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Medical Optics and Biotechnology|16 Article(s)
Multiparameter assessment of hepatobiliary excretion dysfunction in cholestasis via dynamical photoacoustic and NIR-II fluorescence imaging
Qi Zhou, Guojia Huang, Jiali Chen, Aoji Qin, Honghui Li, and Liming Nie
Cholestatic liver diseases (CLD) lead to bile accumulation, hepatobiliary dysfunction, and progressive liver damage. Early, accurate evaluation of cholestasis is essential for improving prognosis. In this study, we developed a cross-scale, noninvasive optical imaging platform designed to evaluate both microstructure and metabolic functions in cases of intrahepatic cholestasis, such as primary biliary cholangitis, as well as extrahepatic cholestasis resulting from bile duct ligation. We employed high-resolution photoacoustic microscopy to assess changes in bile duct permeability, hepatic lobular architecture, and blood oxygen saturation following varying degrees of bile duct injury. Meanwhile, we utilized near-infrared-II fluorescence imaging to track the transport of indocyanine green, thereby mapping the absorption and excretion dynamics throughout the liver. Liver function reserve was monitored in situ using contrast-enhanced photoacoustic computed tomography. The imaging manifestations of microstructural alterations and functional impairments associated with cholestasis were quantitatively characterized, demonstrating a correlation with disease progression and validation of our findings. This platform enables dynamic, high-resolution assessment of small bile duct injury and hepatobiliary dysfunction, offering a promising tool for early diagnosis, monitoring, and therapeutic evaluation of CLD. Cholestatic liver diseases (CLD) lead to bile accumulation, hepatobiliary dysfunction, and progressive liver damage. Early, accurate evaluation of cholestasis is essential for improving prognosis. In this study, we developed a cross-scale, noninvasive optical imaging platform designed to evaluate both microstructure and metabolic functions in cases of intrahepatic cholestasis, such as primary biliary cholangitis, as well as extrahepatic cholestasis resulting from bile duct ligation. We employed high-resolution photoacoustic microscopy to assess changes in bile duct permeability, hepatic lobular architecture, and blood oxygen saturation following varying degrees of bile duct injury. Meanwhile, we utilized near-infrared-II fluorescence imaging to track the transport of indocyanine green, thereby mapping the absorption and excretion dynamics throughout the liver. Liver function reserve was monitored in situ using contrast-enhanced photoacoustic computed tomography. The imaging manifestations of microstructural alterations and functional impairments associated with cholestasis were quantitatively characterized, demonstrating a correlation with disease progression and validation of our findings. This platform enables dynamic, high-resolution assessment of small bile duct injury and hepatobiliary dysfunction, offering a promising tool for early diagnosis, monitoring, and therapeutic evaluation of CLD.
Photonics Research
- Publication Date: Aug. 28, 2025
- Vol. 13, Issue 9, 2679 (2025)
Wearable nanoplasmonic sensor based on surface-enhanced Raman scattering for multiplexed analysis of sweat|On the Cover
Nan Wang, Youliang Weng, Yi Liu, Yangmin Wu, Shuohong Weng, Yi Shen, Shangyuan Feng, and Duo Lin
Wearable sweat sensors that enable non-invasive sampling, efficient and rapid detection, and real-time monitoring capabilities have become an integral and critical component of human health management, with the potential to provide meaningful clinical information related to physiologic diseases in the healthcare field. Here, a flexible nanoplasmonic paper-based sensor based on surface-enhanced Raman scattering (SERS) was developed, in which silver nanoparticles were loaded in the cellulose paper to enhance the Raman signals of targets via the generation of SERS “hotspots.” By incorporating the filter paper channel with a natural core absorbing liquid, the multifunctional chip is formed, which integrates the collection, transmission, and detection of trace sweat. This paper-based chip is soft and stretchable, and fits perfectly onto the human skin surface without causing any damage or irritation. Combined with a hand-held Raman spectrometer, quantitative detection of multiple sweat components can be achieved with the limit of detection of 17 and 1 μmol/L for uric acid and glucose, respectively, and the measurable range is 4–7.5 for pH, enabling wearable and in-situ optical sensing for sweat markers under the condition of human physiology and pathology, within only 5 min for uric acid and glucose detection. This wearable biosensor would provide, to our knowledge, a new way for continuously monitoring the health status by collection and analysis of multiple components in human sweat, contributing to point-of-care testing and personalized medicine