High-Frequency 3D Photoacoustic Computed Tomography Using an Optical Microring Resonator

3D photoacoustic computed tomography(3D-PACT)has made great advances in volumetric imaging of biological tissues,with high spatial-temporal resolutions and large penetration depth.The development of 3D-PACT requires high-performance acoustic sensors with a small size,large detection bandwidth,and high sensitivity.In this work,we present a new high-frequency 3D-PACT system that uses a microring resonator(MRR)as the acoustic sensor.The MRR sensor has a size of 80μm in diameter and was fabricated using the nanoimprint lithography technology.Using the MRR sensor,we have developed a transmission-mode 3D-PACT system that has achieved a detection bandwidth of~23 MHz,an imaging depth of~8 mm,a lateral resolution of 114μm,and an axial resolution of 57μm.We have demonstrated the 3D PACT’s performance on in vitro phantoms,ex vivo mouse brain,and in vivo mouse ear and tadpole.The MRR-based 3D-PACT system can be a promising tool for structural,functional,and molecular imaging of biological tissues at depths.

Concurrent photoacoustic and ultrasound microscopy with a coaxial dual-element ultrasonic transducer

Simultaneous photoacoustic and ultrasound(PAUS)imaging has attracted increasing attention in biomedical research to probe the optical and mechanical properties of tissue.However,the resolution for majority of the existing PAUS systems is on the order of 1 mm as the majority are designed for clinical use with low-frequency US detection.Here we developed a concurrent PAUS microscopy that consists of optical-resolution photoacoustic microscopy(OR-PAM)and high-frequency US pulse-echo imaging.This dual-modality system utilizes a novel coaxial dual-element ultrasonic transducer(DE-UST)and provides anatomical and functional information with complementary contrast mechanisms,achieving a spatial resolution of 7μm for PA imaging and 106μm for US imaging.We performed phantom studies to validate the system’s performance.The vasculature of a mouse’s hind paw was imaged to demonstrate the potential of this hybrid system for biomedical applications.

The sound of blood:photoacoustic imaging in blood analysis

Blood analysis is a ubiquitous and critical aspect of modern medicine.Analyzing blood samples requires invasive techniques,various testing systems,and samples are limited to relatively small volumes.Photoacoustic imaging(PAI)is a novel imaging modality that utilizes non-ionizing energy that shows promise as an alternative to current methods.This paper seeks to review current applications of PAI in blood analysis for clinical use.Furthermore,we discuss obstacles to implementation and future directions to overcome these challenges.Firstly,we discuss three applications to cellular analysis of blood:sickle cell,bacteria,and circulating tumor cell detection.We then discuss applications to the analysis of blood plasma,including glucose detection and anticoagulation quantification.As such,we hope this article will serve as inspiration for PAI's potential application in blood analysis and prompt further studies to ultimately implement PAI into clinical practice.

Real-time whole-brain imaging of hemodynamics and oxygenation at micro-vessel resolution with ultrafast wide-field photoacoustic microscopy

High-speed high-resolution imaging of the whole-brain hemodynamics is critically important to facilitating neurovascular research.High imaging speed and image quality are crucial to visualizing real-time hemodynamics in complex brain vascular networks,and tracking fast pathophysiological activities at the microvessel level,which will enable advances in current queries in neurovascular and brain metabolism research,including stroke,dementia,and acute brain injury.Further,real-time imaging of oxygen saturation of hemoglobin(sO_(2))can capture fast-paced oxygen delivery dynamics,which is needed to solve pertinent questions in these fields and beyond.Here,we present a novel ultrafast functional photoacoustic microscopy(UFF-PAM)to image the whole-brain hemodynamics and oxygenation.UFF-PAM takes advantage of several key engineering innovations,including stimulated Raman scattering(SRS)based dual-wavelength laser excitation,water-immersible 12-facet-polygon scanner,high-sensitivity ultrasound transducer,and deep-learning-based image upsampling.A volumetric imaging rate of 2 Hz has been achieved over a field of view(FOV)of 11×7.5×1.5 mm^(3) with a high spatial resolution of~10 μm.Using the UFF-PAM system,we have demonstrated proof-of-concept studies on the mouse brains in response to systemic hypoxia,sodium nitroprusside,and stroke.We observed the mouse brain's fast morphological and functional changes over the entire cortex,including vasoconstriction,vasodilation,and deoxygenation.More interestingly,for the first time,with the whole-brain FOV and micro-vessel resolution,we captured the vasoconstriction and hypoxia simultaneously in the spreading depolarization(SD)wave.We expect the new imaging technology will provide a great potential for fundamental brain research under various pathological and physiological conditions.

