Photoacoustic Tomography with Temporal Encoding Reconstruction (PATTERN) for cross-modal individual analysis of the whole brain.

Cross-modal analysis of the same whole brain is an ideal strategy to uncover brain function and dysfunction. However, it remains challenging due to the slow speed and destructiveness of traditional whole-brain optical imaging techniques. Here we develop a new platform, termed Photoacoustic Tomography with Temporal Encoding Reconstruction (PATTERN), for non-destructive, high-speed, 3D imaging of ex vivo rodent, ferret, and non-human primate brains. Using an optimally designed image acquisition scheme and an accompanying machine-learning algorithm, PATTERN extracts signals of genetically-encoded probes from photobleaching-based temporal modulation and enables reliable visualization of neural projection in the whole central nervous system with 3D isotropic resolution. Without structural and biological perturbation to the sample, PATTERN can be combined with other whole-brain imaging modalities to acquire the whole-brain image with both high resolution and morphological fidelity. Furthermore, cross-modal transcriptome analysis of an individual brain is achieved by PATTERN imaging. Together, PATTERN provides a compatible and versatile strategy for brain-wide cross-modal analysis at the individual level.

Adaptive machine learning method for photoacoustic computed tomography based on sparse array sensor data.

BACKGROUND AND OBJECTIVE: Photoacoustic computed tomography (PACT) is a non-invasive biomedical imaging technology that has developed rapidly in recent decades, especially has shown potential for small animal studies and early diagnosis of human diseases. To obtain high-quality images, the photoacoustic imaging system needs a high-element-density detector array. However, in practical applications, due to the cost limitation, manufacturing technology, and the system requirement in miniaturization and robustness, it is challenging to achieve sufficient elements and high-quality reconstructed images, which may even suffer from artifacts. Different from the latest machine learning methods based on removing distortions and artifacts to recover high-quality images, this paper proposes an adaptive machine learning method to firstly predict and complement the photoacoustic sensor channel data from sparse array sampling and then reconstruct images through conventional reconstruction algorithms. METHODS: We develop an adaptive machine learning method to predict and complement the photoacoustic sensor channel data. The model consists of XGBoost and a neural network named SS-net. To handle data sets of different sizes and improve the generalization, a tunable parameter is used to control the weights of XGBoost and SS-net outputs. RESULTS: The proposed method achieved superior performance as demonstrated by simulation, phantom experiments, and in vivo experiment results. Compared with linear interpolation, XGBoost, CAE, and U-net, the simulation results show that the SSIM value is increased by 12.83%, 6.78%, 21.46%, and 12.33%. Moreover, the median R2 is increased by 34.4%, 8.1%, 28.6%, and 84.1% with the in vivo data. CONCLUSIONS: This model provides a framework to predict the missed photoacoustic sensor data on a sparse ring-shaped array for PACT imaging and has achieved considerable improvements in reconstructing the objects. Compared with linear interpolation and other deep learning methods qualitatively and quantitatively, our proposed methods can effectively suppress artifacts and improve image quality. The advantage of our methods is that there is no need for preparing a large number of images as the training dataset, and the data for training is directly from the sensors. It has the potential to be applied to a wide range of photoacoustic imaging detector arrays for low-cost and user-friendly clinical applications.

In situ synthesized nanozyme for photoacoustic-imaging-guided photothermal therapy and tumor hypoxia relief.

Nanozymes have attracted extensive research interest due to their ideal enzymatic catalytic performance; however, uncontrollable activities and nonspecific accumulation limit their further clinical application. To overcome these obstacles, we proposed in situ synthesized nanozyme, and realized the concept through an intelligent nanosystem (ISSzyme) based on Prussian blue (PB) precursor. PB nanozyme was synthesized at the tumor sites through the interaction of ISSzyme with glutathione, which was demonstrated by comparing with conventional PB nanozyme. ISSzyme is capable of tumor-specific photoacoustic imaging (PAI) and photothermal therapy (PTT), reducing the false-positive signals of PAI and the treatment side effects of PTT. ISSzyme has catalase-like activities, resulting in tumor hypoxia relief and metastasis inhibition. More importantly, the in situ synthesized PB nanozyme has the favorable property of minimal liver accumulation. Considering the above advantages, ISSzyme is expected to shed light on the design of the next-generation artificial enzymes, with many new biomedical applications.

