Label-Free White Blood Cell Classification Using Refractive Index Tomography and Deep LearningRead the full article
The open access journal BME Frontiers, published in association with SIBET CAS, is a platform for the multidisciplinary community of biomedical engineering, publishing wide-ranging research in the field.
BME Frontiers' editorial board is led by Xingde Li (Johns Hopkins University), Yuguo Tang (Suzhou Institute of Biomedical Engineering and Technology), and Guoqi Zhang (Delft University of Technology) and is comprised of leading experts in the field of biomedical engineering.
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Recent Advances in Photoacoustic Tomography
Photoacoustic tomography (PAT) that integrates the molecular contrast of optical imaging with the high spatial resolution of ultrasound imaging in deep tissue has widespread applications in basic biological science, preclinical research, and clinical trials. Recently, tremendous progress has been made in PAT regarding technical innovations, preclinical applications, and clinical translations. Here, we selectively review the recent progresses and advances in PAT, including the development of advanced PAT systems for small-animal and human imaging, newly engineered optical probes for molecular imaging, broad-spectrum PAT for label-free imaging of biological tissues, high-throughput snapshot photoacoustic topography, and integration of machine learning for image reconstruction and processing. We envision that PAT will have further technical developments and more impactful applications in biomedicine.
Optical Detection of Distal Lung Enzyme Activity in Human Inflammatory Lung Disease
Objective and Impact Statement. There is a need to develop platforms delineating inflammatory biology of the distal human lung. We describe a platform technology approach to detect in situ enzyme activity and observe drug inhibition in the distal human lung using a combination of matrix metalloproteinase (MMP) optical reporters, fibered confocal fluorescence microscopy (FCFM), and a bespoke delivery device. Introduction. The development of new therapeutic agents is hindered by the lack of in vivo in situ experimental methodologies that can rapidly evaluate the biological activity or drug-target engagement in patients. Methods. We optimised a novel highly quenched optical molecular reporter of enzyme activity (FIB One) and developed a translational pathway for in-human assessment. Results. We demonstrate the specificity for matrix metalloproteases (MMPs) 2, 9, and 13 and probe dequenching within physiological levels of MMPs and feasibility of imaging within whole lung models in preclinical settings. Subsequently, in a first-in-human exploratory experimental medicine study of patients with fibroproliferative lung disease, we demonstrate, through FCFM, the MMP activity in the alveolar space measured through FIB One fluorescence increase (with pharmacological inhibition). Conclusion. This translational in situ approach enables a new methodology to demonstrate active drug target effects of the distal lung and consequently may inform therapeutic drug development pathways.
Real-Time High-Resolution MRI Endoscopy at up to 10 Frames per Second
Objective. Atherosclerosis is a leading cause of mortality and morbidity. Optical endoscopy, ultrasound, and X-ray offer minimally invasive imaging assessments but have limited sensitivity for characterizing disease and therapeutic response. Magnetic resonance imaging (MRI) endoscopy is a newer idea employing tiny catheter-mounted detectors connected to the MRI scanner. It can see through vessel walls and provide soft-tissue sensitivity, but its slow imaging speed limits practical applications. Our goal is high-resolution MRI endoscopy with real-time imaging speeds comparable to existing modalities. Methods. Intravascular (3 mm) transmit-receive MRI endoscopes were fabricated for highly undersampled radial-projection MRI in a clinical 3-tesla MRI scanner. Iterative nonlinear reconstruction was accelerated using graphics processor units connected via a single ethernet cable to achieve true real-time endoscopy visualization at the scanner. MRI endoscopy was performed at 6-10 frames/sec and 200-300 μm resolution in human arterial specimens and porcine vessels ex vivo and in vivo and compared with fully sampled 0.3 frames/sec and three-dimensional reference scans using mutual information (MI) and structural similarity (3-SSIM) indices. Results. High-speed MRI endoscopy at 6-10 frames/sec was consistent with fully sampled MRI endoscopy and histology, with feasibility demonstrated in vivo in a large animal model. A 20-30-fold speed-up vs. 0.3 frames/sec reference scans came at a cost of ~7% in MI and ~45% in 3-SSIM, with reduced motion sensitivity. Conclusion. High-resolution MRI endoscopy can now be performed at frame rates comparable to those of X-ray and optical endoscopy and could provide an alternative to existing modalities, with MRI’s advantages of soft-tissue sensitivity and lack of ionizing radiation.
