Broadband mesoscopic optoacoustic tomography reveals skin layers: publisher's note.

This publisher's note contains corrections to Opt. Lett.39, 6297 (2014)OPLEDP0146-959210.1364/OL.39.006297.

Capsule optoacoustic endoscopy for esophageal imaging.

Detection and monitoring of esophageal cancer severity require an imaging technique sensitive enough to detect early pathological changes in the esophagus and capable of analyzing the esophagus over 360 °in a non-invasive manner. Optoacoustic endoscopy (COE) has been shown to resolve superficial vascular structure of the esophageal lumen in rats and rabbits using catheter-type probes. Although these systems can work well in small animals, they are unsuitable for larger lumens with thicker walls as required for human esophageal screening, due to their lack of position stability along the full organ circumference, sub-optimal acoustic coupling and limited signal-to-noise ratio (SNR). In this work, we introduce a novel capsule COE system that provides high-quality 360° images of the entire lumen, specifically designed for typical dimensions of human esophagus. The pill-shaped encapsulated probe consists of a novel and highly sensitive ultrasound transducer fitted with an integrated miniature pre-amplifier, which increases SNR of 10 dB by minimizing artifacts during signal transmission compared to the configuration without the preamplifier. The scanner rotates helically around the central axis of the probe to capture three-dimensional images with uniform quality. We demonstrate for the first time ex vivo volumetric vascular network images to a depth of 2 mm in swine esophageal lining using COE. Vascular information can be resolved within the mucosa and submucosa layers as confirmed by histology of samples stained with hematoxylin and eosin and with antibody against vascular marker CD31. COE creates new opportunities for optoacoustic screening of esophageal cancer in humans.

Importance of Ultrawide Bandwidth for Optoacoustic Esophagus Imaging.

Optoacoustic (photoacoustic) endoscopy has shown potential to reveal complementary contrast to optical endoscopy methods, indicating clinical relevance. However operational parameters for accurate optoacoustic endoscopy must be specified for optimal performance. Recent support from the EU Horizon 2020 program ESOTRAC to develop a next-generation optoacoustic esophageal endoscope directs the interrogation of the optimal frequency required for accurate implementation. We simulated the frequency response of the esophagus wall and then validated the simulation results with experimental measurements of pig esophagus. Phantoms and fresh pig esophagus samples were measured using two detectors with central frequencies of 15 or 50 MHz, and the imaging performance of both detectors was compared. We analyzed the frequency bandwidth of optoacoustic signals in relation to morphological layer structures of the esophagus and found the 50 MHz detector to differentiate layer structures better than the 15 MHz detector. Furthermore, we identify the necessary detection bandwidth for visualizing esophagus morphology and selecting ultrasound transducers for future optoacoustic endoscopy of the esophagus.

Assessing hyperthermia-induced vasodilation in human skin in vivo using optoacoustic mesoscopy.

The aim of this study was to explore the unique imaging abilities of optoacoustic mesoscopy to visualize skin structures and microvasculature with the view of establishing a robust approach for monitoring heat-induced hyperemia in human skin in vivo. Using raster-scan optoacoustic mesoscopy (RSOM), we investigated whether optoacoustic (photoacoustic) mesoscopy can identify changes in skin response to local heating at microvasculature resolution in a cross-sectional fashion through skin in the human forearm. We visualized the heat-induced hyperemia for the first time with single-vessel resolution throughout the whole skin depth. We quantified changes in total blood volume in the skin and their correlation with local heating. In response to local heating, total blood volume increased 1.83- and 1.76-fold, respectively, in the volar and dorsal aspects of forearm skin. We demonstrate RSOM imaging of the dilation of individual vessels in the skin microvasculature, consistent with hyperemic response to heating at the skin surface. Our results demonstrate great potential of RSOM for elucidating the morphology, functional state and reactivity of dermal microvasculature, with implications for diagnostics and disease monitoring. Image: Cross-sectional view of skin microvasculature dilated in response to hyperthermia.

Continuous wave laser diodes enable fast optoacoustic imaging.