Dual-targeting nanozyme for tumor activatable photo-chemodynamic theranostics.

Tumor phototheranostics holds a great promise on account of its high spatiotemporal resolution, tumor-specificity, and noninvasiveness. However, physical limitation of light penetration and "always on" properties of conventional photothermal-conversion agents usually cause difficulty in accurate diagnosis and completely elimination of tumor. Meanwhile, nanozymes mediated Fenton reactions can well utilize the tumor microenvironment (TME) to generate hydroxyl radicals for chemodynamic therapy (CDT), but limited by the concentration of H2O2 in TME and the delivery efficiency of nanozymes. To overcome these problems, a dual-targeting nanozyme (FTRNPs) is developed for tumor-specific in situ theranostics, based upon the assembling of ultrasmall Fe3O4 nanoparticles, 3,3',5,5'-tetrameth-ylbenzidine (TMB) and the RGD peptide. The FTRNPs after H2O2 treatment exhibits superior photothermal stability and high photothermal conversion efficiency (η = 50.9%). FTRNPs shows extraordinary accumulation and retention in the tumor site by biological/physical dual-targeting, which is 3.54-fold higher than that without active targeting. Cascade-dual-response to TME for nanozymes mediated Fenton reactions and TMB oxidation further improves the accuracy of both photoacoustic imaging and photothermal therapy (PTT). The tumor inhibition rate of photo-chemodynamic therapy is ~ 97.76%, which is ~ 4-fold higher than that of PTT or CDT only. Thus, the combination of CDT and PTT to construct "turn on" nanoplatform is of great significance to overcome their respective limitations. Considering its optimized "all-in-one" performance, this new nanoplatform is expected to provide an advanced theranostic strategy for the future treatment of cancers.

Thermo-optic tunable optical filters with GHz-bandwidth and flat-top passband on thin film lithium niobate platform.

Lithium niobate on insulator (LNOI) is a new photonic integrated platform that provides high optical confinement and retains the inherent excellent properties of lithium niobate (LN). Tunable filters are one of the indispensable devices for integrated optics. Here we design and fabricate a thermo-optic (TO) tunable optical filter using two cascaded racetrack microring resonators (MRRs) based on LNOI. The filter shows a narrow and flat top passband with intra band ripple less than 0.3 dB, 3 dB bandwidth of 4.8 GHz and out-of-band rejection of about 35 dB. The insertion loss of the filter is about -14 dB, including grating coupling loss about -6.5 dB and on-chip loss less than -1 dB. The heating power for center wavelength shift of the filter is about 89.4 mW per free spectral range (FSR). Relevant applications of such filters include optical information processing and microwave photonics.

NanoMi: An open source electron microscope hardware and software platform.

We outline a public license (open source) electron microscopy platform, referred to as NanoMi. NanoMi offers a modular, flexible electron microscope platform that can be utilized for a variety of applications, such as microscopy education and development of proof-of-principle experiments, and can be used to complement an existing experimental apparatus. All components are ultra-high vacuum compatible and the electron optics elements are independent from the vacuum envelope. The individual optical components are mounted on a 127 mm (5-inch) diameter half-pipe, allowing customizing of electron optics for a variety of purposes. The target capabilities include SEM, TEM, scanning TEM (STEM), and electron diffraction (ED) at up to 50 keV incident electron energy. The intended image resolution in SEM, TEM and STEM modes is ≈ 10 nm. We describe the existing components and the interfaces among components that ensure their compatibility and interchangeability. The paper provides a resource for those who consider building or utilizing their own NanoMi.

Photonic sampling analog-to-digital conversion based on time and wavelength interleaved ultra-short optical pulse train generated by using monolithic integrated LNOI intensity and phase modulator.

