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1.
Biosensors (Basel) ; 12(5)2022 May 11.
Article in English | MEDLINE | ID: covidwho-1869468

ABSTRACT

In this study, an "all-in-one" digital microfluidics (DMF) system was developed for automatic and rapid molecular diagnosis and integrated with magnetic bead-based nucleic acid extraction, loop-mediated isothermal amplification (LAMP), and real-time optical signal monitoring. First, we performed on- and off-chip comparison experiments for the magnetic bead nucleic acid extraction module and LAMP amplification function. The extraction efficiency for the on-chip test was comparable to that of conventional off-chip methods. The processing time for the automatic on-chip workflow was only 23 min, which was less than that of the conventional methods of 28 min 45 s. Meanwhile, the number of samples used in on-chip experiments was significantly smaller than that used in off-chip experiments; only 5 µL of E. coli samples was required for nucleic acid extraction, and 1 µL of the nucleic acid template was needed for the amplification reaction. In addition, we selected SARS-CoV-2 nucleic acid reference materials for the nucleic acid detection experiment, demonstrating a limit of detection of 10 copies/µL. The proposed "all-in-one" DMF system provides an on-site "sample to answer" time of approximately 60 min, which can be a powerful tool for point-of-care molecular diagnostics.


Subject(s)
COVID-19 , Nucleic Acids , COVID-19/diagnosis , Escherichia coli , Humans , Microfluidics , Molecular Diagnostic Techniques , Nucleic Acid Amplification Techniques , SARS-CoV-2/genetics
2.
Artif Organs ; 46(7): 1227-1239, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1853611

ABSTRACT

The increasing prevalence of chronic lung disease worldwide, combined with the emergence of multiple pandemics arising from respiratory viruses over the past century, highlights the need for safer and efficacious means for providing artificial lung support. Mechanical ventilation is currently used for the vast majority of patients suffering from acute and chronic lung failure, but risks further injury or infection to the patient's already compromised lung function. Extracorporeal membrane oxygenation (ECMO) has emerged as a means of providing direct gas exchange with the blood, but limited access to the technology and the complexity of the blood circuit have prevented the broader expansion of its use. A promising avenue toward simplifying and minimizing complications arising from the blood circuit, microfluidics-based artificial organ support, has emerged over the past decade as an opportunity to overcome many of the fundamental limitations of the current standard for ECMO cartridges, hollow fiber membrane oxygenators. The power of microfluidics technology for this application stems from its ability to recapitulate key aspects of physiological microcirculation, including the small dimensions of blood vessel structures and gas transfer membranes. An even greater advantage of microfluidics, the ability to configure blood flow patterns that mimic the smooth, branching nature of vascular networks, holds the potential to reduce the incidence of clotting and bleeding and to minimize reliance on anticoagulants. Here, we summarize recent progress and address future directions and goals for this potentially transformative approach to artificial lung support.


Subject(s)
Artificial Organs , Extracorporeal Membrane Oxygenation , Extracorporeal Membrane Oxygenation/adverse effects , Extracorporeal Membrane Oxygenation/methods , Humans , Lung , Microfluidics , Respiration, Artificial
3.
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
4.
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
5.
Lab Chip ; 22(12): 2307-2314, 2022 Jun 14.
Article in English | MEDLINE | ID: covidwho-1805674

ABSTRACT

The global COVID-19 pandemic caused by SARS-CoV-2 has resulted in an unprecedented economic and societal impact. Developing simple and accurate testing methods for point-of-care (POC) diagnosis is crucial not only for the control of COVID-19, but also for better response to similar outbreaks in the future. In this work, we present a novel proof-of-concept of a microfluidic microwave sensing method for POC diagnosis of the SARS-CoV-2 virus. This method relies on the antibody immobilized on the microwave sensor to selectively capture and concentrate the SARS-CoV-2 antigen or virus present in a buffer solution flowing through the sensor region in a microchannel. The capturing of the SARS-CoV-2 antigen or virus results in a change in the permittivity of the medium near the sensor region reflected by the resonance frequency shift which is used for detection. The use of microchannels offers precise control of the sample volume and the continuous flow nature also offers the potential to monitor the dynamic capturing process. The microwave-microfluidic device shows a good sensitivity of 0.1 ng ml-1 for the SARS-CoV-2 antigen and 4000 copies per ml for the SARS-CoV-2 virus. The resonance frequency shift presents a linear relationship with the logarithm of antigen or virus concentration, respectively. This detection method is able to distinguish SARS-CoV-2 from the antigen of human CD4 and two human coronaviruses (MERS and HKU1), which presents a new pathway towards POC diagnosis of the COVID-19 at the community level. It presents the potential to detect other viruses by functionalizing the microwave sensor with respective antibodies.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnosis , Humans , Indicators and Reagents , Microfluidics , Microwaves , Pandemics
6.
Lab Chip ; 22(8): 1469-1473, 2022 04 12.
Article in English | MEDLINE | ID: covidwho-1805673