Clinical Prediction Models for Hepatitis B Virus-related Acute-on-chronic Liver Failure:A Technical Report

Background and Aims:It is critical but challenging to predict the prognosis of hepatitis B virus-related acute-on-chronic liver failure(HBV-ACLF).This study systematically summarized and evaluated the quality and performance of available clinical prediction models(CPMs).Methods:A keyword search of articles on HBV-ACLF CPMs published in PubMed from January 1995 to April 2020 was performed.Both the quality and performance of the CPMs were assessed.Results:Fifty-two CPMs were identified,of which 31 were HBV-ACLF specific.The modeling data were mostly derived from retrospective(83.87%)and single-center(96.77%)cohorts,with sample sizes ranging from 46 to 1,202.Three-month mortality was the most common endpoint.The Asian Pacific Association for the Study of the Liver consensus(51.92%)and Chinese Medical Association liver failure guidelines(40.38%)were commonly used for HBV-ACLF diagnosis.Serum bilirubin(67.74%),the international normalized ratio(54.84%),and hepatic encephalopathy(51.61%)were the most frequent variables used in models.Model discrimination was commonly evaluated(88.46%),but model calibration was seldom performed.The model for end-stage liver disease score was the most widely used(84.62%);however,varying performance was reported among the studies.Conclusions:Substantial limitations lie in the quality of HBV-ACLF-specific CPMs.Disease severity of study populations may impact model performance.The clinical utility of CPMs in predicting short-term prognosis of HBV-ACLF remains to be undefined.

Microglial Exosome miR-7239-3p Promotes Glioma Progression by Regulating Circadian Genes

Glioma-associated microglial cells,a key component of the tumor microenvironment,play an important role in glioma progression.In this study,the mouse glioma cell line GL261 and the mouse microglia cell line BV2 were chosen.First,circadian gene expression in glioma cells co-cultured with either M1 or M2 microglia was assessed and the exosomes of M2-polarized and unpolarized BV-2 microglia were extracted.Subsequently,we labeled the exosomes with PKH67 and treated GL261 cells with them to investigate the exosome distribution.GL261 cell phenotypes and related protein expression were used to explore the role of M2 microglial exosomes in gliomas.Then a specific miR-7239-3p inhibitor was added to verify miR-7239-3p functions.Finally,the mouse subcutaneous tumorigenic model was used to verify the tumorigenic effect of M2 microglial exosomes in vivo.Our results showed that in gliomas co-cultured with M2 microglia,the expression of the BMAL1 protein was decreased(P<0.01),while the expression of the CLOCK protein was increased(P<0.05);opposite results were obtained in gliomas co-cultured with M1 microglia.After treatment with M2 microglial exosomes,the apoptosis of GL261 cells decreased(P<0.001),while the viability,proliferation,and migration of GL261 cells increased.Increased expression of N-cadherin and Vimentin,and decreased E-cadherin expression occurred upon treatment with M2 microglial exosomes.Addition of an miR-7239-3p inhibitor to M2 microglial exosomes reversed these results.In summary,we found that miR-7239-3p in the glioma microenvironment is recruited to glioma cells by exosomes and inhibits Bmal1 expression.M2 microglial exosomes promote the proliferation and migration of gliomas by regulating tumor-related protein expression and reducing apoptosis.

