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1.
Anal Bioanal Chem ; 413(22): 5619-5632, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-2174032

ABSTRACT

In the face of the COVID-19 pandemic, the need for rapid serological tests that allow multiplexing emerged, as antibody seropositivity can instruct about individual immunity after an infection with SARS-CoV-2 or after vaccination. As many commercial antibody tests are either time-consuming or tend to produce false negative or false positive results when only one antigen is considered, we developed an automated, flow-based chemiluminescence microarray immunoassay (CL-MIA) that allows for the detection of IgG antibodies to SARS-CoV-2 receptor-binding domain (RBD), spike protein (S1 fragment), and nucleocapsid protein (N) in human serum and plasma in less than 8 min. The CoVRapid CL-MIA was tested with a set of 65 SARS-CoV-2 serology positive or negative samples, resulting in 100% diagnostic specificity and 100% diagnostic sensitivity, thus even outcompeting commercial tests run on the same sample set. Additionally, the prospect of future quantitative assessments (i.e., quantifying the level of antibodies) was demonstrated. Due to the fully automated process, the test can easily be operated in hospitals, medical practices, or vaccination centers, offering a valuable tool for COVID-19 serosurveillance. Graphical abstract.


Subject(s)
Antibodies, Viral/blood , COVID-19 Serological Testing/methods , Immunoassay/methods , Immunoglobulin G/blood , SARS-CoV-2/immunology , Antigens, Viral/chemistry , Antigens, Viral/immunology , Automation, Laboratory , Coronavirus Nucleocapsid Proteins/immunology , Humans , Immobilized Proteins/chemistry , Immobilized Proteins/immunology , Immune Sera , Immunoassay/instrumentation , Lab-On-A-Chip Devices , Luminescent Measurements , Phosphoproteins/immunology , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Time Factors
2.
Nature ; 605(7910): 429-430, 2022 05.
Article in English | MEDLINE | ID: covidwho-1849582
3.
Nat Commun ; 13(1): 4902, 2022 08 20.
Article in English | MEDLINE | ID: covidwho-2031823

ABSTRACT

A lab-on-a-chip system with Point-of-Care testing capability offers rapid and accurate diagnostic potential and is useful in resource-limited settings where biomedical equipment and skilled professionals are not readily available. However, a Point-of-Care testing system that simultaneously possesses all required features of multifunctional dispensing, on-demand release, robust operations, and capability for long-term reagent storage is still a major challenge. Here, we describe a film-lever actuated switch technology that can manipulate liquids in any direction, provide accurate and proportional release response to the applied pneumatic pressure, as well as sustain robustness during abrupt movements and vibrations. Based on the technology, we also describe development of a polymerase chain reaction system that integrates reagent introduction, mixing and reaction functions all in one process, which accomplishes "sample-in-answer-out" performance for all clinical nasal samples from 18 patients with Influenza and 18 individual controls, in good concordance of fluorescence intensity with standard polymerase chain reaction (Pearson coefficients > 0.9). The proposed platform promises robust automation of biomedical analysis, and thus can accelerate the commercialization of a range of Point-of-Care testing devices.


Subject(s)
Lab-On-A-Chip Devices , Microfluidic Analytical Techniques , Automation , Humans , Point-of-Care Systems , Point-of-Care Testing , Polymerase Chain Reaction
4.
Nat Biomed Eng ; 6(8): 968-978, 2022 08.
Article in English | MEDLINE | ID: covidwho-1984391

ABSTRACT

Rapid, accurate and frequent detection of the RNA of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and of serological host antibodies to the virus would facilitate the determination of the immune status of individuals who have Coronavirus disease 2019 (COVID-19), were previously infected by the virus, or were vaccinated against the disease. Here we describe the development and application of a 3D-printed lab-on-a-chip that concurrently detects, via multiplexed electrochemical outputs and within 2 h, SARS-CoV-2 RNA in saliva as well as anti-SARS-CoV-2 immunoglobulins in saliva spiked with blood plasma. The device automatedly extracts, concentrates and amplifies SARS-CoV-2 RNA from unprocessed saliva, and integrates the Cas12a-based enzymatic detection of SARS-CoV-2 RNA via isothermal nucleic acid amplification with a sandwich-based enzyme-linked immunosorbent assay on electrodes functionalized with the Spike S1, nucleocapsid and receptor-binding-domain antigens of SARS-CoV-2. Inexpensive microfluidic electrochemical sensors for performing multiplexed diagnostics at the point of care may facilitate the widespread monitoring of COVID-19 infection and immunity.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , COVID-19/diagnosis , Humans , Lab-On-A-Chip Devices , Plasma , RNA, Viral , Saliva , Spike Glycoprotein, Coronavirus
5.
Biosensors (Basel) ; 12(7)2022 Jul 09.
Article in English | MEDLINE | ID: covidwho-1963723

