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.

Alicia Megia-Fernandez

Adam Marshall

Ahsan R. Akram

Bethany Mills

Sunay V. Chankeshwara

Emma Scholefield

Amy Miele

Bruce C. McGorum

Chesney Michaels

Nathan Knighton

Tom Vercauteren

Francois Lacombe

Veronique Dentan

Annya M. Bruce

Joanne Mair

Robert Hitchcock

Nik Hirani

Chris Haslett

Mark Bradley

Kevin Dhaliwal

Optical Detection of Distal Lung Enzyme Activity in Human Inflammatory Lung Disease

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&#x2009;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&#x2009;&#x03BC;m 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 &#x007E;7&#x0025; in MI and &#x007E;45&#x0025; 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&#x2019;s advantages of soft-tissue sensitivity and lack of ionizing radiation.

Xiaoyang Liu

Parag Karmarkar

Dirk Voit

Jens Frahm

Clifford R. Weiss

Dara L. Kraitchman

Paul A. Bottomley

Real-Time High-Resolution MRI Endoscopy at up to 10 Frames per Second

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.

Darian S. James

Paul J. Campagnola

Recent Advancements in Optical Harmonic Generation Microscopy: Applications and Perspectives

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.

Wubin Bai

Masahiro Irie

Zhonghe Liu

Haiwen Luan

Daniel Franklin

Khizar Nandoliya

Hexia Guo

Hao Zang

Yang Weng

Di Lu

Di Wu

Yixin Wu

Joseph Song

Mengdi Han

Enming Song

Yiyuan Yang

Xuexian Chen

Hangbo Zhao

Wei Lu

Giuditta Monti

Iwona Stepien

Irawati Kandela

Chad R. Haney

Changsheng Wu

Sang Min Won

Hanjun Ryu

Alina Rwei

Haixu Shen

Jihye Kim

Hong-Joon Yoon

Wei Ouyang

Yihan Liu

Emily Suen

Huang-yu Chen

Jerry Okina

Jushen Liang

Yonggang Huang

Guillermo A. Ameer

Weidong Zhou

John A. Rogers

Bioresorbable Multilayer Photonic Cavities as Temporary Implants for Tether-Free Measurements of Regional Tissue Temperatures

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 <svg xmlns="http://www.w3.org/2000/svg" id="M1" style="vertical-align:-2.73183pt" height="11.467pt" version="1.1" viewBox="-0.0498162 -8.73517 102.552 11.467" width="102.552pt">


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</svg>. 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.

Waleed Tahir

Sreekanth Kura

Jiabei Zhu

Xiaojun Cheng

Rafat Damseh

Fetsum Tadesse

Alex Seibel

Blaire S. Lee

Fr&#x00E9;d&#x00E9;ric Lesage

Sava Sakad&#x017E;ic

David A. Boas

Lei Tian

Anatomical Modeling of Brain Vasculature in Two-Photon Microscopy by Generalizable Deep Learning

Understanding how brain activity encodes information and controls behavior is a long-standing question in neuroscience. This complex problem requires converging efforts from neuroscience and engineering, including technological solutions to perform high-precision and large-scale recordings of neuronal activity in vivo as well as unbiased methods to reliably measure and quantify behavior. Thanks to advances in genetics, molecular biology, engineering, and neuroscience, in recent decades, a variety of optical imaging and electrophysiological approaches for recording neuronal activity in awake animals have been developed and widely applied in the field. Moreover, sophisticated computer vision and machine learning algorithms have been developed to analyze animal behavior. In this review, we provide an overview of the current state of technology for neuronal recordings with a focus on optical and electrophysiological methods in rodents. In addition, we discuss areas that future technological development will need to cover in order to further our understanding of the neural activity underlying behavior.

Richard H. Roth

Jun B. Ding

From Neurons to Cognition: Technologies for Precise Recording of Neural Activity Underlying Behavior

Objective and Impact Statement. This is the first longitudinal study investigating the effects of histotripsy on local tumor progression in an in vivo orthotopic, immunocompetent rat hepatocellular carcinoma (HCC) model. Introduction. Histotripsy is the first noninvasive, nonionizing, nonthermal, mechanical ablation technique using ultrasound to generate acoustic cavitation to liquefy the target tissue into acellular debris with millimeter accuracy. Previously, histotripsy has demonstrated in vivo ablation of noncancerous liver tissue. Methods. N1-S1 HCC tumors were generated in the livers of immunocompetent rats (<svg xmlns="http://www.w3.org/2000/svg" id="M1" style="vertical-align:-0.1688595pt" height="8.90403pt" version="1.1" viewBox="-0.0498162 -8.73517 28.7695 8.90403" width="28.7695pt">


