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Hydrogen sulfide (H2S) has been recognized to influence a wide range of physiological and pathological processes. Its underlying molecular events, however, are still poorly understood. An activatab...

Current embodiments of photoacoustic imaging require either serial detection with a single-element ultrasonic transducer or parallel detection with an ultrasonic array, necessitating a trade-off between cost and throughput. Here, we present photoacoustic topography through an ergodic relay (PATER) for low-cost high-throughput snapshot wide-field imaging. Encoding spatial information with randomized temporal signatures through ergodicity, PATER requires only a single-element ultrasonic transducer to capture a wide-field image with a single laser shot. We applied PATER to demonstrate both functional imaging of haemodynamic responses and high-speed imaging of blood pulse wave propagation in mice in vivo. Leveraging the high frame rate of 2 kHz, PATER tracked and localized moving melanoma tumour cells in the mouse brain in vivo, which enabled flow velocity quantification and super-resolution imaging. Among the potential biomedical applications of PATER, wearable devices to monitor human vital signs in particular is envisaged.

Optical-resolution photoacoustic microscopy (OR-PAM) is used for in vivo imaging of a variety of albino and pigmented eyes taking advantages of requiring no exogenous dye, performing high-resolution imaging, and achieving morphologic and functional imaging at the same time. However, to accurately diagnose the ophthalmic disease in the OR-PAM images, vascular enhancement algorithms are necessary for extracting vessels and quantifying them correctly. Vascular enhancement algorithms developed for other imaging technologies, are not suitable to be used for OR-PAM, because of the underlying differences in the physics of the formation of images. In this study, a new vascular enhancement algorithm called photoacoustic imaging vasculature enhancement filter (PAIVEF) is proposed, which not only enhances vasculature including micro-vessels signals, suppresses noise signals effectively, but also achieves highly sensitive and accurate enhancement of the vasculature within a large depth range in and out of the system's depth of focus (DOF). Using the PAIVEF, the morphologic and functional 3D images of the whole rat's ocular anterior vasculature segment was displayed simultaneously for a depth range of ~0.6 mm, which was ~7 times of the system's DOF. This study paves the way for the application of OR-PAM technology in ophthalmic disease research.

Early diagnosis and effective treatment of hepatocellular carcinoma (HCC) is quite critical for improving patients’ prognosis. The combination of second near-infrared window photoacoustic imaging (NIR-II PAI) and T2-magnetic resonance imaging (T2-MRI) is promising for achieving omnibearing information on HCC diagnosis due to the complementary advantages of outstanding optical contrast, high temporospatial resolution and soft-tissue resolution. Thus, the rational design of a multifunctional targeted nanoplatform with outstanding performance in dual-modal NIR-II PAI/T2-MRI is particularly valuable for precise diagnosis and imaging-guided non-invasive photothermal therapy (PTT) of early-stage HCC. Herein, a versatile targeted organic–inorganic hybrid nanoprobe was synthesized as a HCC-specific contrast agent for sensitive and efficient theranostics. The developed multifunctional targeted nanoprobe yielded superior HCC specificity, reliable stability and biocompatibility, high imaging contrast in both NIR-II PAI and T2-MRI, and an excellent photothermal conversion efficiency (74.6%). Furthermore, the theranostic efficiency of the targeted nanoprobe was systematically investigated using the orthotopic early HCC-bearing mice model. The NIR-II PAI exhibited sensitive detection of ultra-small HCCs (diameter less than 1.8 mm) and long-term real-time monitoring of the tumor and nanoprobe targeting process in deep tissues. The T2-MRI demonstrated clear imaging contrast and a spatial relationship between micro-HCC and adjacent structures for a comprehensive description of the tumor. Moreover, when using the targeted nanoprobe, the non-invasively targeted PTT of orthotopic early HCC was carried out under reliable dual-modal imaging guidance with remarkable anti-tumor efficiency and biosafety. This study provides an insight for constructing a multifunctional targeted nanoplatform for precise and comprehensive theranostics of early-stage HCC, which would greatly benefit the patients in the era of precision medicine.

We present a new spatial compounding method to improve the contrast of ultrasonic images for non-delayed sequential beamforming (NDSB). Sequential beamforming adopts more than one beamformer to reconstruct B-mode images which has the advantage of simple front-end electronics and fast data transfer rate. Via field pattern analysis, we propose a compounding method where two more sub-images can be reconstructed along with the NDSB sub-image. These sub-images can be seen as being produced with different transmit origins, thus, their summation enhances image contrast. Image quality was analyzed in terms of spatial resolution, contrast ratio (CR), and contrast-to-noise ratio (CNR). The proposed compounding method improves the lateral resolution up to 41%. In vitro results confirm a 13.0-dB CR and 4.0-dB CNR improvement. In vivo results reveal 10.9-dB and 6.0-dB improvement in CR and CNR for cross-section jugular vein and 8.0-dB and 4.5-dB improvement in CR and CNR for the longitudinal-section carotid artery.