ABSTRACT

Integrated biosensor platforms have become subjects of high interest for consolidated assay preparation and analysis to reduce sample-to-answer response times. By compactly combining as many biosensor processes and functions as possible into a single lab-on-chip device, all-in-one point-of-care devices can aid in the accessibility and speed of deployment due to their compact size and portability. Biomarker assay preparation and sensing are functionalities that are often carried out on separate devices, thus increasing opportunity of contamination, loss of sample volume, and other forms of error. Here, we demonstrate a complete lab-on-chip system combining sample preparation, on-chip optofluidic dye laser, and optical detection. We first show the integration of an on-chip distributed feedback dye laser for alignment-free optical excitation of particles moving through a fluidic channel. This capability is demonstrated by using Rhodamine 6G as the gain medium to excite single fluorescent microspheres at 575 nm. Next, we present an optofluidic PDMS platform combining a microvalve network (automaton) for sample preparation of nanoliter volumes, on-chip distributed feedback dye laser for target excitation, and optical detection. We conduct concurrent capture and fluorescence tagging of Zika virus nucleic acid on magnetic beads in 30 min. Target-carrying beads are then optically excited using the on-chip laser as they flow through an analysis channel, followed by highly specific fluorescence detection. This demonstration of a complete all-in-one biosensor is a tangible step in the development of a rapid, point-of-care device that can assist in limiting the severity of future outbreaks.


Subject(s)
Biosensing Techniques , Zika Virus Infection , Zika Virus , Humans , Lab-On-A-Chip Devices , Lasers , Microspheres
6.
Biosensors (Basel) ; 12(7)2022 Jun 26.
Article in English | MEDLINE | ID: covidwho-1963720

ABSTRACT

Zoonoses and animal diseases threaten human health and livestock biosecurity and productivity. Currently, laboratory confirmation of animal disease outbreaks requires centralized laboratories and trained personnel; it is expensive and time-consuming, and it often does not coincide with the onset or progress of diseases. Point-of-care (POC) diagnostics are rapid, simple, and cost-effective devices and tests, that can be directly applied on field for the detection of animal pathogens. The development of POC diagnostics for use in human medicine has displayed remarkable progress. Nevertheless, animal POC testing has not yet unfolded its full potential. POC devices and tests for animal diseases face many challenges, such as insufficient validation, simplicity, and portability. Emerging technologies and advanced materials are expected to overcome some of these challenges and could popularize animal POC testing. This review aims to: (i) present the main concepts and formats of POC devices and tests, such as lateral flow assays and lab-on-chip devices; (ii) summarize the mode of operation and recent advances in biosensor and POC devices for the detection of farm animal diseases; (iii) present some of the regulatory aspects of POC commercialization in the EU, USA, and Japan; and (iv) summarize the challenges and future perspectives of animal POC testing.


Subject(s)
Animal Diseases , Biosensing Techniques , Animal Diseases/diagnosis , Animals , Animals, Domestic , Farms , Humans , Lab-On-A-Chip Devices , Laboratories , Point-of-Care Systems , Point-of-Care Testing
7.
Biosensors (Basel) ; 12(7)2022 Jul 03.
Article in English | MEDLINE | ID: covidwho-1957223

ABSTRACT

In vitro diagnosis (IVD) has become a hot topic in laboratory research and achievement transformation. However, due to the high cost, and time-consuming and complex operation of traditional technologies, some new technologies are being introduced into IVD, to solve the existing problems. As a result, IVD has begun to develop toward point-of-care testing (POCT), a subdivision field of IVD. The pandemic has made governments and health institutions realize the urgency of accelerating the development of POCT. Microfluidic paper-based analytical devices (µPADs), a low-cost, high-efficiency, and easy-to-operate detection platform, have played a significant role in advancing the development of IVD. µPADs are composed of paper as the core material, certain unique substances as reagents for processing the paper, and sensing devices, as auxiliary equipment. The published reviews on the same topic lack a comprehensive and systematic introduction to µPAD classification and research progress in IVD segmentation. In this paper, we first briefly introduce the origin of µPADs and their role in promoting IVD, in the introduction section. Then, processing and detection methods for µPADs are summarized, and the innovative achievements of µPADs in IVD are reviewed. Finally, we discuss and prospect the upgrade and improvement directions of µPADs, in terms of portability, sensitivity, and automation, to help researchers clarify the progress and overcome the difficulties in subsequent µPAD research.