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</svg>, treatment). Real-time ultrasound-guided histotripsy was applied to ablate either <svg xmlns="http://www.w3.org/2000/svg" id="M3" style="vertical-align:-2.78203pt" height="11.5172pt" version="1.1" viewBox="-0.0498162 -8.73517 205.486 11.5172" width="205.486pt">


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</svg>, complete treatment) or 50-75% tumor volume (<svg xmlns="http://www.w3.org/2000/svg" id="M5" style="vertical-align:-0.1688595pt" height="8.90403pt" version="1.1" viewBox="-0.0498162 -8.73517 28.7695 8.90403" width="28.7695pt">


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</svg>, partial treatment) by delivering 1-2 cycle histotripsy pulses at 100 Hz PRF (pulse repetition frequency) with <svg xmlns="http://www.w3.org/2000/svg" id="M6" style="vertical-align:-2.73183pt" height="11.467pt" version="1.1" viewBox="-0.0498162 -8.73517 44.0096 11.467" width="44.0096pt">


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</svg> MPa using a custom 1 MHz transducer. Rats were monitored weekly using MRI (magnetic resonance imaging) for 3 months or until tumors reached ~25 mm. Results. MRI revealed effective post-histotripsy reduction of tumor burden with near-complete resorption of the ablated tumor in 14/15 (93.3%) treated rats. Histopathology showed &lt;5 mm shrunken, non-tumoral, fibrous tissue at the treatment site at 3 months. Rats with increased tumor burden (3/6 control and 1 partial treatment) were euthanized early by 2-4 weeks. In 3 other controls, histology revealed fibrous tissue at original tumor site at 3 months. There was no evidence of histotripsy-induced off-target tissue injury. Conclusion. Complete and partial histotripsy ablation resulted in effective tumor removal for 14/15 rats, with no evidence of local tumor progression or recurrence.

Tejaswi Worlikar

Mishal Mendiratta-Lala

Eli Vlaisavljevich

Ryan Hubbard

Jiaqi Shi

Timothy L. Hall

Clifford S. Cho

Fred T. Lee

Joan Greve

Zhen Xu

Effects of Histotripsy on Local Tumor Progression in an in vivo Orthotopic Rodent Liver Tumor Model

Objective and Impact Statement. To study the feasibility of combined functional photoacoustic (PA) and quantitative ultrasound (US) for diagnosis of osteoporosis in vivo based on the detection of chemical and microarchitecture (BMA) information in calcaneus bone. Introduction. Clinically available X-ray or US technologies for the diagnosis of osteoporosis do not report important parameters such as chemical information and BMA. With unique advantages, including good sensitivity to molecular and metabolic properties, PA bone assessment techniques hold a great potential for clinical translation. Methods. By performing multiwavelength PA measurements, the chemical information in the human calcaneus bone, including mineral, lipid, oxygenated-hemoglobin, and deoxygenated-hemoglobin, were assessed. In parallel, by performing PA spectrum analysis, the BMA as an important bone physical property was quantified. An unpaired <svg xmlns="http://www.w3.org/2000/svg" id="M1" style="vertical-align:-0.1876597pt" height="7.43768pt" version="1.1" viewBox="-0.0498162 -7.25002 5.2507 7.43768" width="5.2507pt">


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</svg>-test and a two-way ANOVA test were conducted to compare the outcomes from the two subject groups. Results. Multiwavelength PA measurement is capable of assessing the relative contents of several chemical components in the trabecular bone in vivo, including both minerals and organic materials such as oxygenated-hemoglobin, deoxygenated-hemoglobin, and lipid, which are relevant to metabolic activities and bone health. In addition, PA measurements of BMA show good correlations (<svg xmlns="http://www.w3.org/2000/svg" id="M2" style="vertical-align:-0.04979992pt" height="10.5659pt" version="1.1" viewBox="-0.0498162 -10.5161 13.4942 10.5659" width="13.4942pt">


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</svg> up to 0.65) with DEXA. Both the chemical and microarchitectural measurements from PA techniques can differentiate the two subject groups. Conclusion. The results from this initial clinical study suggest that PA techniques, by providing additional chemical and microarchitecture information relevant to bone health, may lead to accurate and early diagnosis, as well as sensitive monitoring of the treatment of osteoporosis.