Hemostasis is vital to save lives, reducing risks of organ failure and hemorrhagic shock. Exploring novel hemostatic materials and precise monitoring of the hemostatic status is of great importance for efficient hemostasis. We present the development of chitosan–graphene oxide-based hemostatic composite and multi-scale photoacoustic evaluation of the hemostatic performance. The hemostatic sponge can quickly and efficiently absorb the blood with its porous cavity and specific surficial property. We inspect the hemostatic performance via an in vitro blood absorption test and in vivo mouse bleeding injury experiments. Results show that the synthesized hemostatic sponge can not only absorb plasma in blood fast with its interior porous structure but also stimulate the interfacial reaction with erythrocytes and platelets. The superiority of multi-scale photoacoustic imaging for guiding, monitoring, and evaluating the hemostatic stages of sponges is demonstrated with high spatial resolution and great sensitivity at depths. Photoacoustic evaluation of a chitosan–graphene oxide-based hemostatic sponge has the potential to be transferred toward the clinical assessment of wound healing.

Optical-resolution photoacoustic microscopy (OR-PAM) enjoys superior spatial resolution and has received intense attention in recent years. The application, however, has been limited to shallow depths because of strong scattering of light in biological tissues. In this work, we propose to achieve deep-penetrating OR-PAM performance by using deep learning enabled image transformation on blurry living mouse vascular images that were acquired with an acoustic-resolution photoacoustic microscopy (AR-PAM) setup. A generative adversarial network (GAN) was trained in this study and improved the imaging lateral resolution of AR-PAM from 54.0 µm to 5.1 µm, comparable to that of a typical OR-PAM (4.7 µm). The feasibility of the network was evaluated with living mouse ear data, producing superior microvasculature images that outperforms blind deconvolution. The generalization of the network was validated with in vivo mouse brain data. Moreover, it was shown experimentally that the deep-learning method can retain high resolution at tissue depths beyond one optical transport mean free path. Whilst it can be further improved, the proposed method provides new horizons to expand the scope of OR-PAM towards deep-tissue imaging and wide applications in biomedicine.

Full-ring dual-modal ultrasound and photoacoustic imaging provide complementary contrasts, high spatial resolution, full view angle and are more desirable in pre-clinical and clinical applications. However, two long-standing challenges exist in achieving high-quality video-rate dual-modal imaging. One is the increased data processing burden from the dense acquisition. Another one is the object-dependent speed of sound variation, which may cause blurry, splitting artifacts, and low imaging contrast. Here, we develop a video-rate full-ring ultrasound and photoacoustic computed tomography (VF-USPACT) with real-time optimization of the speed of sound. We improve the imaging speed by selective and parallel image reconstruction. We determine the optimal sound speed via co-registered ultrasound imaging. Equipped with a 256-channel ultrasound array, the dual-modal system can optimize the sound speed and reconstruct dual-modal images at 10 Hz in real-time. The optimized sound speed can effectively enhance the imaging quality under various sample sizes, types, or physiological states. In animal and human imaging, the system shows co-registered dual contrasts, high spatial resolution (140 µm), single-pulse photoacoustic imaging (< 50 µs), deep penetration (> 20 mm), full view, and adaptive sound speed correction. We believe VF-USPACT can advance many real-time biomedical imaging applications, such as vascular disease diagnosing, cancer screening, or neuroimaging.

Accurate identification and quantification of microvascular patterns are important for clinical diagnosis and therapeutic monitoring using optical-resolution photoacoustic microscopy (OR-PAM). Due to its limited depth of field, conventional OR-PAM may not fully reveal microvascular patterns with enough details in depth range, which affects the segmentation and quantification. Here, we propose a robust vascular quantification approach via combining multi-focus image fusion with enhancement filtering (MIFEF). The multi-focus image fusion is constructed based on multi-scale gradients and image matting to improve image fusion quality by considerably achieving accurate focus measurement for initial segmentation as well as decision map refinement. The enhancement filtering identifies the vessels and handles noise without deforming microvasculature. The performance of the MIFEF were evaluated employing a leaf phantom, mouse livers and brains. The proposed method for OR-PAM can significantly facilitate the clinical provision of optical biopsy of vascular-related diseases.

We present the development of a new low-cost and portable nanophotonic sensor to measure mechanical or environmental quantities, such as acoustic, bending, stretching, or temperature changes (see Figure 1). The sensor consists of a compact diode laser, a multimode fiber, and a smartphone, and thus, it is quite portable. The laser light emitted from the multimode fiber forms optical speckle patterns on a screen. We experimentally implement the bending sensing on a smartphone. The relationship between the bending curvature and the optical speckle pattern is quantitatively studied, demonstrating its feasibility of bending sensing.

Glutathione is overexpressed in tumor cells and regulates cancer growth, metastasis, and drug resistance. Therefore, detecting glutathione levels may greatly facilitate cancer diagnosis and treatment response monitoring. Photoacoustic (PA) imaging is a noninvasive modality for high-sensitivity, high-resolution, deep-tissue optical imaging. Switchable PA probes that offer signal on/off responses to tumor targets would further improve the detection sensitivity and signal-to-noise ratio of PA imaging. Here, we explore the use of MnO2 nanotubes as a switchable and biodegradable PA probe for dynamic imaging of glutathione in cancer. Glutathione reduces black MnO2 nanotubes into colorless Mn2+ ions, leading to decreased and signal off PA amplitude. In phantoms, we observed a linear response of reduced PA signals of MnO2 nanotubes to increased glutathione concentrations. Using melanoma as the disease model, we demonstrated that MnO2 nanotube-based PA imaging of glutathione successfully distinguished B16F10 melan...