Pulsed laser diodes may offer a smaller, less expensive alternative to conventional optoacoustic laser sources; however they do not provide pulse rates faster than a few tens of kHz and emit at wavelengths only within the near-infrared region. We investigated whether continuous wave (CW) laser diodes, which are available in visible and near-infrared regions, can be good optoacoustic light sources when overdriven with a peak current >40-fold higher than the CW absolute maximum. We found that overdriven CW diodes provided ∼10 ns pulses of ∼200 nJ/pulse and repetition rates higher than 600 kHz without being damaged, outperforming many pulsed laser diodes. Using this system, we obtained images of phantoms and mouse ear and human arm in vivo, confirming their use in optoacoustic imaging and sensing.

Imaging of fatty tumors: appearance of subcutaneous lipomas in optoacoustic images.

A wide variety of subcutaneous soft-tissue masses may be seen in clinical practice. Clinical examination based on palpation alone is often insufficient to identify the nature and exact origin of the mass, in which case imaging is necessary. We used handheld multispectral optoacoustic imaging technology (MSOT) in a proof-of-principle study to image superficial fatty tumors and compare the images with diagnostic ultrasound. Fatty tumors were clearly visualized by MSOT and exhibited a spectral signature which differed from normal fatty tissue or muscle tissue. Our findings further indicated that MSOT offers highly complementary contrast to sonography. Based on the performance achieved, we foresee a promising role for MSOT in the diagnosis and evaluation of subcutaneous soft-tissue masses. Picture: Pseudo-color representation of a cross-sectional multi-spectral optoacoustic slice through a subcutaneous lipoma. Multi-spectral information is encoded in color. The lipoma can clearly be distinguished from the surrounding tissue based on its color. Scalebar 1 cm.

Optoacoustic Dermoscopy of the Human Skin: Tuning Excitation Energy for Optimal Detection Bandwidth With Fast and Deep Imaging in vivo.

Optoacoustic (photoacoustic) dermoscopy offers two principal advantages over conventional optical imaging applied in dermatology. First, it yields high-resolution cross-sectional images of the skin at depths not accessible to other non-invasive optical imaging methods. Second, by resolving absorption spectra at multiple wavelengths, it enables label-free 3D visualization of morphological and functional features. However, the relation of pulse energy to generated bandwidth and imaging depth remains poorly defined. In this paper, we apply computer models to investigate the optoacoustic frequency response generated by simulated skin. We relate our simulation results to experimental measurements of the detection bandwidth as a function of optical excitation energy in phantoms and human skin. Using raster-scan optoacoustic mesoscopy, we further compare the performance of two broadband ultrasonic detectors (a bandwidth of 20-180 and 10-90MHz) in acquiring optoacoustic readouts. Based on the findings of this paper, we propose energy ranges required for skin imaging with considerations of laser safety standards.

Hybrid optical and acoustic resolution optoacoustic endoscopy.

We propose the implementation of hybrid optical and acoustic resolution optoacoustic endoscopy. Laser light is transmitted to tissue by two types of illumination for achieving optical and acoustic resolution imaging. A 20 MHz ultrasound detector is used for recording optoacoustic signals. The endoscopy probe attains a 3.6 mm diameter and is fully encapsulated into a catheter system. We validate the imaging performance of the hybrid endoscope on phantoms and ex vivo, and discuss the necessity for the extended resolution and depth range of endoscopy achieved.

Statistical Molecular Target Detection Framework for Multispectral Optoacoustic Tomography.

Statistical sub-pixel detection via the adaptive matched filter (AMF) has been shown to improve the molecular imaging sensitivity and specificity of optoacoustic (photoacoustic) imaging. Applied to multispectral optoacoustic tomography (MSOT), AMF assumes that the spatially-varying tissue spectra follow a multivariate Gaussian distribution, that the spectrum of the target molecule is precisely known and that the molecular target lies in "low probability" within the data. However, when these assumptions are violated, AMF may result in considerable performance degradation. The objective of this work is to develop a robust statistical detection framework that is appropriately suited to the characteristics of MSOT molecular imaging. Using experimental imaging data, we perform a statistical characterization of MSOT tissue images and conclude to a detector that is based on the t-distribution. More importantly, we introduce a method for estimating the covariance matrix of the background-tissue statistical distribution, which enables robust detection performance independently of the molecular target size or intensity. The performance of the statistical detection framework is assessed through simulations and experimental in vivo measurements and compared to previously used methods.