ABSTRACT

The COVID-19 pandemic has proven the need for point-of-care diagnosis of respiratory diseases and microfluidic technology has risen to the occasion. Mesa Biotech (San Diego, CA) originally developed the Accula platform for the diagnosis of influenza A and B and then extended the platform to SARS-CoV-2. Mesa Biotech has experienced tremendous success, culminating in acquisition by Thermo Fisher for up to $550m USD. The Accula microfluidics platform accomplished the leap from the lab to commercial product through clever design and engineering choices. Through information obtained from interviews with key Mesa Biotech leaders and publicly-available documents, we describe the keys to Mesa's success and how they might inform other lab-on-a-chip companies.


Subject(s)
COVID-19 , Pandemics , Biotechnology , COVID-19/diagnosis , Humans , Microfluidics , SARS-CoV-2
7.
Lab Chip ; 22(9): 1690-1701, 2022 05 03.
Article in English | MEDLINE | ID: covidwho-1795646

ABSTRACT

Despite their rarity in peripheral blood, basophils play important roles in allergic disorders and other diseases including sepsis and COVID-19. Existing basophil isolation methods require many manual steps and suffer from significant variability in purity and recovery. We report an integrated basophil isolation device (i-BID) in microfluidics for negative immunomagnetic selection of basophils directly from 100 µL of whole blood within 10 minutes. We use a simulation-driven pipeline to design a magnetic separation module to apply an exponentially increasing magnetic force to capture magnetically tagged non-basophils flowing through a microtubing sandwiched between magnetic flux concentrators sweeping across a Halbach array. The exponential profile captures non-basophils effectively while preventing their excessive initial buildup causing clogging. The i-BID isolates basophils with a mean purity of 93.9% ± 3.6% and recovery of 95.6% ± 3.4% without causing basophil degradation or unintentional activation. Our i-BID has the potential to enable basophil-based point-of-care diagnostics such as rapid allergy assessment.


Subject(s)
COVID-19 , Hypersensitivity , Basophils , Humans , Hypersensitivity/diagnosis , Leukocyte Count , Microfluidics
8.
Sheng Wu Gong Cheng Xue Bao ; 38(3): 943-960, 2022 Mar 25.
Article in Chinese | MEDLINE | ID: covidwho-1771822

ABSTRACT

Polymerase chain reaction (PCR) is the gold standard for nucleic acid amplification in molecular diagnostics. The PCR includes multiple reaction stages (denaturation, annealing, and extension), and a complicated thermalcycler is required to repetitively provide different temperatures for different stages for 30-40 cycles within at least 1-2 hours. Due to the complicated devices and the long amplification time, it is difficult to adopt conventional PCR in point-of-care testing (POCT). Comparing to conventional PCR, isothermal amplification is able to provide a much faster and more convenient nucleic acid detection because of highly efficient amplification at a constant reaction temperature provided by a simple heating device. When isothermal amplification is combined with microfluidics, a more competent platform for POCT can be established. For example, various diagnosis devices based on isothermal amplification have been used to rapidly and conveniently detect SARS-CoV-2 viruses. This review summarized the recent development and applications of the microfluidics-based isothermal amplification. First, different typical isothermal amplification methods and related detection methods have been introduced. Subsequently, different types of microfluidic systems with isothermal amplification were discussed based on their characteristics, for example, functionality, system structure, flow control, and operation principles. Furthermore, detection of pathogens (e.g. SARS-CoV-2 viruses) based on isothermal amplification was introduced. Finally, the combination of isothermal amplification with other new technologies, e.g. CRISPR, has been introduced as well.