Here we report a high performance fiber-based photoacoustic microscope for brain sO2 imaging. The critical element is a fiber-optic ultrasound sensor, which translates the megahertz acoustic waves into detectable lasing frequency variations. Its working bandwidth has been extended to 40 MHz, by reducing the fiber diameter to 58 μm via chemical etching, this sensor should good result in brain sO2 imaging. The fiber-based PAM offers a new strategy to implement a head-mounted microscope to continuously monitor the brain activities of an awake, free-moving small animal.

Optical-resolution photoacoustic microscopy (OR-PAM) can image the blood oxygen saturation (sO2) in vivo without labeling. OR-PAM assumes a linear relationship between the photoacoustic amplitude and the optical absorption coefficient and ignores the wavelength-dependent optical fluence attenuation in tissue. However, strong scattering in biological tissues may significantly change the optical energy deposition, leading to inaccurate sO2 measurement. Here, we report fluence-compensated OR-PAM to correct the sO2 imaging. In a narrow optical spectrum, we assume the scattered fluence is linearly related to the optical wavelength. Using three optical wavelengths, we can compensate for the scattering-induced photoacoustic signal change and thus improve the accuracy of sO2 measurement. We use a Monta Carlo model to validate the linear assumption of the scattered fluence. In in vivo experiments, we demonstrate that the optical fluence compensation can effectively improve the sO2 accuracy. The compensated arterial sO2 values are in the range of 0.95 ~ 0.99, which is consistent with normal physiological values. Compared with the uncompensated ones, the accuracy has been improved greatly. Enabled by the accurate sO2 imaging tool, we can reliably observe the sO2 gradient in the vascular network. We expect this new technique will further broaden the preclinical and clinical applications of functional OR-PAM.

Optical-resolution photoacoustic microscopy (OR-PAM) has been developed for anatomical, functional, and molecular imaging but usually requires multiple scanning for different contrasts. We present five-wavelength OR-PAM for simultaneous imaging of hemoglobin concentration, oxygen saturation, blood flow speed, and lymphatic vessels in single raster scanning. We develop a five-wavelength pulsed laser via stimulated Raman scattering. The five pulsed wavelengths, i.e., 532, 545, 558, 570, and 620 / 640 nm, are temporally separated by several hundreds of nanoseconds via different optical delays in fiber. Five photoacoustic images at these wavelengths are simultaneously acquired in a single scanning. The 532- and 620 / 640-nm wavelengths are used to image the blood vessels and dye-labeled lymphatic vessels. The blood flow speed is measured by a dual-pulse method. The oxygen saturation is calculated and compensated for by the Gruneisen-relaxation effect. In vivo imaging of hemoglobin concentration, oxygen saturation, blood flow speed, and lymphatic vessels is demonstrated in preclinical applications of cancer detection, lymphatic clearance monitoring, and functional brain imaging.

We report fiber-based confocal visible/near-infrared optical-resolution photoacoustic microscopy that can image tumor microvasculature, oxygen saturation, and nanoprobes in a single scanning. It offers a new tool for early detection of tumors with multiple contrast modes.

Oxygen saturation (sO2) imaging can offer useful information for pathological studies and clinical diagnostics. Here we report on a fiber-based photoacoustic microscope for functional brain imaging. The critical element is a fiber-optic ultrasound sensor, which translates the megahertz acoustic waves into detectable lasing frequency variations. Its working bandwidth has been extended to 40 MHz, by reducing the fiber diameter to 58 μm via chemical etching. As a result, in vivo sO2 imaging of a mouse brain can be performed by using a dual-wavelength excitation scheme, taking advantage of the difference in the absorption spectrum between the oxygenated (HbO2) and deoxygenated hemoglobin (HbR). The broadband ultrasound detection can effectively overcome the saturation effect originated from the strong optical absorption. The fiber optic photoacoustic probe paves the way for the implementation of a light-weight, wearable brain imager for awake, freely-moving animals.

In nature, animals or plants often use soft organs to move and hunt. Research works on bioinspired materials and devices have attracted more and more interest as which show the potential for future intelligent robots. As key components of soft robots, biomimetic soft actuators are adapted to greater requirements for convenient, accurate, and programmable controlling robots. Here, a class of materials and processing routes of ultrathin actuators are reported for bioinspired piecewise controllable soft robots, where the actuators associate with thermal-responsible soft silicone thin film with thickness as thin as 45 µm and electrically driven by well mechanical designed metallic thin film electrodes. Multiple electrodes in the robots in charge of individual segments control allow the soft robots exhibiting similar functionalities of animals or plants (for example, imitating the tongue of a reptile, such as chameleon to hunt moving preys, and mimicking vines to tightly wind around objects). These bionic results in the soft robots demonstrate their advantages in precise and flexible operation, which provides a good reference for the future research of intelligent soft actuators and robots. acceptedVersion

We report wide-field polygon-scanning functional OR-PAM that for the first time achieves 1-MHz A-line rate of oxygen saturation in vivo. We address two technical challenges. The first is a 1-MHz dual-wavelength pulsed laser that has sufficient pulse energy and ultrafast wavelength switching. The second is a polygon-scanning imaging probe that has a fast scanning speed, a large field of view, and great sensitivity. The OR-PAM system offers a B-scan rate of 477.5 Hz in a 12-mm range and a volumetric imaging rate of ∼1 Hz over a 12 × 5 mm2 scanning area. We image microvasculature and blood oxygen saturation in a 12 × 12 mm2 scanning area in 5 s. Dynamic imaging of oxygen saturation in the mouse ear is demonstrated to monitor fast response to epinephrine injection. The new wide-field fast functional imaging ability broadens the biomedical application of OR-PAM.