Three-dimensional multispectral optoacoustic mesoscopy reveals melanin and blood oxygenation in human skin in vivo.

Optical imaging plays a major role in disease detection in dermatology. However, current optical methods are limited by lack of three-dimensional detection of pathophysiological parameters within skin. It was recently shown that single-wavelength optoacoustic (photoacoustic) mesoscopy resolves skin morphology, i.e. melanin and blood vessels within epidermis and dermis. In this work we employed illumination at multiple wavelengths for enabling three-dimensional multispectral optoacoustic mesoscopy (MSOM) of natural chromophores in human skin in vivo operating at 15-125 MHz. We employ a per-pulse tunable laser to inherently co-register spectral datasets, and reveal previously undisclosed insights of melanin, and blood oxygenation in human skin. We further reveal broadband absorption spectra of specific skin compartments. We discuss the potential of MSOM for label-free visualization of physiological biomarkers in skin in vivo.

Improving Optoacoustic Image Quality via Geometric Pixel Super-Resolution Approach.

High fidelity optoacoustic (photoacoustic) tomography requires dense spatial sampling of optoacoustic signals using point acoustic detectors. However, in practice, spatial resolution of the images is often limited by limited sampling either due to coarse multi-element arrays or time in raster scan measurements. Herein, we investigate a method that integrates information from multiple optoacoustic images acquired at sub-diffraction steps into one high resolution image by means of an iterative registration algorithm. Experimental validations performed in target phantoms and ex vivo tissue samples confirm that the suggested approach renders significant improvements in terms of optoacoustic image resolution and quality without introducing significant alterations into the signal acquisition hardware or inversion algorithms.

Optoacoustic Tomography Using Accelerated Sparse Recovery and Coherence Factor Weighting.

Sparse recovery algorithms have shown great potential to accurately reconstruct images using limited-view optoacoustic (photoacoustic) tomography data sets, but these are computationally expensive. In this paper, we propose an improvement of the fast converging Split Augmented Lagrangian Shrinkage Algorithm method based on least square QR inversion for improving the reconstruction speed. We further show image fidelity improvement when using a coherence factor to weight the reconstruction result. Phantom and in vivo measurements show that the accelerated Split Augmented Lagrangian Shrinkage Algorithm method with coherence factor weighting offers images with reduced artifacts and provides faster convergence compared with existing sparse recovery algorithms.

Optoacoustic endoscopy with curved scanning.

The optoacoustic (photoacoustic) technique has been shown to resolve anatomical, functional, and molecular features at depths that go beyond the reach of epi-illumination optical microscopy, offering new opportunities for endoscopic imaging. In this Letter, we investigate the merits of optoacoustic endoscopy implemented by translating a sound detector in linear or curved geometries. The linear and curved detection geometries are achieved by employing an intravascular ultrasound transducer within a plastic guide shaped to a line or a curve. This concept could be used together with optical endoscopes to yield hybrid optical and optoacoustic imaging.

Implications of ultrasound frequency in optoacoustic mesoscopy of the skin.

Raster-scan optoacoustic mesoscopy (RSOM) comes with high potential for in vivo diagnostic imaging in dermatology, since it allows for high resolution imaging of the natural chromophores melanin, and hemoglobin at depths of several millimeters. We have applied ultra-wideband RSOM, in the 10-160 MHz frequency band, to image healthy human skin at distinct locations. We analyzed the anatomical information contained at different frequency ranges of the optoacoustic (photoacoustic) signals in relation to resolving features of different skin layers in vivo. We further compared results obtained from glabrous and hairy skin and identify that frequencies above 60 MHz are necessary for revealing the epidermal thickness, a prerequisite for determining the invasion depth of melanoma in future studies. By imaging a benign nevus we show that the applied RSOM system provides strong contrast of melanin-rich structures. We further identify the spectral bands responsible for imaging the fine structures in the stratum corneum, assessing dermal papillae, and resolving microvascular structures in the horizontal plexus.

Isotropic high resolution optoacoustic imaging with linear detector arrays in bi-directional scanning.