Ting Feng

Yunhao Zhu

Richard Morris

Kenneth M. Kozloff

Xueding Wang

Functional Photoacoustic and Ultrasonic Assessment of Osteoporosis: A Clinical Feasibility Study

Terahertz (THz) waves are electromagnetic waves with frequency in the range from 0.1 to 10 THz. THz waves have great potential in the biomedical field, especially in cancer diagnosis, because they exhibit low ionization energy and can be used to discern most biomolecules based on their spectral fingerprints. In this paper, we review the recent progress in two applications of THz waves in cancer diagnosis: imaging and spectroscopy. THz imaging is expected to help researchers and doctors attain a direct intuitive understanding of a cancerous area. THz spectroscopy is an efficient tool for component analysis of tissue samples to identify cancer biomarkers. Additionally, the advantages and disadvantages of the developed technologies for cancer diagnosis are discussed. Furthermore, auxiliary techniques that have been used to enhance the spectral signal-to-noise ratio (SNR) are also reviewed.

Yan Peng

Chenjun Shi

Xu Wu

Yiming Zhu

Songlin Zhuang

Terahertz Imaging and Spectroscopy in Cancer Diagnostics: A Technical Review

In an age where digitization is widespread in clinical and preclinical workflows, pathology is still predominantly practiced by microscopic evaluation of stained tissue specimens affixed on glass slides. Over the last decade, new high throughput digital scanning microscopes have ushered in the era of digital pathology that, along with recent advances in machine vision, have opened up new possibilities for Computer-Aided-Diagnoses. Despite these advances, the high infrastructural costs related to digital pathology and the perception that the digitization process is an additional and nondirectly reimbursable step have challenged its widespread adoption. Here, we discuss how emerging virtual staining technologies and machine learning can help to disrupt the standard histopathology workflow and create new avenues for the diagnostic paradigm that will benefit patients and healthcare systems alike via digital pathology.

Yair Rivenson

Kevin de Haan

W. Dean Wallace

Aydogan Ozcan

Emerging Advances to Transform Histopathology Using Virtual Staining

Objective. The goal is to increase the precision of radiation delivery during radiotherapy by tracking the movements of the tumor and other surrounding normal tissues due to respiratory and other body motions. Introduction. This work presents the recent advancement of X-ray-induced radiation acoustic imaging (xRAI) technology and the evaluation of its feasibility for real-time monitoring of geometric and morphological misalignments of the X-ray field with respect to the target tissue by combining xRAI with established ultrasound (US) imaging, thereby improving radiotherapy tumor eradication and limiting treatment side effects. Methods. An integrated xRAI and B-mode US dual-modality system was established based on a clinic-ready research US platform. The performance of this dual-modality imaging system was evaluated via experiments on phantoms and ex vivo and in vivo rabbit liver models. Results. This system can alternatively switch between the xRAI and the US modes, with spatial resolutions of 1.1&#x2009;mm and 0.37&#x2009;mm, respectively. 300 times signal averaging was required for xRAI to reach a satisfactory signal-to-noise ratio, and a frame rate of 1.1&#x2009;Hz was achieved with a clinical linear accelerator. The US imaging frame rate was 22&#x2009;Hz, which is sufficient for real-time monitoring of the displacement of the target due to internal body motion. Conclusion. Our developed xRAI, in combination with US imaging, allows for mapping of the dose deposition in biological samples in vivo, in real-time, during radiotherapy. Impact Statement. The US-based image-guided radiotherapy system presented in this work holds great potential for personalized cancer treatment and better outcomes.

Wei Zhang

Ibrahim Oraiqat

Hao Lei

Paul L. Carson

Issam EI Naqa

Dual-Modality X-Ray-Induced Radiation Acoustic and Ultrasound Imaging for Real-Time Monitoring of Radiotherapy

Xingde Li

Guoqi Zhang

Yuguo Tang

BME Frontiers: A Platform for Engineering the Future of Biomedicine

About this journal

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.

Journal profile

Meet the editorial board

BME Frontiers' editorial board is led by Xingde Li&nbsp;(Johns Hopkins University), Yuguo Tang&nbsp;(Suzhou Institute of Biomedical Engineering and Technology), and&nbsp;Guoqi Zhang&nbsp;(Delft University of Technology) and is comprised of leading experts in the field of biomedical engineering.

Editorial board

More special issue details

•&nbsp;BME Frontiers is now considering submissions for its second 
special issue:&nbsp;<a href="https://spj.sciencemag.org/bme-frontiers-special-issues/ai-biomed">AI for Advanced Biomedical Applications</a>

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•&nbsp;BME Frontiers has been accepted to <a href="https://doaj.org/toc/2765-8031">DOAJ</a>.