As a traditional Chinese medicine practice, cupping therapy has been widely used for thousands of years to promote blood circulation and release symptoms of some diseases. The actual effect, however, has been debatable due to the lack of scientific evidence. Aiming to objectively assess the treatment effect, in this study we introduce optical-resolution photoacoutic microscopy to monitor the structural and functional changes of microenvironment parameters pre- and post-cupping through facial cups. Whilst further investigation is in demand, this pilot study provides a new imaging perspective to understand the mechanism and evaluate the effect of cupping therapy.

Label-free chemical bond imaging is of great importance in biology and medicine. Photoacoustic imaging at the third near-infrared windows (1600-1870 nm, nearinfrared-III) provides a stable molecular vibrational imaging tool for lipid-rich tissue owing to the first overtone transition of the C-H bond at 1.7 _m. However, lacking high-energy pulsed laser sources at 1.7 _m and the strong water absorption significantly limit the signal-to-noise ratio of the lipid imaging, especially for thin lipid tissues. To circumvent this barrier, we develop near-infrared-III double-illumination optical-resolution photoacoustic microscopy (DIOR-PAM) for improving the sensitivity of label-free lipid imaging. Using the same laser, DIOR-PAM can enhance the sensitivity by nearly 100%, which we prove in the Monte Carlo simulation.We experimentally demonstrated 50%i100% sensitivity enhancement on non-biological and biological lipid-rich samples. This article is protected by copyright. All rights reserved.

Photoacoustic agents have been of vital importance for improving the imaging contrast and reliability against self-interference from endogenous substances. Herein, we synthesized a series of thiadiazoloquinoxaline (TQ)-based semiconducting polymers (SPs) with a broad absorption covering from NIR-I to NIR-II regions. Among them, the excited s-BDT-TQE, a repeating unit of SPs, shows a large dihedral angle and narrow adiabatic energy as well as low radiative decay, attributing to its strongly electron-deficient ester-substituted TQ-segment. In addition, its more vigorous molecular motions trigger a higher reorganization energy that further yields an efficient photoinduced nonradiative decay, which has been carefully examined and understood by theoretical calculation. Thus, BDT-TQE SP-cored nanoparticles with twisted intramolecular charge transfer (TICT) feature exhibit a high NIR-II photothermal conversion efficiency (61.6 %) and preferable PA tracking of in situ hepatic tumor growth for more than 20 days. This study highlights a unique strategy for constructing efficient NIR-II photoacoustic agents via TICT-enhanced PNRD effect, advancing their applications for in vivo bioimaging.

Type 1 diabetes (T1D) is an incurable disease that affects 1. 25 million Americans. Diabetic patients typically rely on subcutaneous insulin infusions to regulate their glucose levels. A major contributor to their blood glucose levels is the amount of sugar intake, which cannot be easily tracked. While ultrasound imaging has been used to investigate the relationship between food characteristics and tongue movement, the technique utilized a bulky transducer array that cannot be translated into daily monitoring. Capitalizing on advanced electronics and data processing technologies, we developed a portable system that utilizes only a single ceramic disk to quantify the tongue movement in response to various levels of sweetness. After acquiring 32 subject datasets, we found a significant correlation between food sweetness and tongue movement. Our system can potentially be miniaturized into a wearable device for monitoring sugar intake, which will ultimately help T1D patients to better monitor and control their blood glucose levels and balance their diets accordingly.

Precise diagnosis and effective treatment of gliomas still remain a huge challenge. Photoacoustic-guided photothermal therapy (PTT) has unique advantages over conventional techniques for brain tumor theranostics, but existing nanoagents for photoacoustic imaging (PAI)-guided PTT are mainly organic small molecules or inorganic nanoparticles, which have the limitations of poor photostability and biocompatibility. Besides, the restricted absorption in the first near-infrared window (NIR-I) of the most existing nanoagents compromises their effectiveness for deep tissue PAI and PTT. We herein develop novel semiconducting polymer nanoparticles (SPNs) that are strongly absorptive in the second NIR window (NIR-II) to alleviate these problems. With the merits of excellent photoacoustic and photothermal performance, high photostability, proper size, and low toxicity, SPNs not only show efficient cellular uptake for PAI and PTT toward U87 glioma cells but also demonstrate effective accumulation in both subcutaneous tumors and brain tumors upon intravenous injection, thereby realizing efficient PAI-guided PTT toward gliomas under NIR-II light irradiation.

The potassium ion (K

This Conference Presentation, “Compressed Ultrafast Spectral Temporal (CUST) photography” was recorded at Photonics West LASE 2020, held in San Francisco, California, United States of America.

Due to limited ultrasound detection angle, photoacoustic microscopy may own a relatively low sensitivity. To break this limit, we develop an ultra-sensitive optical resolution photoacoustic microscopy based on a customized acoustic lens with high numerical aperture (0.74) (HNA-OR-PAM). The sensitivity of HNA-OR-PAM is improved to around 160% as the state-of-the-art OR-PAM. It has the capability to measure oxygen saturation of mice’s ear in vivo with ~10nJ pulse energy, reducing the nonlinear effect induced by high pulse energy. In addition, photoacoustic signal of tilted objects could be enhanced due to augmented ultrasound detection angle, which has been validated in our phantom study and the brain imaging experiment in vivo.