Subject(s)
Microfluidic Analytical Techniques , Paper , Lab-On-A-Chip Devices , Microfluidics , Point-of-Care Testing
8.
Methods Mol Biol ; 2511: 235-244, 2022.
Article in English | MEDLINE | ID: covidwho-1941379

ABSTRACT

Most people infected by the SARS-CoV-2 virus which causes COVID-19 disease experience mild or no symptoms. Severe forms of the disease are often marked by a hyper-inflammatory response known as a cytokine storm. Thus, biomarker tests which can identify these patients and place them on the appropriate treatment regime at the earliest possible phase would help to improve outcomes. Here we describe an automated microarray-based immunoassay using the Fraunhofer lab-on-a-chip platform for analysis of C-reactive protein due to its role in the hyper-inflammatory response.


Subject(s)
COVID-19 , COVID-19/diagnosis , Cytokines/metabolism , Humans , Immunoassay , Lab-On-A-Chip Devices , SARS-CoV-2
9.
Methods Mol Biol ; 2511: 117-131, 2022.
Article in English | MEDLINE | ID: covidwho-1941371

ABSTRACT

Since the original SARS-CoV-2 virus emerged from Wuhan, China, in late December 2019, a number of variants have arisen with enhanced infectivity, and some may even be capable of escaping the existing vaccines. Here we describe a rapid automated nucleic acid microarray hybridization and readout in less than 15 min using the Fraunhofer lab-on-a-chip platform for identification of bacterial species and antibiotic resistance. This platform allows a fast adaptation of new biomarkers enabling identification of different genes and gene mutations, such as those seen in the case the SARS-CoV-2 variants.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnosis , China , Humans , Lab-On-A-Chip Devices , SARS-CoV-2/genetics
10.
Chem Soc Rev ; 51(14): 5805-5841, 2022 Jul 18.
Article in English | MEDLINE | ID: covidwho-1900672

ABSTRACT

The effect of the on-going COVID-19 pandemic on global healthcare systems has underlined the importance of timely and cost-effective point-of-care diagnosis of viruses. The need for ultrasensitive easy-to-use platforms has culminated in an increased interest for rapid response equipment-free alternatives to conventional diagnostic methods such as polymerase chain reaction, western-blot assay, etc. Furthermore, the poor stability and the bleaching behavior of several contemporary fluorescent reporters is a major obstacle in understanding the mechanism of viral infection thus retarding drug screening and development. Owing to their extraordinary surface-to-volume ratio as well as their quantum confinement and charge transfer properties, nanomaterials are desirable additives to sensing and imaging systems to amplify their signal response as well as temporal resolution. Their large surface area promotes biomolecular integration as well as efficacious signal transduction. Due to their hole mobility, photostability, resistance to photobleaching, and intense brightness, nanomaterials have a considerable edge over organic dyes for single virus tracking. This paper reviews the state-of-the-art of combining carbon-allotrope, inorganic and organic-based nanomaterials with virus sensing and tracking methods, starting with the impact of human pathogenic viruses on the society. We address how different nanomaterials can be used in various virus sensing platforms (e.g. lab-on-a-chip, paper, and smartphone-based point-of-care systems) as well as in virus tracking applications. We discuss the enormous potential for the use of nanomaterials as simple, versatile, and affordable tools for detecting and tracing viruses infectious to humans, animals, plants as well as bacteria. We present latest examples in this direction by emphasizing major advantages and limitations.


Subject(s)
COVID-19 , Nanostructures , Viruses , Animals , COVID-19/diagnosis , Humans , Lab-On-A-Chip Devices , Pandemics
11.
ACS Sens ; 7(7): 2084-2092, 2022 07 22.
Article in English | MEDLINE | ID: covidwho-1900429

ABSTRACT

With the rapid spread and multigeneration variation of coronavirus, rapid drug development has become imperative. A major obstacle to addressing this issue is adequately constructing the cell membrane at the molecular level, which enables in vitro observation of the cell response to virus and drug molecules quantitatively, shortening the drug experiment cycle. Herein, we propose a rapid and label-free supported lipid bilayer-based lab-on-a-chip biosensor for the screening of effective inhibition drugs. An extended gate electrode was prepared and functionalized by an angiotensin-converting enzyme II (ACE2) receptor-incorporated supported lipid bilayer (SLB). Such an integrated system can convert the interactions of targets and membrane receptors into real-time charge signals. The platform can simulate the cell membrane microenvironment in vitro and accurately capture the interaction signal between the target and the cell membrane with minimized interference, thus observing the drug action pathway quantitatively and realizing drug screening effectively. Due to these label-free, low-cost, convenient, and integrated advantages, it is a suitable candidate method for the rapid drug screening for the early treatment and prevention of worldwide spread of coronavirus.