applications. Wearable sweat sensors that enable non-invasive sampling, efficient and rapid detection, and real-time monitoring capabilities have become an integral and critical component of human health management, with the potential to provide meaningful clinical information related to physiologic diseases in the healthcare field. Here, a flexible nanoplasmonic paper-based sensor based on surface-enhanced Raman scattering (SERS) was developed, in which silver nanoparticles were loaded in the cellulose paper to enhance the Raman signals of targets via the generation of SERS “hotspots.” By incorporating the filter paper channel with a natural core absorbing liquid, the multifunctional chip is formed, which integrates the collection, transmission, and detection of trace sweat. This paper-based chip is soft and stretchable, and fits perfectly onto the human skin surface without causing any damage or irritation. Combined with a hand-held Raman spectrometer, quantitative detection of multiple sweat components can be achieved with the limit of detection of 17 and 1 μmol/L for uric acid and glucose, respectively, and the measurable range is 4–7.5 for pH, enabling wearable and in-situ optical sensing for sweat markers under the condition of human physiology and pathology, within only 5 min for uric acid and glucose detection. This wearable biosensor would provide, to our knowledge, a new way for continuously monitoring the health status by collection and analysis of multiple components in human sweat, contributing to point-of-care testing and personalized medicine applications.
Photonics Research
- Publication Date: Aug. 01, 2025
- Vol. 13, Issue 8, 2316 (2025)
Fast parallel quantification for near-infrared genetically encoded reporters with self-calibrated photoacoustic screening|Editors' Pick
Xuanhao Wang, Yan Luo, Fudong Xue, Lijuan Ma, Yang Xiao, Dikui Zhou, Junhui Shi, Mingshu Zhang, Pingyong Xu, and Cheng Ma
The integration of near-infrared genetically encoded reporters (NIR-GERs) with photoacoustic (PA) imaging enables visualizing deep-seated functions of specific cell populations at high resolution, though the imaging depth is primarily constrained by reporters’ PA response intensity. Directed evolution can optimize NIR-GERs’ performance for PA imaging, yet precise quantifying of PA responses in mutant proteins expressed in E. coli colonies across iterative rounds poses challenges to the imaging speed and quantification capabilities of the screening platforms. Here, we present self-calibrated photoacoustic screening (SCAPAS), an imaging-based platform that can detect samples in parallel within 5 s (equivalent to 50 ms per colony), achieving a considerable quantification accuracy of approximately 2.8% and a quantification precision of about 6.47%. SCAPAS incorporates co-expressed reference proteins in sample preparation and employs a ring transducer array with switchable illumination for rapid, wide-field dual-wavelength PA imaging, enabling precisely calculating the PA response using the self-calibration method. Numerical simulations validated the image optimization strategy, quantification process, and noise robustness. Tests with co-expression samples confirmed SCAPAS’s superior screening speed and quantification capabilities. We believe that SCAPAS will facilitate the development of novel NIR-GERs suitable for PA imaging and has the potential to significantly impact the advancement of PA probes and molecular imaging. The integration of near-infrared genetically encoded reporters (NIR-GERs) with photoacoustic (PA) imaging enables visualizing deep-seated functions of specific cell populations at high resolution, though the imaging depth is primarily constrained by reporters’ PA response intensity. Directed evolution can optimize NIR-GERs’ performance for PA imaging, yet precise quantifying of PA responses in mutant proteins expressed in E. coli colonies across iterative rounds poses challenges to the imaging speed and quantification capabilities of the screening platforms. Here, we present self-calibrated photoacoustic screening (SCAPAS), an imaging-based platform that can detect samples in parallel within 5 s (equivalent to 50 ms per colony), achieving a considerable quantification accuracy of approximately 2.8% and a quantification precision of about 6.47%. SCAPAS incorporates co-expressed reference proteins in sample preparation and employs a ring transducer array with switchable illumination for rapid, wide-field dual-wavelength PA imaging, enabling precisely calculating the PA response using the self-calibration method. Numerical simulations validated the image optimization strategy, quantification process, and noise robustness. Tests with co-expression samples confirmed SCAPAS’s superior screening speed and quantification capabilities. We believe that SCAPAS will facilitate the development of novel NIR-GERs suitable for PA imaging and has the potential to significantly impact the advancement of PA probes and molecular imaging.