Fast switch between pulses of sufficient energy but different wavelengths plays an important role in fast functional photoacoustic imaging. Commonly used Stimulated Raman scattering through a long optical fiber can produce multiple wavelengths, but longer fiber means lower energy, which would decrease image quality. Shorter optical fiber is thus more desired for fast imaging. However, it should be noted that too short pulse separation may generate photoacoustic signals that are temporally overlapped. Here, we propose an approach to solve this overlapping problem in ultrafast PA imaging using a Fourier-domain based method. The validity of this method is confirmed through simulation firstly, and then it is applied to separate overlapped PA signals. Lastly, in vivo OR-PAM mapping of mouse ear’s sO2 photoacoustic imaging is achieved.

Fast functional and molecular photoacoustic microscopy requires pulsed laser excitations at multiple wavelengths with enough pulse energy and short wavelength-switching time. Recent development of stimulated Raman scattering in optical fiber offers a low-cost laser source for multiwavelength photoacoustic imaging. In this approach, long fibers temporally separate different wavelengths via optical delay. The time delay between adjacent wavelengths may eventually limits the highest A-line rate. In addition, a long-time delay in fiber may limit the highest pulse energy, leading to poor image quality. In order to achieve high pulse energy and ultrafast dual-wavelength excitation, we present optical-resolution photoacoustic microscopy with ultrafast dual-wavelength excitation and a signal separation method. The signal separation method is validated in numerical simulation and phantom experiments. We show that when two photoacoustic signals are partially overlapped with a 50-ns delay, they can be recovered with 98% accuracy. We apply this ultrafast dual-wavelength excitation technique to in vivo OR-PAM. Results demonstrate that A-lines at two wavelengths can be successfully separated, and sO2 values can be reliably computed from the separated data. The ultrafast dual-wavelength excitation enables fast functional photoacoustic microscopy with negligible misalignment among different wavelengths and high pulse energy, which is important for in vivo imaging of microvascular dynamics.

It remains highly challenging to identify small molecule-based photothermal agents with a high photothermal conversion efficiency (PTCE). Herein, we adopt a double bond-based molecular motor concept to develop a new class of small photothermal agents to break the current design bottleneck. As the double-bond is twisted by strong twisted intramolecular charge transfer (TICT) upon irradiation, the excited agents can deactivate non-radiatively through the conical intersection (CI) of internal conversion, which is called photoinduced nonadiabatic decay. Such agents possess a high PTCE of 90.0 %, facilitating low-temperature photothermal therapy in the presence of a heat shock protein 70 inhibitor. In addition, the behavior and mechanism of NIR laser-triggered molecular motions for generating heat through the CI pathway have been further understood through theoretical and experimental evidence, providing a design principle for highly efficient photothermal and photoacoustic agents.

Optical detection of ultrasound for photoacoustic imaging has received great interest. Recently, we have developed a new fiber-optic ultrasound sensor by exploiting dual-polarization fiber laser. It offers high sensitivity (40 Pa over 50 MHz) as well as good stability as a result of the self-heterodyning detection. In this work, the signal-to-noise ratio has been enhanced by suppressing the noise of the ultrasound sensing system via signal averaging. As a result of multiple measurements of a single photoacoustic signal, the total noise was reduced by 40%. With the enhanced detection capability, the sensors have been deployed as photoacoustic probes in different imaging modalities. We demonstrate fastscanning photoacoustic microscopy with a field-of-view 2×2 mm2, a frame rate of 2 Hz to visualize the blood flow dynamics. By bending the flexible fiber optic sensor for geometrical focusing, PACT was realized to image a mouse brain with a spatial resolution of 70 μm. An all-fiber photoacoustic endoscope was built to in vivo image the vascular network of a rat rectum, with a lateral resolution of 10 μm, with a 2.3-mm probe diameter.

Limited by the numerical aperture of ultrasonic detection, optical resolution photoacoustic microscopy (OR-PAM) has not achieved optimal sensitivity. To address this problem, we have developed a high acoustic numerical aperture ( ∼ 0.74 ) OR-PAM (HNA-OR-PAM). Via engineering the acoustic lens, we implement the highest acoustic numerical aperture that a spherical concave lens can achieve. The sensitivity of HNA-OR-PAM is improved to around 160%—the state-of-the-art OR-PAM. Without averaging, the new system can image oxygen saturation in vivo with only 10-nJ pulse energy. The improved sensitivity allows us to image weaker absorbers, penetrate deeper, and reduce nonlinear effects induced by high pulse energy. Moreover, the photoacoustic view angle is augmented to 51.8 deg and makes tilted features more visible. We validate the improved view angle in both a phantom study and brain imaging.