Subject(s)
COVID-19 , Microfluidics , COVID-19/diagnosis , Humans , Nucleic Acid Amplification Techniques , Polymerase Chain Reaction , SARS-CoV-2/genetics
9.
ACS Infect Dis ; 8(4): 790-799, 2022 04 08.
Article in English | MEDLINE | ID: covidwho-1768765

ABSTRACT

Recent efforts in understanding the course and severity of SARS-CoV-2 infections have highlighted both potentially beneficial and detrimental effects of cross-reactive antibodies derived from memory immunity. Specifically, due to a significant degree of sequence similarity between SARS-CoV-2 and other members of the coronavirus family, memory B-cells that emerged from previous infections with endemic human coronaviruses (HCoVs) could be reactivated upon encountering the newly emerged SARS-CoV-2, thus prompting the production of cross-reactive antibodies. Determining the affinity and concentration of these potentially cross-reactive antibodies to the new SARS-CoV-2 antigens is therefore particularly important when assessing both existing immunity against common HCoVs and adverse effects like antibody-dependent enhancement (ADE) in COVID-19. However, these two fundamental parameters cannot easily be disentangled by surface-based assays like enzyme-linked immunosorbent assays (ELISAs), which are routinely used to assess cross-reactivity. Here, we have used microfluidic antibody affinity profiling (MAAP) to quantitatively evaluate the humoral immune response in COVID-19 convalescent patients by determining both antibody affinity and concentration against spike antigens of SARS-CoV-2 directly in nine convalescent COVID-19 patient and three pre-pandemic sera that were seropositive for common HCoVs. All 12 sera contained low concentrations of high-affinity antibodies against spike antigens of HCoV-NL63 and HCoV-HKU1, indicative of past exposure to these pathogens, while the affinity against the SARS-CoV-2 spike protein was lower. These results suggest that cross-reactivity as a consequence of memory reactivation upon an acute SARS-CoV-2 infection may not be a significant factor in generating immunity against SARS-CoV-2.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Antibody Affinity , Humans , Microfluidics , Spike Glycoprotein, Coronavirus
10.
Chemistry ; 28(18): e202104054, 2022 Mar 28.
Article in English | MEDLINE | ID: covidwho-1767322

ABSTRACT

The ongoing outbreak of the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has spread globally and poses a threat to public health and National economic development. Rapid and high-throughput SARS-CoV-2 RNA detection without the need of RNA extraction and amplification remain a key challenge. In this study, a new SARS-CoV-2 RNA detection strategy using a microfluidic biochip for the rapid and ultrasensitive detection of SARS-CoV-2 without RNA extraction and amplification was developed. This new strategy takes advantage of the specific SARS-CoV-2 RNA and probe DNA reaction in the microfluidic channel, fluorescence signal regulation by nanomaterials, and accurate sample control by the microfluidic chip. It presents an ultralow limit of detection of 600 copies mL-1 in a large linear detection regime from 1 aM to 100 fM. Fifteen samples were simultaneously detected in 40 min without the need for RNA purification and amplification. The detection accuracy of the strategy was validated through quantitative reverse transcription polymerase chain reaction (qRT-PCR), with a recovery of 99-113 %. Therefore, the SARS-CoV-2 RNA detection strategy proposed in this study can potentially be used for the quantitative diagnosis of viral infectious diseases.


Subject(s)
COVID-19 Testing , COVID-19 , Microfluidics , SARS-CoV-2 , COVID-19/diagnosis , COVID-19 Testing/methods , Humans , Nucleic Acid Amplification Techniques , RNA, Viral/genetics , SARS-CoV-2/genetics , Sensitivity and Specificity
11.
Adv Drug Deliv Rev ; 184: 114197, 2022 05.
Article in English | MEDLINE | ID: covidwho-1763526

ABSTRACT

Gene therapy has emerged as a potential platform for treating several dreaded and rare diseases that would not have been possible with traditional therapies. Viral vectors have been widely explored as a key platform for gene therapy due to their ability to efficiently transport nucleic acid-based therapeutics into the cells. However, the lack of precision in their delivery has led to several off-target toxicities. As such, various strategies in the form of non-viral gene delivery vehicles have been explored and are currenlty employed in several therapies including the SARS-CoV-2 vaccine. In this review, we discuss the opportunities lipid nanoparticles (LNPs) present for efficient gene delivery. We also discuss various synthesis strategies via microfluidics for high throughput fabrication of non-viral gene delivery vehicles. We conclude with the recent applications and clinical trials of these vehicles for the delivery of different genetic materials such as CRISPR editors and RNA for different medical conditions ranging from cancer to rare diseases.