Subject(s)
Biosensing Techniques , Coronavirus , Cell Membrane/metabolism , Coronavirus/metabolism , Lab-On-A-Chip Devices , Lipid Bilayers/metabolism
12.
Nature ; 605(7910): 464-469, 2022 05.
Article in English | MEDLINE | ID: covidwho-1852427

ABSTRACT

Chain reactions, characterized by initiation, propagation and termination, are stochastic at microscopic scales and underlie vital chemical (for example, combustion engines), nuclear and biotechnological (for example, polymerase chain reaction) applications1-5. At macroscopic scales, chain reactions are deterministic and limited to applications for entertainment and art such as falling dominoes and Rube Goldberg machines. On the other hand, the microfluidic lab-on-a-chip (also called a micro-total analysis system)6,7 was visualized as an integrated chip, akin to microelectronic integrated circuits, yet in practice remains dependent on cumbersome peripherals, connections and a computer for automation8-11. Capillary microfluidics integrate energy supply and flow control onto a single chip by using capillary phenomena, but programmability remains rudimentary with at most a handful (eight) operations possible12-19. Here we introduce the microfluidic chain reaction (MCR) as the conditional, structurally programmed propagation of capillary flow events. Monolithic chips integrating a MCR are three-dimensionally printed, and powered by the free energy of a paper pump, autonomously execute liquid handling algorithms step-by-step. With MCR, we automated (1) the sequential release of 300 aliquots across chained, interconnected chips, (2) a protocol for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) antibodies detection in saliva and (3) a thrombin generation assay by continuous subsampling and analysis of coagulation-activated plasma with parallel operations including timers, iterative cycles of synchronous flow and stop-flow operations. MCRs are untethered from and unencumbered by peripherals, encode programs structurally in situ and can form a frugal, versatile, bona fide lab-on-a-chip with wide-ranging applications in liquid handling and point-of-care diagnostics.


Subject(s)
COVID-19 , Microfluidic Analytical Techniques , Humans , Lab-On-A-Chip Devices , Microfluidic Analytical Techniques/methods , Microfluidics/methods , Polymerase Chain Reaction , SARS-CoV-2/genetics
13.
ACS Appl Bio Mater ; 5(5): 2046-2068, 2022 05 16.
Article in English | MEDLINE | ID: covidwho-1815472

ABSTRACT

Recent advances in microfluidics-based point-of-care testing (POCT) technology such as paper, array, and beads have shown promising results for diagnosing various infectious diseases. The fast and timely detection of viral infection has proven to be a critical step for deciding the therapeutic outcome in the current COVID-19 pandemic, which in turn not only enhances the patient survival rate but also reduces the disease-associated comorbidities. In the present scenario, rapid, noninvasive detection of the virus using low cost and high throughput microfluidics-based POCT devices embraces the advantages over existing diagnostic technologies, for which a centralized lab facility, expensive instruments, sample pretreatment, and skilled personnel are required. Microfluidic-based multiplexed POCT devices can be a boon for clinical diagnosis in developing countries that lacks a centralized health care system and resources. The microfluidic devices can be used for disease diagnosis and exploited for the development and testing of drug efficacy for disease treatment in model systems. The havoc created by the second wave of COVID-19 led several countries' governments to the back front. The lack of diagnostic kits, medical devices, and human resources created a huge demand for a technology that can be remotely operated with single touch and data that can be analyzed on a phone. Recent advancements in information technology and the use of smartphones led to a paradigm shift in the development of diagnostic devices, which can be explored to deal with the current pandemic situation. This review sheds light on various approaches for the development of cost-effective microfluidics POCT devices. The successfully used microfluidic devices for COVID-19 detection under clinical settings along with their pros and cons have been discussed here. Further, the integration of microfluidic devices with smartphones and wireless network systems using the Internet-of-things will enable readers for manufacturing advanced POCT devices for remote disease management in low resource settings.


