared using the standard recipe make excellent breast tissue phantoms.

We present a laboratory version of a photoacoustic mammoscope, based on a parallel plate geometry. The instrument is built around a flat high-density ultrasound detector matrix. The light source is a Q-switched Nd:YAG laser with a pulse duration of 5 ns. To test the instrument, a novel photoacoustic phantom is developed using poly(vinyl alcohol) gel, prepared by a simple procedure that imparts optical scattering suggestive of breast tissue to it without the requirement for extraneous scattering particles. Tumor simulating poly(vinyl alcohol) gel spheres appropriately dyed at the time of preparation are characterized for optical absorption coefficients. These are then embedded in the phantom to serve as tumors with absorption contrasts ranging from 2 to 7, with respect to the background. Photoacoustic studies in transmission mode are performed, by acquiring the laser-induced ultrasound signals from regions of interest in the phantom. Image reconstruction is based on a delay-and-sum beamforming algorithm. The results of these studies provide an insight into the capabilities of the prototype. Various recommendations that will guide the evolving of our laboratory prototype into a clinical version are also discussed., (Copyright 2004 Society of Photo-Optical Instrumentation Engineers.)