Photonics Research
- Publication Date: Apr. 01, 2025
- Vol. 13, Issue 4, 941 (2025)
High-quality endoscopic laser speckle contrast imaging with conical fiber illumination
Junshuai Yan, Qinxin Han, Liangwei Meng, Tingyu Sun, Yan Yan, Shijie Feng, Shaomin Yuan, Jinling Lu, and Pengcheng Li
Blood flow is essential for maintaining normal physiological functions of the human body. Endoscopic laser speckle contrast imaging (LSCI) can achieve rapid, high-resolution, label-free, and long-term blood flow perfusion velocity monitoring in minimally invasive surgery. However, conventional endoscopic LSCI uses a low-coherence laser illumination scheme, leading to restricted angles of illumination, compromised laser coherence, uneven laser illumination distribution, and low coupling efficiency, all of which degrade the quality of LSCI in the endoscope. In this paper, we propose that conical fiber (CF)-coupled high-coherence laser can be used to achieve large-angle, high-coherence, high-uniformity, and high coupling efficiency laser illumination in the endoscope. Additionally, we establish an effective model for calculating the divergence angle of CFs. Through phantom and animal experiments, we reveal that laser illumination based on CF markedly enhances endoscopic LSCI performance. This technology broadens the imaging field of view, enhances the signal-to-noise ratio, enables more sensitive detection of minute blood flow changes, expands the detectable flow range, and improves signal-to-background ratio of endoscopic LSCI. Our findings suggest that CF-based laser illumination stands as a highly promising advancement in endoscopic LSCI. Blood flow is essential for maintaining normal physiological functions of the human body. Endoscopic laser speckle contrast imaging (LSCI) can achieve rapid, high-resolution, label-free, and long-term blood flow perfusion velocity monitoring in minimally invasive surgery. However, conventional endoscopic LSCI uses a low-coherence laser illumination scheme, leading to restricted angles of illumination, compromised laser coherence, uneven laser illumination distribution, and low coupling efficiency, all of which degrade the quality of LSCI in the endoscope. In this paper, we propose that conical fiber (CF)-coupled high-coherence laser can be used to achieve large-angle, high-coherence, high-uniformity, and high coupling efficiency laser illumination in the endoscope. Additionally, we establish an effective model for calculating the divergence angle of CFs. Through phantom and animal experiments, we reveal that laser illumination based on CF markedly enhances endoscopic LSCI performance. This technology broadens the imaging field of view, enhances the signal-to-noise ratio, enables more sensitive detection of minute blood flow changes, expands the detectable flow range, and improves signal-to-background ratio of endoscopic LSCI. Our findings suggest that CF-based laser illumination stands as a highly promising advancement in endoscopic LSCI.
Photonics Research
- Publication Date: Feb. 18, 2025
- Vol. 13, Issue 3, 583 (2025)
Monocular depth estimation based on deep learning for intraoperative guidance using surface-enhanced Raman scattering imaging
Aniwat Juhong, Bo Li, Yifan Liu, Cheng-You Yao, Chia-Wei Yang, A. K. M. Atique Ullah, Kunli Liu, Ryan P. Lewandowski, Jack R. Harkema, Dalen W. Agnew, Yu Leo Lei, Gary D. Luker, Xuefei Huang, Wibool Piyawattanametha, and Zhen Qiu
Imaging of surface-enhanced Raman scattering (SERS) nanoparticles (NPs) has been intensively studied for cancer detection due to its high sensitivity, unconstrained low signal-to-noise ratios, and multiplexing detection capability. Furthermore, conjugating SERS NPs with various biomarkers is straightforward, resulting in numerous successful studies on cancer detection and diagnosis. However, Raman spectroscopy only provides spectral data from an imaging area without co-registered anatomic context. This is not practical and suitable for clinical applications. Here, we propose a custom-made Raman spectrometer with computer-vision-based positional tracking and monocular depth estimation using deep learning (DL) for the visualization of 2D and 3D SERS NPs imaging, respectively. In addition, the SERS NPs used in this study (hyaluronic acid-conjugated SERS NPs) showed clear tumor targeting capabilities (target CD44 typically overexpressed in tumors) by an ex vivo experiment and immunohistochemistry. The combination of Raman spectroscopy, image processing, and SERS molecular imaging, therefore, offers a robust and feasible potential for clinical applications. Imaging of surface-enhanced Raman scattering (SERS) nanoparticles (NPs) has been intensively studied for cancer detection due to its high sensitivity, unconstrained low signal-to-noise ratios, and multiplexing detection capability. Furthermore, conjugating SERS NPs with various biomarkers is straightforward, resulting in numerous successful studies on cancer detection and diagnosis. However, Raman spectroscopy only provides spectral data from an imaging area without co-registered anatomic context. This is not practical and suitable for clinical applications. Here, we propose a custom-made Raman spectrometer with computer-vision-based positional tracking and monocular depth estimation using deep learning (DL) for the visualization of 2D and 3D SERS NPs imaging, respectively. In addition, the SERS NPs used in this study (hyaluronic acid-conjugated SERS NPs) showed clear tumor targeting capabilities (target CD44 typically overexpressed in tumors) by an ex vivo experiment and immunohistochemistry. The combination of Raman spectroscopy, image processing, and SERS molecular imaging, therefore, offers a robust and feasible potential for clinical applications.