Subject(s)
COVID-19 , Nanoparticles , Nucleic Acids , COVID-19 Vaccines , Humans , Lipids , Liposomes , Microfluidics , Rare Diseases , SARS-CoV-2
12.
Biosensors (Basel) ; 12(3)2022 Mar 17.
Article in English | MEDLINE | ID: covidwho-1753435

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the ongoing COVID-19 (coronavirus disease-2019) outbreak and has unprecedentedly impacted the public health and economic sector. The pandemic has forced researchers to focus on the accurate and early detection of SARS-CoV-2, developing novel diagnostic tests. Among these, microfluidic-based tests stand out for their multiple benefits, such as their portability, low cost, and minimal reagents used. This review discusses the different microfluidic platforms applied in detecting SARS-CoV-2 and seroprevalence, classified into three sections according to the molecules to be detected, i.e., (1) nucleic acid, (2) antigens, and (3) anti-SARS-CoV-2 antibodies. Moreover, commercially available alternatives based on microfluidic platforms are described. Timely and accurate results allow healthcare professionals to perform efficient treatments and make appropriate decisions for infection control; therefore, novel developments that integrate microfluidic technology may provide solutions in the form of massive diagnostics to control the spread of infectious diseases.


Subject(s)
Biosensing Techniques/methods , COVID-19/diagnosis , Microfluidics , SARS-CoV-2/isolation & purification , Antibodies, Viral/blood , COVID-19/epidemiology , Humans , Point-of-Care Systems , Point-of-Care Testing , SARS-CoV-2/immunology , Seroepidemiologic Studies
13.
Biosens Bioelectron ; 207: 114192, 2022 Jul 01.
Article in English | MEDLINE | ID: covidwho-1739563

ABSTRACT

Respiratory viruses, especially coronaviruses, have resulted in worldwide pandemics in the past couple of decades. Saliva-based paper microfluidic assays represent an opportunity for noninvasive and rapid screening, yet both the sample matrix and test method come with unique challenges. In this work, we demonstrated the rapid and sensitive detection of SARS-CoV-2 from saliva samples, which could be simpler and more comfortable for patients than existing methods. Furthermore, we systematically investigated the components of saliva samples that affected assay performance. Using only a smartphone, an antibody-conjugated particle suspension, and a paper microfluidic chip, we made the assay user-friendly with minimal processing. Unlike the previously established flow rate assays that depended solely on the flow rate or distance, this unique assay analyzes the flow profile to determine infection status. Particle-target immunoagglutination changed the surface tension and subsequently the capillary flow velocity profile. A smartphone camera automatically measured the flow profile using a Python script, which was not affected by ambient light variations. The limit of detection (LOD) was 1 fg/µL SARS-CoV-2 from 1% saliva samples and 10 fg/µL from simulated saline gargle samples (15% saliva and 0.9% saline). This method was highly specific as demonstrated using influenza A/H1N1. The sample-to-answer assay time was <15 min, including <1-min capillary flow time. The overall accuracy was 89% with relatively clean clinical saline gargle samples. Despite some limitations with turbid clinical samples, this method presents a potential solution for rapid mass testing techniques during any infectious disease outbreak as soon as the antibodies become available.


Subject(s)
Biosensing Techniques , COVID-19 , Influenza A Virus, H1N1 Subtype , COVID-19/diagnosis , Humans , Microfluidics , SARS-CoV-2 , Smartphone
14.
Lab Chip ; 22(7): 1297-1309, 2022 03 29.
Article in English | MEDLINE | ID: covidwho-1730327

