Explore the vast range of titles available.

The ability to non-invasively visualize endogenous chromophores and exogenous probes and sensors across the entire rodent brain with the high spatial and temporal resolution has empowered optoacoustic imaging modalities with unprecedented capacities for interrogating the brain under physiological and diseased conditions. This has rapidly transformed optoacoustic microscopy (OAM) and multi-spectral optoacoustic tomography (MSOT) into emerging research tools to study animal models of brain diseases. In this review, we describe the principles of optoacoustic imaging and showcase recent technical advances that enable high-resolution real-time brain observations in preclinical models. In addition, advanced molecular probe designs allow for efficient visualization of pathophysiological processes playing a central role in a variety of neurodegenerative diseases, brain tumors, and stroke. We describe outstanding challenges in optoacoustic imaging methodologies and propose a future outlook.

Fast tracking of biological dynamics across multiple murine organs using the currently commercially available whole-body preclinical imaging systems is hindered by their limited contrast, sensitivity and spatial or temporal resolution. Spiral volumetric optoacoustic tomography (SVOT) provides optical contrast, with an unprecedented level of spatial and temporal resolution, by rapidly scanning a mouse using spherical arrays, thus overcoming the current limitations in whole-body imaging. The method enables the visualization of deep-seated structures in living mammalian tissues in the near-infrared spectral window, while further providing unrivalled image quality and rich spectroscopic optical contrast. Here, we describe the detailed procedures for SVOT imaging of mice and provide specific details on how to implement a SVOT system, including component selection, system arrangement and alignment, as well as the image processing methods. The step-by-step guide for the rapid panoramic (360°) head-to-tail whole-body imaging of a mouse includes the rapid visualization of contrast agent perfusion and biodistribution. The isotropic spatial resolution possible with SVOT can reach 90 µm in 3D, while alternative steps enable whole-body scans in less than 2 s, unattainable with other preclinical imaging modalities. The method further allows the real-time (100 frames per second) imaging of biodynamics at the whole-organ level. The multiscale imaging capacity provided by SVOT can be used for visualizing rapid biodynamics, monitoring responses to treatments and stimuli, tracking perfusion, and quantifying total body accumulation and clearance dynamics of molecular agents and drugs. Depending on the imaging procedure, the protocol requires 1–2 h to complete by users trained in animal handling and biomedical imaging. The authors describe spiral volumetric optoacoustic tomography for the visualization of contrast agent perfusion and biodistribution in mice, featuring excellent scalability to achieve spatial resolution down to 90 µm or whole-body scans in <2 s.

Noradrenaline (NA) release from the locus coeruleus (LC) changes activity and connectivity in neuronal networks across the brain, modulating multiple behavioral states. NA release is mediated by both tonic and burst-like LC activity. However, it is unknown whether the functional changes in target areas depend on these firing patterns. Using optogenetics, photometry, electrophysiology and functional magnetic resonance imaging in mice, we show that tonic and burst-like LC firing patterns elicit brain responses that hinge on their distinct NA release dynamics. During moderate tonic LC activation, NA release engages regions associated with associative processing, while burst-like stimulation biases the brain toward sensory processing. These activation patterns locally couple with increased astrocytic and inhibitory activity and change the brain’s topological configuration in line with the hierarchical organization of the cerebral cortex. Together, these findings reveal how the LC–NA system achieves a nuanced regulation of global circuit operations. Tonic and burst-like locus coeruleus firing distinctly tune brain topology toward associative and sensory regions, recruiting both astrocytic and neuronal inhibitory activity.

Rapid progress in the development of multispectral optoacoustic tomography techniques has enabled unprecedented insights into biological dynamics and molecular processes in vivo and noninvasively at penetration and spatiotemporal scales not covered by modern optical microscopy methods. Ultrasound imaging provides highly complementary information on elastic and functional tissue properties and further aids in enhancing optoacoustic image quality. We devised the first hybrid transmission–reflection optoacoustic ultrasound (TROPUS) small animal imaging platform that combines optoacoustic tomography with both reflection- and transmission-mode ultrasound computed tomography. The system features full-view cross-sectional tomographic imaging geometry for concomitant noninvasive mapping of the absorbed optical energy, acoustic reflectivity, speed of sound, and acoustic attenuation in whole live mice with submillimeter resolution and unrivaled image quality. Graphics-processing unit (GPU)-based algorithms employing spatial compounding and bent-ray-tracing iterative reconstruction were further developed to attain real-time rendering of ultrasound tomography images in the full-ring acquisition geometry. In vivo mouse imaging experiments revealed fine details on the organ parenchyma, vascularization, tissue reflectivity, density, and stiffness. We further used the speed of sound maps retrieved by the transmission ultrasound tomography to improve optoacoustic reconstructions via two-compartment modeling. The newly developed synergistic multimodal combination offers unmatched capabilities for imaging multiple tissue properties and biomarkers with high resolution, penetration, and contrast.Hybridized optoacoustic ultrasound computed tomographyA three-in-one imaging platform combines the advantages of each individual technique to provide whole body tomographic imaging of small animals. Developed by the group of Daniel Razansky from the University of Zurich and ETH Zurich in Switzerland and collaborators in Germany and Spain, the hybrid platform combines optoacoustic tomography with reflection and transmission mode ultrasonography. By launching ultrasound and laser pulses into tissues, the technique allows the construction of cross-sectional tomographic images that reveal fine details on organ function, tissue vascularization, reflectivity, stiffness and density. As an added value of the hybrid combination, images retrieved by one modality are also used to enhance the reconstruction quality of the other two modalities. The platform could thus be used for probing and quantifying multiple anatomical, functional and molecular properties of tissues in health and disease.