Subject(s)
COVID-19 , Microfluidics , COVID-19/diagnosis , Humans , Lab-On-A-Chip Devices , Pandemics , Point-of-Care Testing
14.
Biosensors (Basel) ; 12(4)2022 Mar 24.
Article in English | MEDLINE | ID: covidwho-1809704

ABSTRACT

Lab-on-a-Chip (LoC) devices are described as versatile, fast, accurate, and low-cost platforms for the handling, detection, characterization, and analysis of a wide range of suspended particles in water-based environments. However, for gas-based applications, particularly in atmospheric aerosols science, LoC platforms are rarely developed. This review summarizes emerging LoC devices for the classification, measurement, and identification of airborne particles, especially those known as Particulate Matter (PM), which are linked to increased morbidity and mortality levels from cardiovascular and respiratory diseases. For these devices, their operating principles and performance parameters are introduced and compared while highlighting their advantages and disadvantages. Discussing the current applications will allow us to identify challenges and determine future directions for developing more robust LoC devices to monitor and analyze airborne PM.


Subject(s)
Lab-On-A-Chip Devices , Particulate Matter , Environmental Monitoring , Particle Size , Particulate Matter/analysis
15.
J Vis Exp ; (181)2022 03 22.
Article in English | MEDLINE | ID: covidwho-1786125

ABSTRACT

The development of functional lipid nanoparticles (LNPs) is one of the major challenges in the field of drug delivery systems (DDS). Recently, LNP-based RNA delivery systems, namely, RNA-loaded LNPs have attracted attention for RNA therapy. In particular, mRNA-loaded LNP vaccines were approved to prevent COVID-19, thereby leading to the paradigm shift toward the development of next-generation nanomedicines. For the LNP-based nanomedicines, the LNP size is a significant factor in controlling the LNP biodistribution and LNP performance. Therefore, a precise LNP size control technique is indispensable for the LNP production process. Here, we report a protocol for size controlled LNP production using a microfluidic device, named iLiNP. siRNA loaded LNPs are also produced using the iLiNP device and evaluated by in vitro experiment. Representative results are shown for the LNP size, including siRNA-loaded LNPs, Z-potential, siRNA encapsulation efficiency, cytotoxicity, and target gene silencing activity.


Subject(s)
COVID-19 , Nanoparticles , Humans , Lab-On-A-Chip Devices , Lipids , Liposomes , RNA, Small Interfering/metabolism , Tissue Distribution
16.
Proc Natl Acad Sci U S A ; 119(13): e2115276119, 2022 03 29.
Article in English | MEDLINE | ID: covidwho-1774039

ABSTRACT

SignificanceThe treatment of hypoxemia that is refractory to the current standard of care is time-sensitive and requires skilled caregivers and use of specialized equipment (e.g., extracorporeal membrane oxygenation). Most patients experiencing refractory hypoxemia will suffer organ dysfunction, and death is common in this cohort. Here, we describe a new strategy to stabilize and support patients using a microfluidic device that administers oxygen gas directly to the bloodstream in real time and on demand using a process that we call sequential shear-induced bubble breakup. If successful, the described technology may help to avoid or decrease the incidence of ventilator-related lung injury from refractory hypoxemia.


Subject(s)
Extracorporeal Membrane Oxygenation , Lung Injury , Extracorporeal Membrane Oxygenation/adverse effects , Humans , Hypoxia , Lab-On-A-Chip Devices , Oxygen , Ventilators, Mechanical/adverse effects
17.
Science ; 373(6561): 1304-1306, 2021 Sep 17.
Article in English | MEDLINE | ID: covidwho-1741512
18.
Sci Rep ; 12(1): 3539, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1730309

ABSTRACT

Microfluidics has emerged rapidly over the past 20 years and has been investigated for a variety of applications from life sciences to environmental monitoring. Although continuous-flow microfluidics is ubiquitous, segmented-flow or droplet microfluidics offers several attractive features. Droplets can be independently manipulated and analyzed with very high throughput. Typically, microfluidics is carried out within planar networks of microchannels, namely, microfluidic chips. We propose that fibers offer an interesting alternative format with key advantages for enhanced optical coupling. Herein, we demonstrate the generation of monodisperse droplets within a uniaxial optofluidic Lab-in-a-Fiber scheme. We combine droplet microfluidics with laser-induced fluorescence (LIF) detection achieved through the development of an optical side-coupling fiber, which we term a periscope fiber. This arrangement provides stable and compact alignment. Laser-induced fluorescence offers high sensitivity and low detection limits with a rapid response time making it an attractive detection method for in situ real-time measurements. We use the well-established fluorophore, fluorescein, to characterize the Lab-in-a-Fiber device and determine the generation of [Formula: see text] 0.9 nL droplets. We present characterization data of a range of fluorescein concentrations, establishing a limit of detection (LOD) of 10 nM fluorescein. Finally, we show that the device operates within a realistic and relevant fluorescence regime by detecting reverse-transcription loop-mediated isothermal amplification (RT-LAMP) products in the context of COVID-19 diagnostics. The device represents a step towards the development of a point-of-care droplet digital RT-LAMP platform.