When pressure meets light: detecting the photoacoustic effect at the origin

Modern optical microscopy1,including confocal microscopy,twophoton microscopy and optical coherence tomography(OCT),has revolutionized life sciences by providing detailed information of biological samples with cellular and subcellular resolutions,and has become an essential tool for biomedical research labs.However,optical microscopy typically has a limited penetration depth of~1 mm in biological tissue due to strong optical scattering2,3.Moreover,with respective contrast mechanisms,confocal and two-photon microscopy usually rely on fluorescent labeling of the samples and OCT still lacks sensitivity to many biological functions.In contrast,optical-resolution photoacoustic microscopy(OR-PAM)has emerged over the last decade as a complementary imaging tool to the existing optical microscopy by taking advantage of its unique optical absorption contrast4.By acoustically detecting the optical absorption in the tissue,OR-PAM has been proven a powerful tool for anatomical,functional and molecular imaging with endogenous or exogenous contrast agents.In particular,using hemoglobin as the endogenous optical absorber,OR-PAM currently represents the most sensitive blood detector and has been widely used for in vivo imaging of the blood perfusion and oxygenation,especially for cancer and brain studies.Nevertheless,the acoustic detection in OR-PAM is a doubleedged sword;on the one hand,it provides a relatively deep penetration with one-way optical attenuation and negligible acoustic attenuation,but on the other hand,the acoustic detection typically needs a coupling medium,such as water and ultrasound gel,between the tissue surface and the ultrasound transducer.The need for acoustic coupling has become one of the major factors that has hindered the wide adoption of OR-PAM by biomedical researchers whenever the biological samples are not compatible with an aquatic environment.Therefore,contact-free detection of the photoacoustic signals(that is,without the need for acoustic coupling)has captured the attention of the photoacoustic imaging community and resulted in many exciting advancements.If successful,the contact-free photoacoustic technologies will free up the working space and greatly expand the territory of PAM applications.

Interobserver Agreement for Classifying Infections in Patients with Decompensated Cirrhosis Based on Centers for Disease Control and Prevention Criteria

Background:Bacterial infections are common in patients with decompensated cirrhosis,largely owing to bacterial translocation and cirrhosis-associated immune dysfunction.This study aims to determine the reliability for classifying infections in patients with decompensated cirrhosis based on the Centers for Disease Control and Prevention(CDC)criteria.Methods:The patients with decompensated cirrhosis with suspicious infection in a registered prospective cohort of cirrhosis from May 1,2014 to February 25,2015 in the ward of First Affiliated Hospital of Zhejiang University were retrospectively identified.Agreement assessment was conducted focusing on site of infection,the possibility of infection,and pathogens of infection on both system level and specific diagnosis level.A subgroup analysis was performed based on with/without acute-on-chronic liver failure(ACLF).Results:A total of 402 infectious episodes among 351 patients were enrolled for consistency analysis.The overall agreement for site of infection was 94%(378/402)(k=0.90,95%CI 0.86–0.94)on system level and 86%(346/402)(k=0.84,95%CI 0.80–0.88)on specific diagnosis level.On possibility of infection,the overall agreement was 81%(306/378)(weighted k=0.71,95%CI 0.65–0.77),with 84%(224/267)(weighted k=0.75,95%CI 0.63–0.87)in patients with ACLF and 80%(70/88)(weighted k=0.68,95%CI 0.60–0.76)in patients without ACLF,respectively.On pathogens of infection,the overall agreement was 72%(60/83)(k=0.70,95%CI 0.60–0.80)among most frequent infections.Conclusion:The agreement for classifying infections in patients with decompensated cirrhosis based on CDC criteria is acceptable overall,suggesting that it can be a useful tool for clinical management in patients with decompensated cirrhosis with suspicious infections.