Optoacoustic (photoacoustic) imaging is often performed with one-dimensional transducer arrays, in analogy to ultrasound imaging. Optoacoustic imaging using linear arrays offers ease of implementation but comes with several performance drawbacks, in particular poor elevation resolution, i.e. the resolution along the axis perpendicular to the focal plane. Herein, we introduce and investigate a bi-directional scanning approach using linear arrays that can improve the imaging performance to quasi-isotropic transverse resolution. We study the approach theoretically and perform numerical simulations and phantom measurements to evaluate its performance under defined conditions. Finally, we discuss the features and the limitations of the proposed method.

Broadband mesoscopic optoacoustic tomography reveals skin layers.

We have imaged for the first time to our knowledge human skin in vivo with a raster-scan optoacoustic mesoscopy system based on a spherically focused transducer with a central frequency of 102.8 MHz and large bandwidth (relative bandwidth 105%). Using tissue phantoms we have studied the ability of the system to image vessels of sizes within the anatomically significant range from the key anatomical vasculature sites. The reconstructed images from experiments in vivo show several structures from the capillary loops at the dermal papillae, the horizontal plexus, and the difference between the dermis and the epidermis layers.

Estimation of optoacoustic contrast agent concentration with self-calibration blind logarithmic unmixing.

Chromophore quantification in optoacoustic tomography is challenging due to signal contributions from strongly absorbing background tissue chromophores and the depth-dependent light attenuation. Herein we present a procedure capable of correcting for wavelength-dependent light fluence variations using a logarithmic representation of the images taken at different wavelengths assisted with a blind unmixing approach. It is shown that the serial expansion of the logarithm of an optoacoustic image contains a term representing the ratio between absorption of the probe of interest and other background components. Under assumptions of tissue-like background absorption variations, this term can be readily isolated with an unmixing algorithm, attaining quantitative maps of photo-absorbing agent distribution.

24-MHz scanner for optoacoustic imaging of skin and burn.

Optoacoustic (photoacoustic) imaging uniquely visualizes optical contrast in high resolution and comes with very attractive characteristics for clinical imaging applications. In this paper, we showcase the performance of a scanner based on a 24 MHz center-frequency 128 element array, developed for applications in dermatology. We perform system characterization to examine the imaging performance achieved. We then showcase its imaging ability on healthy tissue and cancer. Finally, we image burns and human lesions in vivo and gain insights on the benefits and challenges of this approach as it is considered for diagnostic and treatment follow-up applications in dermatology and beyond.

Volumetric optoacoustic imaging with multi-bandwidth deconvolution.

Optoacoustic (photoacoustic) imaging based on cylindrically focused 1-D transducer arrays comes with powerful characteristics in visualizing optical contrast. Parallel reading of multiple detectors arranged around a tissue cross section enables capturing data for generating images of this plane within micro-seconds. Dedicated small animals scanners and handheld systems using 1-D cylindrically focused ultrasound transducer arrays have demonstrated real-time cross-sectional imaging and high in-plane resolution. Yet, the resolution achieved along the axis perpendicular to the focal plane, i.e., the elevation resolution, is determined by the focusing capacities of the detector and is typically lower than the in-plane resolution. Herein, we investigated whether deconvolution of the sensitivity field of the transducer could lead to tangible image improvements. We showcase the findings on experimental measurements from phantoms and animals and discuss the features and the limitations of the approach in improving resolution along the elevation dimension.

Modeling the shape of cylindrically focused transducers in three-dimensional optoacoustic tomography.

Cross sectional tomographic systems based on cylindrically focused transducers are widely used in optoacoustic (photoacoustic) imaging due to important advantages they provide such as high-cross sectional resolution, real-time imaging capacity, and high-throughput performance. Tomographic images in such systems are commonly obtained by means of two-dimensional (2-D) reconstruction procedures assuming point-like detectors, and volumetric (whole-body) imaging is performed by superimposing the cross sectional images for different positions along the scanning direction. Such reconstruction strategy generally leads to in-plane and out-of-plane artifacts as well as significant quantification errors. Herein, we introduce two equivalent full three-dimensional (3-D) models capable of accounting for the shape of cylindrically focused transducers. The performance of these models in 3-D reconstructions considering several scanning positions is analyzed in this work. Improvements of the results rendered with the introduced reconstruction procedure as compared with the 2-D-based approach are described and discussed for simulations and experiments with phantoms and biological tissues.