Functional intestinal imaging holds importance for the diagnosis and evaluation of treatment of gastrointestinal diseases. Currently, preclinical imaging of intestinal motility in animal models is performed either invasively with excised intestines or noninvasively under anesthesia, and cannot reveal intestinal dynamics in the awake condition. Capitalizing on near-infrared optics and a high-absorbing contrast agent, we report the Trans-illumination Intestine Projection (TIP) imaging system for free-moving mice. After a complete system evaluation, we performed in vivo studies, and obtained peristalsis and segmentation motor patterns of free-moving mice. We show the in vivo typical segmentation motor pattern, that was previously shown in ex vivo studies to be controlled by intestinal pacemaker cells. We also show the effects of anesthesia on motor patterns, highlighting the possibility to study the role of the extrinsic nervous system in controlling motor patterns, which requires unanesthetized live animals. Combining with light-field technologies, we further demonstrated 3D imaging of intestine in vivo (3D-TIP). Importantly, the added depth information allows us to extract intestines located away from the abdominal wall, and to quantify intestinal motor patterns along different directions. The TIP system should open up avenues for functional imaging of the GI tract in conscious animals in natural physiological states., Current preclinical imaging of intestine in animal models cannot reveal intestinal dynamics in awake condition. Here the authors report a Transillumination Intestine Projection (TIP) imaging system for free-moving mice, and showed the intestine dynamics in conscious animal in natural physiological states.

Micro/nanorobots have long been expected to reach all parts of the human body through blood vessels for medical treatment or surgery. However, in the current stage, it is still challenging to drive a microrobot in viscous media at high speed and difficult to observe the shape and position of a single microrobot once it enters the bloodstream. Here, we propose a new micro-rocket robot and an all-optic driving and imaging system that can actuate and track it in blood with microscale resolution. To achieve a high driving force, we engineer the microrobot to have a rocket-like triple-tube structure. Owing to the interface design, the 3D-printed micro-rocket can reach a moving speed of 2.8 mm/s (62 body lengths per second) under near-infrared light actuation in a blood-mimicking viscous glycerol solution. We also show that the micro-rocket robot is successfully tracked at a 3.2-µm resolution with an optical-resolution photoacoustic microscope in blood. This work paves the way for microrobot design, actuation, and tracking in the blood environment, which may broaden the scope of microrobotic applications in the biomedical field., Biotechnology: Laser-powered robots rocket through the bloodstream Researchers now report that lasers can be used to safely move tiny robots in the blood. Dr. Dengfeng Li and Mr. Chao Liu from the City University of Hong Kong in China and colleagues used 3D printing to create microscale tubes, connected to resemble a central rocket with two side boosters attached. After applying a light-absorbing gold coating to the micro-rockets, the team irradiated the device with laser pulses. The resulting thermal gradient along the length of the tubes propelled the device steadily through solutions with high viscosity, such as blood. Furthermore, the gold coating generates ultrasonic signals that can be spotted through photoacoustic microscopic techniques. Injections of the micro-rockets into blood revealed they could be tracked with microscale resolution as they were directed to flow through the bloodstream.

Deconvolution is the most commonly used image processing method in optical imaging systems to remove the blur caused by the point-spread function (PSF). While this method has been successful in deblurring, it suffers from several disadvantages, such as slow processing time due to multiple iterations required to deblur and suboptimal in cases where the experimental operator chosen to represent PSF is not optimal. In this paper, we present a deep-learning-based deblurring method that is fast and applicable to optical microscopic imaging systems. We tested the robustness of proposed deblurring method on the publicly available data, simulated data and experimental data (including 2D optical microscopic data and 3D photoacoustic microscopic data), which all showed much improved deblurred results compared to deconvolution. We compared our results against several existing deconvolution methods. Our results are better than conventional techniques and do not require multiple iterations or pre-determined experimental operator. Our method has several advantages including simple operation, short time to compute, good deblur results and wide application in all types of optical microscopic imaging systems. The deep learning approach opens up a new path for deblurring and can be applied in various biomedical imaging fields.

Precise delivery of therapeutic cells to the desired site in vivo is an emerging and promising cellular therapy in precision medicine. This paper presents the development of a magnet-driven and image-guided degradable microrobot that can precisely deliver engineered stem cells for orthotopic liver tumor treatment. The microrobot employs a burr-like porous sphere structure and is made with a synthesized composite to fulfill degradability, mechanical strength, and magnetic actuation capability simultaneously. The cells can be spontaneously released from the microrobots on the basis of the optimized microrobot structure. The microrobot is actuated by a gradient magnetic field and guided by a unique photoacoustic imaging technology. In preclinical experiments on nude mice, microrobots carrying cells are injected via the portal vein and the released cells from the microrobots can inhibit the tumor growth greatly. This paper reveals for the first time of using degradable microrobots for precise delivery of therapeutic cells in vascular tissue and demonstrates its therapeutic effect in preclinical test.