Subject(s)
Lab-On-A-Chip Devices , Viruses/isolation & purification , Fluorescence , Lasers
19.
Sensors (Basel) ; 22(4)2022 Feb 18.
Article in English | MEDLINE | ID: covidwho-1699467

ABSTRACT

The early diagnosis of infectious diseases is critical because it can greatly increase recovery rates and prevent the spread of diseases such as COVID-19; however, in many areas with insufficient medical facilities, the timely detection of diseases is challenging. Conventional medical testing methods require specialized laboratory equipment and well-trained operators, limiting the applicability of these tests. Microfluidic point-of-care (POC) equipment can rapidly detect diseases at low cost. This technology could be used to detect diseases in underdeveloped areas to reduce the effects of disease and improve quality of life in these areas. This review details microfluidic POC equipment and its applications. First, the concept of microfluidic POC devices is discussed. We then describe applications of microfluidic POC devices for infectious diseases, cardiovascular diseases, tumors (cancer), and chronic diseases, and discuss the future incorporation of microfluidic POC devices into applications such as wearable devices and telemedicine. Finally, the review concludes by analyzing the present state of the microfluidic field, and suggestions are made. This review is intended to call attention to the status of disease treatment in underdeveloped areas and to encourage the researchers of microfluidics to develop standards for these devices.


Subject(s)
COVID-19 , Point-of-Care Systems , COVID-19/diagnosis , Humans , Lab-On-A-Chip Devices , Microfluidics , Quality of Life , SARS-CoV-2
20.
Lab Chip ; 22(6): 1171-1186, 2022 03 15.
Article in English | MEDLINE | ID: covidwho-1684131

ABSTRACT

Coronavirus disease 2019 (COVID-19) was primarily identified as a novel disease causing acute respiratory syndrome. However, as the pandemic progressed various cases of secondary organ infection and damage by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported, including a breakdown of the vascular barrier. As SARS-CoV-2 gains access to blood circulation through the lungs, the virus is first encountered by the layer of endothelial cells and immune cells that participate in host defense. Here, we developed an approach to study SARS-CoV-2 infection using vasculature-on-a-chip. We first modeled the interaction of virus alone with the endothelialized vasculature-on-a-chip, followed by the studies of the interaction of the virus exposed-endothelial cells with peripheral blood mononuclear cells (PBMCs). In an endothelial model grown on a permeable microfluidic bioscaffold under flow conditions, both human coronavirus (HCoV)-NL63 and SARS-CoV-2 presence diminished endothelial barrier function by disrupting VE-cadherin junctions and elevating the level of pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, and angiopoietin-2. Inflammatory cytokine markers were markedly more elevated upon SARS-CoV-2 infection compared to HCoV-NL63 infection. Introduction of PBMCs with monocytes into the vasculature-on-a-chip upon SARS-CoV-2 infection further exacerbated cytokine-induced endothelial dysfunction, demonstrating the compounding effects of inter-cellular crosstalk between endothelial cells and monocytes in facilitating the hyperinflammatory state. Considering the harmful effects of SARS-CoV-2 on endothelial cells, even without active virus proliferation inside the cells, a potential therapeutic approach is critical. We identified angiopoietin-1 derived peptide, QHREDGS, as a potential therapeutic capable of profoundly attenuating the inflammatory state of the cells consistent with the levels in non-infected controls, thereby improving the barrier function and endothelial cell survival against SARS-CoV-2 infection in the presence of PBMC.


Subject(s)
Angiopoietin-1 , COVID-19 , Endothelium, Vascular , Inflammation , SARS-CoV-2 , COVID-19/drug therapy , COVID-19/virology , Endothelial Cells/immunology , Endothelial Cells/virology , Endothelium, Vascular/immunology , Endothelium, Vascular/virology , Humans , Immunity, Innate , Inflammation/drug therapy , Inflammation/virology , Lab-On-A-Chip Devices , Leukocytes, Mononuclear
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