ABSTRACT

Since the beginning of the COVID-19 pandemic, several mutations of the SARS-CoV-2 virus have emerged. Current gold standard detection methods for detecting the virus and its variants are based on PCR-based diagnostics using complex laboratory protocols and time-consuming steps, such as RNA isolation and purification, and thermal cycling. These steps limit the translation of technology to the point-of-care and limit accessibility to under-resourced regions. While PCR-based assays currently offer the possibility of multiplexed gene detection, and commercial products of single gene PCR and isothermal LAMP at point-of-care are also now available, reports of isothermal assays at the point-of-care with detection of multiple genes are lacking. Here, we present a microfluidic assay and device to detect and differentiate the Alpha variant (B.1.1.7) from the SARS-CoV-2 virus early strains in saliva samples. The detection assay, which is based on isothermal RT-LAMP amplification, takes advantage of the S-gene target failure (SGTF) to differentiate the Alpha variant from the SARS-CoV-2 virus early strains using a binary detection system based on spatial separation of the primers specific to the N- and S-genes. We use additively manufactured plastic cartridges in a low-cost optical reader system to successfully detect the SARS-CoV-2 virus from saliva samples (positive amplification is detected with concentration ≥10 copies per µL) within 30 min. We demonstrate that our platform can discriminate the B.1.1.7 variant (USA/CA_CDC_5574/2020 isolate) from SARS-CoV-2 negative samples, but also from the SARS-CoV-2 USA-WA1/2020 isolate. The reliability of the developed point-of-care device was confirmed by testing 38 clinical saliva samples, including 20 samples positive for Alpha variant (sensitivity > 90%, specificity = 100%). This study highlights the current relevance of binary-based testing, as the new Omicron variant also exhibits S-gene target failure and could be tested by adapting the approach presented here.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnosis , Humans , Microfluidics , Molecular Diagnostic Techniques/methods , Nucleic Acid Amplification Techniques/methods , Pandemics , Point-of-Care Systems , RNA, Viral/analysis , RNA, Viral/genetics , Reproducibility of Results , SARS-CoV-2/genetics , Sensitivity and Specificity
15.
ACS Sens ; 7(3): 884-892, 2022 03 25.
Article in English | MEDLINE | ID: covidwho-1721394

ABSTRACT

Microfluidic paper-based analytical devices (µPADs) have experienced an unprecedented story of success. In particular, as of today, most people have likely come into contact with one of their two most famous examples─the pregnancy or the SARS-CoV-2 antigen test. However, their sensing performance is constrained by the optical readout of nanoparticle agglomeration, which typically allows only qualitative measurements. In contrast, single-impact electrochemistry offers the possibility to quantify species concentrations beyond the pM range by resolving collisions of individual species on a microelectrode. Within this work, we investigate the integration of stochastic sensing into a µPAD design by combining a wax-patterned microchannel with a microelectrode array to detect silver nanoparticles (AgNPs) by their oxidative dissolution. In doing so, we demonstrate the possibility to resolve individual nanoparticle collisions in a reference-on-chip configuration. To simulate a lateral flow architecture, we flush previously dried AgNPs along a microchannel toward the electrode array, where we are able to record nanoparticle impacts. Consequently, single-impact electrochemistry poses a promising candidate to extend the limits of lateral flow-based sensors beyond current applications toward a fast and reliable detection of very dilute species on site.


Subject(s)
COVID-19 , Metal Nanoparticles , Electrochemistry , Female , Humans , Microelectrodes , Microfluidics , Pregnancy , SARS-CoV-2 , Silver
16.
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
17.
IEEE Trans Biomed Circuits Syst ; 15(6): 1250-1267, 2021 12.
Article in English | MEDLINE | ID: covidwho-1699141

ABSTRACT

The importance of point-of-care (POC) bio-molecular diagnostics capable of rapid analysis has become abundantly evident after the outbreak of the Covid-19 pandemic. While sensing interfaces for both protein and nucleic-acid based assays have been demonstrated with chip-scale systems, sample preparation in compact form factor has often been a major bottleneck in enabling end-to-end POC diagnostics. Miniaturization of an end-to-end system requires addressing the front-end sample processing, without which, the goal for low-cost POC diagnostics remain elusive. In this paper, we address bulk fluid processing with AC-osmotic based electrokinetic fluid flows that can be fully controlled, processed and automated by CMOS ICs, fabricated in TSMC 65 nm LP process. Here, we combine bulk fluid flow control with bio-molecular sensing, cell manipulation, cytometry, and separation-all of which are controlled with silicon chips for an all-in-one bio-sensing device. We show CMOS controlled pneumatic-free bulk fluid flow with fluid velocities reaching up to 160 µm/s within a microfluidic channel of 100 × 50 µm 2 of cross-sectional area. We incorporate electrode arrays to allow precise control and focused cell flows ( ±2 µm precision) for robust cytometry, and for subsequent separation. We also incorporate a 16-element impedance spectroscopy receiver array for cell and label-free protein sensing. The massive scalability of CMOS-driven microfluidics, manipulation, and sensing can lead to a new design space and a new class of miniaturized sensing technologies.