Phototheranostic technology based on photoacoustic imaging (PAI) and photothermal therapy (PTT) is emerging as a powerful tool for tumor theranostic applications. For effective tumor eradication, a novel PAI/PTT theranostic nanoagent with an excellent optical absorption and photothermal capability is highly desired. Herein, we present a new PAI/PTT nanohybrid named sMoSe2-ICG NSs by covalently conjugating aminated indocyanine green (ICG) onto a single layer of molybdenum selenide nanosheets (sMoSe2 NSs). We first validate the sMoSe2-ICG NS agent for the PAI and PTT effect in vitro and then use it for highly-sensitive PAI guided highly efficient tumor PTT in vivo. The sMoSe2-ICG NS hybrid possesses several advantages for PAI/PTT applications: (1) the sMoSe2-ICG NSs have strong absorbance in the broad near-infrared (NIR) region, enabling a highly efficient PAI/PTT theranostic effect and the selection of the most widely used excitation wavelength of 808 nm for PTT; (2) the photothermal ability of ICG in sMoSe2-ICG NSs is augmented due to ICG aggregation induced fluorescence quenching and the re-absorbance of ICG fluorescence by sMoSe2 NSs, which further enhances the PAI/PTT theranostic effect. (3) The characteristic absorption peak of sMoSe2-ICG NSs is red-shifted compared to free ICG, resulting in a higher PAI signal-to-noise ratio (SNR) in vivo. Thus, combined with the good stability, high biocompatibility and minimal toxicity properties, the obtained sMoSe2-ICG NSs hybrid has bright prospects for use in future PAI/PTT clinical applications.

Viscosity measurement is important in many areas of biomedicine and industry. Traditional viscometers are usually time-consuming and require huge sample volumes. Microfluidic viscometry may overcome the challenge of large sample consumption but suffers from a long process time and a complicated structure design and interaction. Here, we present a photoacoustic method that measures the liquid viscosity in a simple microfluidic-based tube. This new viscosity measurement method embraces fast detection speed and low fluid consumption, offering a new tool for efficient and convenient liquid viscosity measurement in a broad range of applications.

Three-dimensional (3D) optical imaging of whole biological organs with microscopic resolution has remained a challenge. Most versions of such imaging techniques require special preparation of the tissue specimen. Here we demonstrate microtomy-assisted photoacoustic microscopy (mPAM) of mouse brains and other organs, which automatically acquires serial distortion-free and registration-free images with endogenous absorption contrasts. Without tissue staining or clearing, mPAM generates micrometer-resolution 3D images of paraffin- or agarose-embedded whole organs with high fidelity, achieved by label-free simultaneous sensing of DNA/RNA, hemoglobins, and lipids. mPAM provides histology-like imaging of cell nuclei, blood vessels, axons, and other anatomical structures, enabling the application of histopathological interpretation at the organelle level to analyze a whole organ. Its deep tissue imaging capability leads to less sectioning, resulting in negligible sectioning artifact. mPAM offers a new way to better understand complex biological organs., The state-of-the-art three-dimensional biomedical imaging often requires specific tissue preparation that may alter the physical properties of the specimen causing loss of information. Here Wong et al. develop a microtomy-assisted photoacoustic microscopy that allows imaging of biological samples without labelling agents and with reduced sectioning.

Exploration of facile strategies for precise regulation of target gene expression remains highly challenging in the development of gene therapies. Especially, a stimuli-responsive nanocarrier integrated with ability of noninvasive remote control for treating wide types of cancers is rarely developed. Herein, a NIR-II absorbing semiconducting polymer (PBDTQ) is employed to remotely activate the heat-inducible heat-shock protein 70 (HSP70) promoter under laser irradiation, further realizing regulation of gene-directed enzyme prodrug therapy (GDEPT) for cancer treatment in mild hyperthermia. In this multifunctional nanocomposite, the PBDTQ and double suicide gene plasmid (pSG) based on HSP70 promoter are incorporated into a lipid complex. Upon NIR-II laser excitation, the mild photothermal effect (≈43 °C) generated from PBDTQ can cause the release of pSG and activation of HSP70 promoter, and then upregulate suicide gene expression triggered by the HSP70 promoter which can further convert the nontoxic prodrug into its cytotoxic metabolites. Therefore, this work demonstrates a universal NIR-II laser-triggered GDEPT using semiconducting polymers as the photothermal generator for cancer treatment with minimized collateral damage and nontargeted side effects.

Optical resolution photoacoustic microscopy (OR-PAM) provides high-resolution, label-free and non-invasive functional imaging for broad biomedical applications. Dual-polarized fiber laser sensors have high sensitivity, low noise, a miniature size, and excellent stability; thus, they have been used in acoustic detection in OR-PAM. Here, we review recent progress in fiber-laser-based ultrasound sensors for photoacoustic microscopy, especially the dual-polarized fiber laser sensor with high sensitivity. The principle, characterization and sensitivity optimization of this type of sensor are presented. In vivo experiments demonstrate its excellent performance in the detection of photoacoustic (PA) signals in OR-PAM. This review summarizes representative applications of fiber laser sensors in OR-PAM and discusses their further improvements.

We present fast functional optical-resolution photoacoustic microscopy (OR-PAM) that can simultaneously image hemoglobin concentration, blood flow speed, and oxygen saturation with three-pulse excitation. To instantaneously determine the blood flow speed, dual-pulse photoacoustic flowmetry is developed to determine the blood flow speed from photoacoustic signal decay in sub-microseconds. Grueneisen relaxation effect is compensated for in the oxygen saturation calculation. The blood flow imaging is validated in phantom and in vivo experiments. The results show that the flow speed can be measured accurately in sub-microseconds by comparing the dual-pulse flowmetric method with photoacoustic Doppler flowmetry. Wide-field OR-PAM of hemoglobin concentration, blood flow speed, and oxygen saturation are demonstrated in the mouse ear. This technical advance enables more biomedical applications for fast functional OR-PAM. Keywords: Dual-pulse photoacoustic flowmetry, Grueneisen relaxation effect, Multi-functional, Sub-microseconds