High-speed analog-to-digital conversion (ADC) is experimentally demonstrated by employing a time and wavelength interleaved ultra-short optical pulse train to achieve photonic sampling and using wavelength division demultiplexing to realize speed matching between the fast optical front-end and the slow electronic back-end. The sampling optical pulse train is generated from a cavity-less ultra-short optical pulse source involving a packaged device that monolithically integrates an intensity modulator and a phase modulator into a chip based on lithium niobate on insulator (LNOI). In the experiment, the fiber-to-fiber insertion loss of the packaged modulation device is measured to be 6.9 dB. In addition, the half-wave voltages of the Mach-Zehnder modulator and the phase modulator in the LNOI-based modulation device are measured to be 3.6 V and 3.4 V at 5 GHz, respectively. These parameters and the device size are superior to those based on cascaded commercial devices. Through using the packaged modulation device, two ultra-short optical pulse trains centered at 1541.40 nm and 1555.64 nm are generated with time jitters of 19.2 fs and 18.9 fs in the integral offset frequency range of 1 kHz to 10 MHz, respectively, and are perfectly time interleaved into a single pulse train with a repetition rate of 10 GHz and a time jitter of 19.8 fs. Based on the time and wavelength interleaved ultra-short optical pulse train, direct digitization of microwave signals within the frequency range of 1 GHz to 40 GHz is demonstrated by using a two-channel wavelength demultiplexing photonic ADC architecture, where the effective number of bits are 5.85 bits and 3.75 bits for the input signal at 1.1 GHz and 36.3 GHz, respectively.

Multi-segmented feature coupling for jointly reconstructing initial pressure and speed of sound in photoacoustic computed tomography.

SIGNIFICANCE: Photoacoustic computed tomography (PACT) is a fast-growing imaging modality. In PACT, the image quality is degraded due to the unknown distribution of the speed of sound (SoS). Emerging initial pressure (IP) and SoS joint-reconstruction methods promise reduced artifacts in PACT. However, previous joint-reconstruction methods have some deficiencies. A more effective method has promising prospects in preclinical applications. AIM: We propose a multi-segmented feature coupling (MSFC) method for SoS-IP joint reconstruction in PACT. APPROACH: In the proposed method, the ultrasound detectors were divided into multiple sub-arrays with each sub-array and its opposite counterpart considered to be a pair. The delay and sum algorithm was then used to reconstruct two images based on a subarray pair and estimated a direction-specific SoS, based on image correlation and the orientation of the subarrays. Once the data generated by all pairs of subarrays were processed, an image that was optimized in terms of minimal feature splitting in all directions was generated. Further, based on the direction-specific SoS, a model-based method was used to directly reconstruct the SoS distribution. RESULTS: Both phantom and animal experiments demonstrated feasibility and showed promising results compared with conventional methods, with less splitting and blurring and fewer distortions. CONCLUSIONS: The developed MSFC method shows promising results for both IP and SoS reconstruction. The MSFC method will help to optimize the image quality of PACT in clinical applications.

Spectral crosstalk in photoacoustic computed tomography.

Multispectral photoacoustic (PA) imaging faces two major challenges: the spectral coloring effect, which has been studied extensively as an optical inversion problem, and the spectral crosstalk, which is basically a result of non-ideal acoustic inversion. So far, there is no systematic work to analyze the spectral crosstalk because acoustic inversion and spectroscopic measurement are always treated as decoupled. In this work, we theorize and demonstrate through a series of simulations and experiments how imperfect acoustic inversion induces inaccurate PA spectrum measurement. We provide detailed analysis to elucidate how different factors, including limited bandwidth, limited view, light attenuation, out-of-plane signal, and image reconstruction schemes, conspire to render the measured PA spectrum inaccurate. We found that the model-based reconstruction outperforms universal back-projection in suppressing the spectral crosstalk in some cases.

Efficient polarization splitter-rotator on thin-film lithium niobate.

Recently, thin-film lithium niobate coherent modulators have emerged as a promising candidate for the next generation coherent communication system. High performance polarization splitter-rotators (PSRs) are essential to further achieve dual polarization coherent modulators. Here we present a PSR on the lithium niobate on insulator (LNOI) platform with the measured insertion loss less than 1 dB, extinction ratio exceeding 26.6 dB and 19.6 dB for TE0 and TM0 modes, working bandwidth of 1520-1580 nm and total length of 440 µm. In addition, a relatively large fabrication tolerance for waveguide width is also proved. This demonstrated PSR can find its potential application in polarization-division multiplexing (PDM) optical transmitter based on LNOI.

A Skull-Removed Chronic Cranial Window for Ultrasound and Photoacoustic Imaging of the Rodent Brain.

