Multiparametric Brain Hemodynamics Imaging Using a Combined Ultrafast Ultrasound and Photoacoustic System.

Studying brain-wide hemodynamic responses to different stimuli at high spatiotemporal resolutions can help gain new insights into the mechanisms of neuro- diseases and -disorders. Nonetheless, this task is challenging, primarily due to the complexity of neurovascular coupling, which encompasses interdependent hemodynamic parameters including cerebral blood volume (CBV), cerebral blood flow (CBF), and cerebral oxygen saturation (SO2). The current brain imaging technologies exhibit inherent limitations in resolution, sensitivity, and imaging depth, restricting their capacity to comprehensively capture the intricacies of cerebral functions. To address this, a multimodal functional ultrasound and photoacoustic (fUSPA) imaging platform is reported, which integrates ultrafast ultrasound and multispectral photoacoustic imaging methods in a compact head-mountable device, to quantitatively map individual dynamics of CBV, CBF, and SO2 as well as contrast agent enhanced brain imaging at high spatiotemporal resolutions. Following systematic characterization, the fUSPA system is applied to study brain-wide cerebrovascular reactivity (CVR) at single-vessel resolution via relative changes in CBV, CBF, and SO2 in response to hypercapnia stimulation. These results show that cortical veins and arteries exhibit differences in CVR in the stimulated state and consistent anti-correlation in CBV oscillations during the resting state, demonstrating the multiparametric fUSPA system's unique capabilities in investigating complex mechanisms of brain functions.

Dissecting Multiparametric Cerebral Hemodynamics using Integrated Ultrafast Ultrasound and Multispectral Photoacoustic Imaging.

Understanding brain-wide hemodynamic responses to different stimuli at high spatiotemporal resolutions can help study neuro-disorders and brain functions. However, the existing brain imaging technologies have limited resolution, sensitivity, imaging depth and provide information about only one or two hemodynamic parameters. To address this, we propose a multimodal functional ultrasound and photoacoustic (fUSPA) imaging platform, which integrates ultrafast ultrasound and multispectral photoacoustic imaging methods in a compact head-mountable device, to quantitatively map cerebral blood volume (CBV), cerebral blood flow (CBF), oxygen saturation (SO2) dynamics as well as contrast agent enhanced brain imaging with high spatiotemporal resolutions. After systematic characterization, the fUSPA system was applied to quantitatively study the changes in brain hemodynamics and vascular reactivity at single vessel resolution in response to hypercapnia stimulation. Our results show an overall increase in brain-wide CBV, CBF, and SO2, but regional differences in singular cortical veins and arteries and a reproducible anti-correlation pattern between venous and cortical hemodynamics, demonstrating the capabilities of the fUSPA system for providing multiparametric cerebrovascular information at high-resolution and sensitivity, that can bring insights into the complex mechanisms of neurodiseases.

Nanoparticle-Decorated Biomimetic Extracellular Matrix for Cell Nanoencapsulation and Regulation.

Cell encapsulation has been studied for various applications ranging from cell transplantation to biological production. However, current encapsulation technologies focus on cell protection rather than cell regulation that is essential to most if not all cell-based applications. Here we report a method for cell nanoencapsulation and regulation using an ultrathin biomimetic extracellular matrix as a cell nanocapsule to carry nanoparticles (CN2 ). This method allows high-capacity nanoparticle retention at the vicinity of cell surfaces. The encapsulated cells maintain high viability and normal metabolism. When gold nanoparticles (AuNPs) are used as a model to decorate the nanocapsule, light irradiation transiently increases the temperature, leading to the activation of the heat shock protein 70 (HSP70) promoter and the regulation of reporter gene expression. As the biomimetic nanocapsule can be decorated with any or multiple NPs, CN2 is a promising platform for advancing cell-based applications.

A Novel Matching Layer Design for Improving the Performance of Transparent Ultrasound Transducers.

Transparent ultrasound transducer (TUT) technology allows easy co-alignment of optical and acoustic beams in the development of compact photoacoustic imaging (PAI) devices with minimum acoustic coupling. However, TUTs suffer from narrow bandwidth and low pulse-echo sensitivity due to the lack of suitable transparent acoustic matching and backing layers. Here, we studied translucent glass beads (GB) in transparent epoxy as an acoustic matching layer for the transparent lithium niobate piezoelectric material-based TUTs (LN-TUTs). The acoustic and optical properties of various volume fractions of GB matching layers were studied using theoretical calculations, simulations, and experiments. These results demonstrated that the GB matching layer has significantly enhanced the pulse-echo sensitivity and bandwidth of the TUTs. Moreover, the GB matching layer served as a light diffuser to help achieve uniform optical fluence on the tissue surface and also improved the photoacoustic (PA) signal bandwidth. The proposed GB matching layer fabrication is low cost, easy to manufacture using conventional ultrasound transducer fabrication tools, acoustically compatible with soft tissue, and minimizes the use of the acoustic coupling medium.

Photoacoustic imaging for microcirculation.

Microcirculation facilitates the blood-tissue exchange of nutrients and regulates blood perfusion. It is, therefore, essential in maintaining tissue health. Aberrations in microcirculation are potentially indicative of underlying cardiovascular and metabolic pathologies. Thus, quantitative information about it is of great clinical relevance. Photoacoustic imaging (PAI) is a capable technique that relies on the generation of imaging contrast via the absorption of light and can image at micron-scale resolution. PAI is especially desirable to map microvasculature as hemoglobin strongly absorbs light and can generate a photoacoustic signal. This paper reviews the current state of the art for imaging microvascular networks using photoacoustic imaging. We further describe how quantitative information about blood dynamics such as the total hemoglobin concentration, oxygen saturation, and blood flow rate is obtained using PAI. We also discuss its importance in understanding key pathophysiological processes in neurovascular, cardiovascular, ophthalmic, and cancer research fields. We then discuss the current challenges and limitations of PAI and the approaches that can help overcome these limitations. Finally, we provide the reader with an overview of future trends in the field of PAI for imaging microcirculation.