Flexible and stretchable electronics have attracted increasing attention and been widely used in wearable devices and electronic skins, where the circuits for flexible and stretchable electronics are typically in-plane-based 2D geometries. Here, we introduce a 3D microprinting technology that can expand one more dimension of the circuit in flexible electronics. We fabricated three-dimensional serpentine microstructures based on direct laser writing. These microstructures with a thin metal coated layer can be used as stretchable conducting meshes. Soft silicone serving as a substrate and encapsulations for these 3D microstructures enables great light transmittance (>90% in visible light range) and flexibility with 114° bending and 24° twisting. Further optimization of the mechanical design of the 3D microstructures can also enhance the stretchability up to 13.8%. These results indicate 3D flexible electronics can be realized by simple microprinting methods. Furthermore, 3D microprinting would also allow for the precise fabrication of other 3D structures, such as mechanically active 3D mesostructures, for the function of mechanical and electrical testing.

Acquiring ultrafast and high spectral resolution optical images is key to measure transient physical or chemical processes, such as photon propagation, plasma dynamics, and femtosecond chemical reactions. At a trillion Hz frame rate, most ultrafast imaging modalities can acquire only a limited number of frames. Here, we present a compressed ultrafast spectral-temporal (CUST) photographic technique, enabling both an ultrahigh frame rate of 3.85 trillion Hz and a large frame number. We demonstrate that CUST photography records 60 frames, enabling precisely recording light propagation, reflection, and self-focusing in nonlinear media over 30 ps. CUST photography has the potential to further increase the frame number beyond hundreds of frames. Using spectral-temporal coupling, CUST photography can record multiple frames with a subnanometer spectral resolution with a single laser exposure, enabling ultrafast spectral imaging. CUST photography with high frame rate, high spectral resolution, and high frame number in a single modality offer a new tool for observing many transient phenomena with high temporal complexity and high spectral precision.

Optical-resolution photoacoustic microscopy can measure oxygen saturation () in vivo, offering an important tool to assess tissue oxygenation and health condition. Limited by available wavelengths for fast OR-PAM, the accuracy of sO2 imaging may be degraded by absorption saturation due to high absorption in the blood. Here, we report a nonlinear model to solve the saturation problem and increase the accuracy of measurement. The absorption saturation is analyzed by comparing a nonlinear and linear photoacoustic model using numerical simulation, which shows the nonlinear model has an improved accuracy than the linear model when the absorption is high. Phantom experiments on bovine blood further validate the accuracy of the nonlinear sO2 measurement method. In vivo experiments are conducted in the mouse ear. The values in a pair of arteries and veins are calculated using both linear and nonlinear methods, showing that the nonlinear method measures the arterial value closer to normal physiological condition than the conventional linear model. The nonlinear model requires the use of three or more wavelengths (532nm, 545nm, and 558nm in this work). As a result, we demonstrate the saturation effect in OR-PAM can be compensated via a nonlinear model, which may advance the application of functional optical-resolution photoacoustic microscopy.

Glutathione is overexpressed in tumor cells and regulates cancer growth, metastasis, and drug resistance. Therefore, detecting glutathione levels may greatly facilitate cancer diagnosis and treatment response monitoring. Photoacoustic (PA) imaging is a noninvasive modality for high-sensitivity, high-resolution, deep-tissue optical imaging. Switchable PA probes that offer signal on/off responses to tumor targets would further improve the detection sensitivity and signal-to-noise ratio of PA imaging. Here, we explore the use of MnO

Microrobots-assisted drug delivery and surgery have been always in the spotlight and are highly anticipated to solve the challenges of cancer in situ treatment. These versatile small biomedical robots are expected to realize direct access to the tumor or disease site for precise treatment, which requires real-time and high-resolution in vivo tracking as feedback for the microrobots’ actuation and control. Among current biomedical imaging methods, photoacoustic imaging (PAI) is presenting its outstanding performances in the tracking of microrobots in the human body derived from its great advantages of excellent imaging resolution and contrast in deep tissue. In this review, we summarize the PAI techniques, imaging systems, and their biomedical applications in microrobots tracking in vitro and in vivo. From a robotic tracking perspective, we also provide some insight into the future of PAI technology in clinical applications.

Distinguishing early-stage tumors from normal tissues is of great importance in cancer diagnosis. We report fiber-based confocal visible/near-infrared (NIR) optical-resolution photoacoustic microscopy that can image tumor microvasculature, oxygen saturation, and nanoprobes in a single scanning. We develop a cost-efficient single laser source that provides 532, 558, and 1064 nm pulsed light with sub-microseconds wavelength switching time. Via dual-fiber illumination, we can focus the three beams to the same point. The optical and acoustic foci are confocally aligned to optimize the sensitivity. The visible and NIR wavelengths enable simultaneous tumor imaging with three different contrast modes. Results show obvious angiogenesis, significantly elevated oxygen saturation, and accumulated nanoparticles in the tumor regions, which offer comprehensive information to detect the tumor. This approach also allows us to identify feeding and draining vessels of the tumor and thus to determine local oxygen extraction fraction. In the tumor region, the oxygen extraction fraction significantly decreases along with tumor growth, which can also assist in tumor detection and staging. Fiber-based confocal visible/NIR photoacoustic microscopy offers a new tool for early detection of cancer.