Photonics Research
- Publication Date: Jan. 31, 2025
- Vol. 13, Issue 2, 550 (2025)
Enriched photosensitizer for deep-seated-tumor photodynamic therapy
Hongrui Shan, Xueqian Wang, Qiheng Wei, Hailang Dai, and Xianfeng Chen
Photodynamic therapy (PDT) is an innovative approach that utilizes photochemical reactions for non-invasive disease treatment. Conventional PDT is limited by the low penetration depth of visible light required for activation. Herein, we employed upconversion nanoparticles (UCNPs) to extend the activation wavelength of photosensitizers into the infrared range, enabling a treatment depth of over 10 mm. Furthermore, we also used the abundant amino groups of branched polyethyleneimine (PEI) with spatial structure to enhance the loading capacity of protoporphyrin (PPIX), and we ultimately improved skin tumor clearance rates. Moreover, we achieved tumor-specific treatment by utilizing folic acid (FA) targeting and active enrichment of PPIX. According to cellular experimental results, we demonstrated the remarkable reactive oxygen species generation capability of the material and ultra-low dark toxicity. Additionally, we investigated the apoptosis mechanism and demonstrated that the synthesized nanoparticle stimulates the up-regulation of apoptosis-associated proteins Bax/Bcl-2 and Cyto c. During in vivo experiments involving intravenous injection in mouse tails, we investigated the anticancer efficacy of the nanoparticle, confirming its excellent PDT effects. This research provides a promising avenue for future non-invasive treatment of deep-seated tumors, offering a method for the treatment and management of specific cancers. Photodynamic therapy (PDT) is an innovative approach that utilizes photochemical reactions for non-invasive disease treatment. Conventional PDT is limited by the low penetration depth of visible light required for activation. Herein, we employed upconversion nanoparticles (UCNPs) to extend the activation wavelength of photosensitizers into the infrared range, enabling a treatment depth of over 10 mm. Furthermore, we also used the abundant amino groups of branched polyethyleneimine (PEI) with spatial structure to enhance the loading capacity of protoporphyrin (PPIX), and we ultimately improved skin tumor clearance rates. Moreover, we achieved tumor-specific treatment by utilizing folic acid (FA) targeting and active enrichment of PPIX. According to cellular experimental results, we demonstrated the remarkable reactive oxygen species generation capability of the material and ultra-low dark toxicity. Additionally, we investigated the apoptosis mechanism and demonstrated that the synthesized nanoparticle stimulates the up-regulation of apoptosis-associated proteins Bax/Bcl-2 and Cyto c. During in vivo experiments involving intravenous injection in mouse tails, we investigated the anticancer efficacy of the nanoparticle, confirming its excellent PDT effects. This research provides a promising avenue for future non-invasive treatment of deep-seated tumors, offering a method for the treatment and management of specific cancers.