Awake mouse brain photoacoustic and optical imaging through a transparent ultrasound cranial window.

Optical resolution photoacoustic microscopy (OR-PAM) can map the cerebral vasculature at capillary-level resolution. However, the OR-PAM setup's bulky imaging head makes awake mouse brain imaging challenging and inhibits its integration with other optical neuroimaging modalities. Moreover, the glass cranial windows used for optical microscopy are unsuitable for OR-PAM due to the acoustic impedance mismatch between the glass plate and the tissue. To overcome these challenges, we propose a lithium niobate based transparent ultrasound transducer (TUT) as a cranial window on a thinned mouse skull. The TUT cranial window simplifies the imaging head considerably due to its dual functionality as an optical window and ultrasound transducer. The window remains stable for six weeks, with no noticeable inflammation and minimal bone regrowth. The TUT window's potential is demonstrated by imaging the awake mouse cerebral vasculature using OR-PAM, intrinsic optical signal imaging, and two-photon microscopy. The TUT cranial window can potentially also be used for ultrasound stimulation and simultaneous multimodal imaging of the awake mouse brain.

A Transparent Ultrasound Array for Real-Time Optical, Ultrasound, and Photoacoustic Imaging.

Objective and Impact Statement. Simultaneous imaging of ultrasound and optical contrasts can help map structural, functional, and molecular biomarkers inside living subjects with high spatial resolution. There is a need to develop a platform to facilitate this multimodal imaging capability to improve diagnostic sensitivity and specificity. Introduction. Currently, combining ultrasound, photoacoustic, and optical imaging modalities is challenging because conventional ultrasound transducer arrays are optically opaque. As a result, complex geometries are used to coalign both optical and ultrasound waves in the same field of view. Methods. One elegant solution is to make the ultrasound transducer transparent to light. Here, we demonstrate a novel transparent ultrasound transducer (TUT) linear array fabricated using a transparent lithium niobate piezoelectric material for real-time multimodal imaging. Results. The TUT-array consists of 64 elements and centered at ~6 MHz frequency. We demonstrate a quad-mode ultrasound, Doppler ultrasound, photoacoustic, and fluorescence imaging in real-time using the TUT-array directly coupled to the tissue mimicking phantoms. Conclusion. The TUT-array successfully showed a multimodal imaging capability and has potential applications in diagnosing cancer, neurological, and vascular diseases, including image-guided endoscopy and wearable imaging.

A High Sensitivity Transparent Ultrasound Transducer based on PMN-PT for Ultrasound and Photoacoustic Imaging.

We recently introduced piezoelectric lithium niobate (LN) based transparent ultrasound transducers (TUT) as a new platform for developing multimodal optical, ultrasound and photoacoustic imaging systems. However, LN based TUT is limited in its signal-to-noise ratio due to material's low piezoelectricity (d 33). In this paper, we report, for the first time, a 0.2 mm thick transparent lead magnesium niobate-lead titanate (PMN-PT) based TUT (PMN-PT-TUT) for ultrasound and photoacoustic applications and compared its performance with a 0.25 mm thick transparent LN based TUT (LN-TUT). To improve the ultrasound energy transmission efficiency, TUTs were fabricated with a two-matching-layer design. This resulted in a dual frequency response with center frequencies of 7.8 MHz/13.2 MHz and corresponding bandwidths of 28.2%/66.67% for PMN-PT-TUT, and center frequencies of 7.2 MHz/11.8 MHz and bandwidths of 36.1%/62.7% for LN-TUT. The optical transmission rate of PMN-PT-TUTs and LN-TUTs are measured as ~73% and ~91% respectively at 532 nm optical wavelength. The PMN-PT-TUT exhibited higher sensitivity compared to LN-TUT with a nearly three-fold higher pulse echo amplitude and more than two-fold higher photoacoustic amplitude. Furthermore, optical resolution photoacoustic microscopy (ORPAM) experiments on phantom targets demonstrated lateral resolutions of 7 µm and 5.1 µm, and axial resolutions of 285.6 µm and 375.9 µm for PMN-PT-TUT and LN-TUT respectively. These results indicated that PMN-PT is a viable alternative to LN for developing TUT based multimodal ultrasound and photoacoustic imaging systems.

Experimental demonstration of 12.5 GHz wideband chaos in symmetric dual-port EDFRL.

We study the dynamics of chaos in a dual-port erbium-doped fiber ring laser (EDFRL). The laser consists of two erbium-doped fibers, intracavity filters at 1549.32 nm, isolators, and couplers. At both ports, the laser transitions into the chaotic regime for pump currents greater than 100 mA via the period doubling route. We calculate the largest Lyapunov exponent using Rosenstein's algorithm. We obtain positive values for the largest Lyapunov exponent (≈0.2) for embedding dimensions 5, 7, 9, and 11 indicating chaos. We compute the power spectral density of the photocurrents at the output ports of the laser. We observe a bandwidth of 12.5 GHz at both ports. This ultra-wideband nature of chaos obtained has potential applications in high-speed random number generation and communication.