Subject(s)
COVID-19 , Microfluidics , Humans , Pandemics , Point-of-Care Systems , SARS-CoV-2
18.
J Control Release ; 344: 80-96, 2022 04.
Article in English | MEDLINE | ID: covidwho-1693301

ABSTRACT

In 2021, mRNA vaccines against COVID-19 were approved by the Food and Drug Administration. mRNA vaccines are important for preventing severe COVID-19 and returning to normal life. The development of RNA-delivery technology, including mRNA vaccines, has been investigated worldwide for ~30 years. Lipid nanoparticles (LNPs) are a breakthrough technology that stably delivers RNA to target organs, and RNA-loaded LNP-based nanomedicines have been studied for the development of vaccines and nanomedicines for RNA-, gene-, and cell-based therapies. Recently, microfluidic devices and technologies have attracted attention for the production of LNPs, particularly RNA-loaded LNPs. Microfluidics provides many advantages for RNA-loaded LNP production, including precise LNP size controllability, high reproducibility, high-throughput optimization of LNP formulation, and continuous LNP-production processes. In this review, we summarize microfluidic-based RNA-loaded LNP production and its applications in RNA-based therapy and genome editing.


Subject(s)
COVID-19 , Nanoparticles , COVID-19 Vaccines , Humans , Lipids , Liposomes , Microfluidics , RNA, Small Interfering/genetics , Reproducibility of Results
19.
Biofabrication ; 14(2)2022 02 14.
Article in English | MEDLINE | ID: covidwho-1684463

ABSTRACT

The COVID-19 pandemic has highlighted the need for human respiratory tract-based assay platforms for efficient discovery and development of antivirals and disease-modulating therapeutics. Physiologically relevant tissue models of the lower respiratory tract (LRT), including the respiratory bronchioles and the alveolar sacs, are of high interest because they are the primary site of severe SARS-CoV-2 infection and are most affected during the terminal stage of COVID-19. Current epithelial lung models used to study respiratory viral infections include lung epithelial cells at the air-liquid interface (ALI) with fibroblasts and endothelial cells, but such models do not have a perfusable microvascular network to investigate both viral infectivity and viral infection-induced thrombotic events. Using a high throughput, 64-chip microfluidic plate-based platform, we have developed two novel vascularized, LRT multi-chip models for the alveoli and the small airway. Both models include a perfusable microvascular network consisting of human primary microvascular endothelial cells, fibroblasts and pericytes. The established biofabrication protocols also enable the formation of differentiated lung epithelial layers at the ALI on top of the vascularized tissue bed. We validated the physiologically relevant cellular composition, architecture and perfusion of the vascularized lung tissue models using fluorescence microscopy, flow cytometry, and electrical resistance measurements. These vascularized, perfusable microfluidic lung tissue on high throughput assay platforms will enable the development of respiratory viral infection and disease models for research investigation and drug discovery.


Subject(s)
COVID-19 , Microfluidics , Endothelial Cells , Humans , Microvessels , Pandemics , Pericytes , SARS-CoV-2
20.
Anal Chem ; 94(7): 3287-3295, 2022 02 22.
Article in English | MEDLINE | ID: covidwho-1683899

ABSTRACT

The diversification of analytical tools for diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is imperative for effective virus surveillance and transmission control worldwide. Development of robust methods for rapid, simple isolation of viral RNA permits more expedient pathogen detection by downstream real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) to minimize stalled containment and enhance treatment efforts. Here, we describe an automatable rotationally driven microfluidic platform for enrichment and enzymatic extraction of SARS-CoV-2 RNA from multiple sample types. The multiplexed, enclosed microfluidic centrifugal device (µCD) is capable of preparing amplification-ready RNA from up to six samples in under 15 min, minimizing user intervention and limiting analyst exposure to pathogens. Sample enrichment leverages Nanotrap Magnetic Virus Particles to isolate intact SARS-CoV-2 virions from nasopharyngeal and/or saliva samples, enabling the removal of complex matrices that inhibit downstream RNA amplification and detection. Subsequently, viral capsids are lysed using an enzymatic lysis cocktail for release of pathogenic nucleic acids into a PCR-compatible buffer, obviating the need for downstream purification. Early in-tube assay characterization demonstrated comparable performance between our technique and a "gold-standard" commercial RNA extraction and purification kit. RNA obtained using the fully integrated µCDs permitted reliable SARS-CoV-2 detection by real-time RT-PCR. Notably, we successfully analyzed full-process controls, positive clinical nasopharyngeal swabs suspended in viral transport media, and spiked saliva samples, showcasing the method's broad applicability with multiple sample matrices commonly encountered in clinical diagnostics.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Microfluidics , Nasopharynx/chemistry , RNA, Viral/analysis , RNA, Viral/genetics , Sensitivity and Specificity
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