Recent Advancements in Optical Harmonic Generation Microscopy: Applications and Perspectives
Second harmonic generation (SHG) and third harmonic generation (THG) microscopies have emerged as powerful imaging modalities to examine structural properties of a wide range of biological tissues. Although SHG and THG arise from very different contrast mechanisms, the two are complimentary and can often be collected simultaneously using a modified multiphoton microscope. In this review, we discuss the needed instrumentation for these modalities as well as the underlying theoretical principles of SHG and THG in tissue and describe how these can be leveraged to extract unique structural information. We provide an overview of recent advances showing how SHG microscopy has been used to evaluate collagen alterations in the extracellular matrix and how this has been used to advance our knowledge of cancers, fibroses, and the cornea, as well as in tissue engineering applications. Specific examples using polarization-resolved approaches and machine learning algorithms are highlighted. Similarly, we review how THG has enabled developmental biology and skin cancer studies due to its sensitivity to changes in refractive index, which are ubiquitous in all cell and tissue assemblies. Lastly, we offer perspectives and outlooks on future directions of SHG and THG microscopies and present unresolved questions, especially in terms of overall miniaturization and the development of microendoscopy instrumentation.
Bioresorbable Multilayer Photonic Cavities as Temporary Implants for Tether-Free Measurements of Regional Tissue Temperatures
Objective and Impact Statement. Real-time monitoring of the temperatures of regional tissue microenvironments can serve as the diagnostic basis for treating various health conditions and diseases. Introduction. Traditional thermal sensors allow measurements at surfaces or at near-surface regions of the skin or of certain body cavities. Evaluations at depth require implanted devices connected to external readout electronics via physical interfaces that lead to risks for infection and movement constraints for the patient. Also, surgical extraction procedures after a period of need can introduce additional risks and costs. Methods. Here, we report a wireless, bioresorbable class of temperature sensor that exploits multilayer photonic cavities, for continuous optical measurements of regional, deep-tissue microenvironments over a timeframe of interest followed by complete clearance via natural body processes. Results. The designs decouple the influence of detection angle from temperature on the reflection spectra, to enable high accuracy in sensing, as supported by in vitro experiments and optical simulations. Studies with devices implanted into subcutaneous tissues of both awake, freely moving and asleep animal models illustrate the applicability of this technology for in vivo measurements. Conclusion. The results demonstrate the use of bioresorbable materials in advanced photonic structures with unique capabilities in tracking of thermal signatures of tissue microenvironments, with potential relevance to human healthcare.
Anatomical Modeling of Brain Vasculature in Two-Photon Microscopy by Generalizable Deep Learning
Objective and Impact Statement. Segmentation of blood vessels from two-photon microscopy (2PM) angiograms of brains has important applications in hemodynamic analysis and disease diagnosis. Here, we develop a generalizable deep learning technique for accurate 2PM vascular segmentation of sizable regions in mouse brains acquired from multiple 2PM setups. The technique is computationally efficient, thus ideal for large-scale neurovascular analysis. Introduction. Vascular segmentation from 2PM angiograms is an important first step in hemodynamic modeling of brain vasculature. Existing segmentation methods based on deep learning either lack the ability to generalize to data from different imaging systems or are computationally infeasible for large-scale angiograms. In this work, we overcome both these limitations by a method that is generalizable to various imaging systems and is able to segment large-scale angiograms. Methods. We employ a computationally efficient deep learning framework with a loss function that incorporates a balanced binary-cross-entropy loss and total variation regularization on the network’s output. Its effectiveness is demonstrated on experimentally acquired in vivo angiograms from mouse brains of dimensions up to . Results. To demonstrate the superior generalizability of our framework, we train on data from only one 2PM microscope and demonstrate high-quality segmentation on data from a different microscope without any network tuning. Overall, our method demonstrates 10× faster computation in terms of voxels-segmented-per-second and 3× larger depth compared to the state-of-the-art. Conclusion. Our work provides a generalizable and computationally efficient anatomical modeling framework for brain vasculature, which consists of deep learning-based vascular segmentation followed by graphing. It paves the way for future modeling and analysis of hemodynamic response at much greater scales that were inaccessible before.