Photonics Research
- Publication Date: May. 01, 2024
- Vol. 12, Issue 5, 1024 (2024)
Collagen fiber anisotropy characterization by polarized photoacoustic imaging for just-in-time quantitative evaluation of burn severity
Zhenhui Zhang, Wei Chen, Dandan Cui, Jie Mi, Gen Mu, Liming Nie, Sihua Yang, and Yujiao Shi
Just-in-time burn severity assessment plays a vital role in burn treatment and care. However, it is still difficult to quantitatively and promptly evaluate burn severity by existing medical imaging methods via initial burn depth measurement since burn wounds are usually dynamically developed. As an elastic skeleton of skin, the degree of conformational changes of collagen fibers caused by overheating can reflect the burn severity in a timelier manner. Herein, the polarized photoacoustic technique (PPAT) for just-in-time quantitative evaluation of burn severity via collagen fiber anisotropy assessment is proposed. First, phantom experiments demonstrate the ability of PPAT for deep imaging in a transport mean free path and accurately quantify changes in microstructural order by thermal damage. Then, the Pearson correlation coefficient of the PPAT in assessing burn severity is shown to be up to 0.95, validated by burn skin samples. The PPAT provides a just-in-time quantitative strategy for burn severity evaluation. Just-in-time burn severity assessment plays a vital role in burn treatment and care. However, it is still difficult to quantitatively and promptly evaluate burn severity by existing medical imaging methods via initial burn depth measurement since burn wounds are usually dynamically developed. As an elastic skeleton of skin, the degree of conformational changes of collagen fibers caused by overheating can reflect the burn severity in a timelier manner. Herein, the polarized photoacoustic technique (PPAT) for just-in-time quantitative evaluation of burn severity via collagen fiber anisotropy assessment is proposed. First, phantom experiments demonstrate the ability of PPAT for deep imaging in a transport mean free path and accurately quantify changes in microstructural order by thermal damage. Then, the Pearson correlation coefficient of the PPAT in assessing burn severity is shown to be up to 0.95, validated by burn skin samples. The PPAT provides a just-in-time quantitative strategy for burn severity evaluation.
Photonics Research
- Publication Date: May. 01, 2023
- Vol. 11, Issue 5, 817 (2023)
Two-beam phase correlation spectroscopy: a label-free holographic method to quantify particle flow in biofluids|On the Cover
Lan Yu, Yu Wang, Yang Wang, Kequn Zhuo, Min Liu, G. Ulrich Nienhaus, and Peng Gao
We introduce two-beam phase correlation spectroscopy (2B-ΦCS) as a label-free technique to measure the dynamics of flowing particles; e.g., in vitro or in vivo blood flow. 2B-ΦCS combines phase imaging with correlation spectroscopy, using the intrinsic refractive index contrast of particles against the fluid background in correlation analysis. This method starts with the acquisition of a time series of phase images of flowing particles using partially coherent point-diffraction digital holographic microscopy. Then, phase fluctuations from two selected circular regions in the image series are correlated to determine the concentration and flow velocity of the particles by fitting pair correlation curves with a physical model. 2B-ΦCS is a facile procedure when using a microfluidic channel, as shown by the measurements on flowing yeast microparticles, polymethyl methacrylate microparticles, and diluted rat blood. In the latter experiment, the concentration and average diameter of rat blood cells were determined to be (4.7±1.9)×106 μL-1 and 4.6±0.4 μm, respectively. We further analyzed the flow of mainly red blood cells in the tail vessels of live zebrafish embryos. Arterial and venous flow velocities were measured as 290±110 μm s-1 and 120±50 μm s-1, respectively. We envision that our technique will find applications in imaging transparent organisms and other areas of the life sciences and biomedicine. We introduce two-beam phase correlation spectroscopy (2B-ΦCS) as a label-free technique to measure the dynamics of flowing particles; e.g., in vitro or in vivo blood flow. 2B-ΦCS combines phase imaging with correlation spectroscopy, using the intrinsic refractive index contrast of particles against the fluid background in correlation analysis. This method starts with the acquisition of a time series of phase images of flowing particles using partially coherent point-diffraction digital holographic microscopy. Then, phase fluctuations from two selected circular regions in the image series are correlated to determine the concentration and flow velocity of the particles by fitting pair correlation curves with a physical model. 2B-ΦCS is a facile procedure when using a microfluidic channel, as shown by the measurements on flowing yeast microparticles, polymethyl methacrylate microparticles, and diluted rat blood. In the latter experiment, the concentration and average diameter of rat blood cells were determined to be (4.7±1.9)×106 μL-1 and 4.6±0.4 μm, respectively. We further analyzed the flow of mainly red blood cells in the tail vessels of live zebrafish embryos. Arterial and venous flow velocities were measured as 290±110 μm s-1 and 120±50 μm s-1, respectively. We envision that our technique will find applications in imaging transparent organisms and other areas of the life sciences and biomedicine.