Ultrasound and photoacoustic imaging are emerging as powerful tools to study brain structures and functions. The skull introduces significant distortion and attenuation of the ultrasound signals deteriorating image quality. For biological studies employing rodents, craniotomy is often times performed to enhance image qualities. However, craniotomy is unsuitable for longitudinal studies, where a long-term cranial window is needed to prevent repeated surgeries. Here, we propose a mouse model to eliminate sound blockage by the top portion of the skull, while minimum physiological perturbation to the imaged object is incurred. With the new mouse model, no craniotomy is needed before each imaging experiment. The effectiveness of our method was confirmed by three imaging systems: photoacoustic computed tomography, ultrasound imaging, and photoacoustic mesoscopy. Functional photoacoustic imaging of the mouse brain hemodynamics was also conducted. We expect new applications to be enabled by the new mouse model for photoacoustic and ultrasound imaging.

Development of a digital breast phantom for photoacoustic computed tomography.

Photoacoustic (PA) imaging provides morphological and functional information about angiogenesis and thus is potentially suitable for breast cancer diagnosis. However, the development of PA breast imaging has been hindered by inadequate patients and a lack of ground truth images. Here, we report a digital breast phantom with realistic acoustic and optical properties, with which a digital PA-ultrasound imaging pipeline is developed to create a diverse pool of virtual patients with three types of masses: ductal carcinoma in situ, invasive breast cancer, and fibroadenoma. The experimental results demonstrate that our model is realistic, flexible, and can be potentially useful for accelerating the development of PA breast imaging technology.

High-efficient coupler for thin-film lithium niobate waveguide devices.

Lithium niobate (LN) devices have been widely used in optical communication and nonlinear optics due to its attractive optical properties. The emergence of the thin-film lithium niobate on insulator (LNOI) improves performances of LN-based devices greatly. However, a high-efficient fiber-chip optical coupler is still necessary for the LNOI-based devices for practical applications. In this paper, we demonstrate a highly efficient and polarization-independent edge coupler based on LNOI. The coupler, fabricated by a standard semiconductor process, shows a low fiber-chip coupling loss of 0.54 dB/0.59 dB per facet at 1550 nm for TE/TM light, respectively, when coupled with an ultra-high numerical aperture fiber (UHNAF) of which the mode field diameter is about 3.2 µm. The coupling loss is lower than 1dB/facet for both TE and TM light in the wavelength range of 1527 nm to 1630 nm. A relatively large tolerance for optical misalignment is also proved, due to the coupler's large mode spot size up to 3.2 µm. The coupler shows a promising stability in high optical power and temperature variation.

Streak artifact suppression in photoacoustic computed tomography using adaptive back projection.

For photoacoustic computed tomography (PACT), an insufficient number of ultrasound detectors can cause serious streak-type artifacts. These artifacts get overlaid on top of image features, and thus locally jeopardize image quality and resolution. Here, a reconstruction algorithm, termed Contamination-Tracing Back-Projection (CTBP), is proposed for the mitigation of streak-type artifacts. During reconstruction, CTBP adaptively adjusts the back-projection weight, whose value is determined by the likelihood of contamination, to minimize the negative influences of strong absorbers. An iterative solution of the eikonal equation is implemented to accurately trace the time of flight of different pixels. Numerical, phantom and in vivo experiments demonstrate that CTBP can dramatically suppress streak artifacts in PACT and improve image quality.

Feature coupling photoacoustic computed tomography for joint reconstruction of initial pressure and sound speed in vivo.

Photoacoustic imaging relies on diffused photons for optical contrast and diffracted ultrasound for high resolution. As a tomographic imaging modality, often an inverse problem of acoustic diffraction needs to be solved to reconstruct a photoacoustic image. The inverse problem is complicated by the fact that the acoustic properties, including the speed of sound distribution, in the image field of view are unknown. During reconstruction, subtle changes of the speed of sound in the acoustic ray path may accumulate and give rise to noticeable blurring in the image. Thus, in addition to the ultrasound detection bandwidth, inaccurate acoustic modeling, especially the unawareness of the speed of sound, defines the image resolution and influences image quantification. Here, we proposed a method termed feature coupling to jointly reconstruct the speed of sound distribution and a photoacoustic image with improved sharpness, at no additional hardware cost. Simulations, phantom studies, and in vivo experiments demonstrated the effectiveness and reliability of our method.