Super-resolution optoacoustic imaging of microvascular structures deep in mammalian tissues has so far been impeded by strong absorption from densely-packed red blood cells. Here we devised 5 µm biocompatible dichloromethane-based microdroplets exhibiting several orders of magnitude higher optical absorption than red blood cells at near-infrared wavelengths, thus enabling single-particle detection in vivo. We demonstrate non-invasive three-dimensional microangiography of the mouse brain beyond the acoustic diffraction limit (<20 µm resolution). Blood flow velocity quantification in microvascular networks and light fluence mapping was also accomplished. In mice affected by acute ischemic stroke, the multi-parametric multi-scale observations enabled by super-resolution and spectroscopic optoacoustic imaging revealed significant differences in microvascular density, flow and oxygen saturation in ipsi- and contra-lateral brain hemispheres. Given the sensitivity of optoacoustics to functional, metabolic and molecular events in living tissues, the new approach paves the way for non-invasive microscopic observations with unrivaled resolution, contrast and speed. Optoacoustic super-resolution at millimeter-scale depths has been impeded by the strong background absorption from blood cells. Here, the authors use dichloromethane microdroplets with high optical absorption and demonstrate 3D microangiography of the mouse brain via optoacoustic localization.

Fluorescent proteins have become essential reporter molecules for studying life at the cellular and sub-cellular level, re-defining the ways in which we investigate biology. However, because of intense light scattering, most organisms and tissues remain inaccessible to current fluorescence microscopy techniques at depths beyond several hundred micrometres. We describe a multispectral opto-acoustic tomography technique capable of high-resolution visualization of fluorescent proteins deep within highly light-scattering living organisms. The method uses multiwavelength illumination over multiple projections combined with selective-plane opto-acoustic detection for artifact-free data collection. Accurate image reconstruction is enabled by making use of wavelength-dependent light propagation models in tissue. By performing whole-body imaging of two biologically important and optically diffuse model organisms, Drosophila melanogaster pupae and adult zebrafish, we demonstrate the facility to resolve tissue-specific expression of eGFP and mCherrry fluorescent proteins for precise morphological and functional observations in vivo . Opto-acoustic imaging of fluorescent proteins deep within living organisms ( Drosophila melanogaster and zebrafish) is reported. The approach uses multiple wavelength illumination of the sample to generate ultrasound waves which are then detected and converted into images.

Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer's, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as fluorescent protein tomography and multispectral optoacoustic tomography. Overall, great potential is foreseen for nanocarriers in medical diagnostics, therapeutics and molecular targeting. A proposed roadmap for ongoing and future research directions is therefore discussed in detail with emphasis on the development of novel approaches for functionalization, targeting and imaging of nano-based drug delivery systems, a cutting-edge technology poised to change the ways medicine is administered.

The breakthrough capacity of optoacoustics for three-dimensional visualization of dynamic events in real time has been recently showcased. Yet, efficient spectral unmixing for functional imaging of entire volumetric regions is significantly challenged by motion artifacts in concurrent acquisitions at multiple wavelengths. Here, we introduce a method for simultaneous acquisition of multispectral volumetric datasets by introducing a microsecond-level delay between excitation laser pulses at different wavelengths. Robust performance is demonstrated by real-time volumetric visualization of functional blood parametrers in human vasculature with a handheld matrix array optoacoustic probe. This approach can avert image artifacts imposed by velocities greater than 2 m/s, thus, does not only facilitate imaging influenced by respiratory, cardiac or other intrinsic fast movements in living tissues, but can achieve artifact-free imaging in the presence of more significant motion, e.g. abrupt displacements during handheld-mode operation in a clinical environment.

The characterization of pharmacokinetic and biodistribution profiles is an essential step in the development process of new candidate drugs or imaging agents. Simultaneously, the assessment of organ function related to the uptake and clearance of drugs is of great importance. To this end, we demonstrate an imaging platform capable of high-rate characterization of the dynamics of fluorescent agents in multiple organs using multispectral optoacoustic tomography (MSOT). A spatial resolution of approximately 150 µm through mouse cross-sections allowed us to image blood vessels, the kidneys, the liver and the gall bladder. In particular, MSOT was employed to characterize the removal of indocyanine green from the systemic circulation and its time-resolved uptake in the liver and gallbladder. Furthermore, it was possible to track the uptake of a carboxylate dye in separate regions of the kidneys. The results demonstrate the acquisition of agent concentration metrics at rates of 10 samples per second at a single wavelength and 17 s per multispectral sample with 10 signal averages at each of 5 wavelengths. Overall, such imaging performance introduces previously undocumented capabilities of fast, high resolution in vivo imaging of the fate of optical agents for drug discovery and basic biological research.

Ultrasound imaging is an essential part of the modern clinical routine. However, its dependence on costly multichannel electronics limits its use in chronic monitoring of disease. Single-detector compressed-sensing approaches have been proposed to simplify the signal acquisition pipeline, but they suffer from reduced acoustic sensitivity due to reliance on multiple scattering topologies. We propose foldable origami structures with built-in ultrasound sensing capabilities for single-pixel imaging that increase the acoustic sensitivity by leveraging a foldable transducer geometry. By detecting ultrasound fields at various origami folding states, target images in two- and three-dimensions are recovered using model-based reconstruction techniques. We simulated the Foldable Origami-based Compressive Ultrasound Sensing (FOCUS) concept and inverse designed the origami geometry for maximum imaging performance. We quantified the performance of the FOCUS concept with the reconstruction accuracy of synthetic target images including point-scatterers and vessel-like structures, reaching an average structure similarity index measure of 0.63 and error of 11.89. We showed that the optimized FOCUS pattern remains effective even when exposed to geometric distortions and electrical noise. Our approach can tailor the FOCUS design to various targets, scales, and applications, potentially transforming ultrasound imaging devices through miniaturized single-channel electronics.