Photonics Research
- Publication Date: Apr. 28, 2023
- Vol. 11, Issue 5, 757 (2023)
High-axial-resolution optical stimulation of neurons in vivo via two-photon optogenetics with speckle-free beaded-ring patterns
Cheng Jin, Chi Liu and Lingjie Kong
Two-photon optogenetics has become an indispensable technology in neuroscience, due to its capability in precise and specific manipulation of neural activities. A scanless holographic approach is generally adopted to meet the requirement of stimulating neural ensembles simultaneously. However, the commonly used disk patterns fail in achieving single-neuron resolution, especially in axial dimension, and their inherent speckles decrease stimulation efficiency. Here, we propose a novel speckle-free, beaded-ring pattern for high-axial-resolution optical stimulation of neurons in vivo. Using a dye pool and a fluorescent thin film as samples, we verify that, compared to those with disk patterns, higher axial resolution and better localization ability can be achieved with beaded-ring patterns. Furthermore, we perform two-photon based all-optical physiology with neurons in mouse S1 cortex in vivo, and demonstrate that the axial resolution obtained by beaded-ring patterns can be improved by 24% when stimulating multiple neurons, compared to that of disk patterns. Two-photon optogenetics has become an indispensable technology in neuroscience, due to its capability in precise and specific manipulation of neural activities. A scanless holographic approach is generally adopted to meet the requirement of stimulating neural ensembles simultaneously. However, the commonly used disk patterns fail in achieving single-neuron resolution, especially in axial dimension, and their inherent speckles decrease stimulation efficiency. Here, we propose a novel speckle-free, beaded-ring pattern for high-axial-resolution optical stimulation of neurons in vivo. Using a dye pool and a fluorescent thin film as samples, we verify that, compared to those with disk patterns, higher axial resolution and better localization ability can be achieved with beaded-ring patterns. Furthermore, we perform two-photon based all-optical physiology with neurons in mouse S1 cortex in vivo, and demonstrate that the axial resolution obtained by beaded-ring patterns can be improved by 24% when stimulating multiple neurons, compared to that of disk patterns.
Photonics Research
- Publication Date: May. 12, 2022
- Vol. 10, Issue 6, 06001367 (2022)
Single-cell detection by enhancement of fluorescence in waveguides for cancer diagnosis and therapy
Hailang Dai, Hongrui Shan, Zhangchi Sun, Daopeng Dai, Yuxi Shang, Zhuangqi Cao, and Xianfeng Chen
Cancer is one of the most common diseases to threaten human health. If individuals are diagnosed with malignant tumors via a single cell, medical workers are greatly advantageous to early diagnose and intervene in malignant tumors therapy. In this paper, we propose a fluorescence detection map to rapidly distinguish whether the chromosomes of a cell are normal or abnormal by detecting the fluorescent intensity of a single cell. Herein, we draw a map from a single cell with an abnormal number of chromosomes that is monitored in real time. Moreover, this way offers precise and prompt detection of the surviving of cancer cells at or near the site of the tumor after treatments for cancer, which can achieve personalized cancer diagnosis and therapy. Therefore, cancer recurrences and metastasis can be effectively identified, utilizing this ultrasensitive detection method of an abnormal chromosome number. Cancer is one of the most common diseases to threaten human health. If individuals are diagnosed with malignant tumors via a single cell, medical workers are greatly advantageous to early diagnose and intervene in malignant tumors therapy. In this paper, we propose a fluorescence detection map to rapidly distinguish whether the chromosomes of a cell are normal or abnormal by detecting the fluorescent intensity of a single cell. Herein, we draw a map from a single cell with an abnormal number of chromosomes that is monitored in real time. Moreover, this way offers precise and prompt detection of the surviving of cancer cells at or near the site of the tumor after treatments for cancer, which can achieve personalized cancer diagnosis and therapy. Therefore, cancer recurrences and metastasis can be effectively identified, utilizing this ultrasensitive detection method of an abnormal chromosome number.
Photonics Research
- Publication Date: Nov. 15, 2021
- Vol. 9, Issue 12, 12002381 (2021)
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