Impedance-Based Neutralizing Antibody Detection Biosensor with Application in SARS-CoV-2 Infection.

Although safe and efficacious coronavirus disease-2019 (COVID-19) vaccines are available, real protective immunity is revealed by the serum COVID-19 neutralizing antibody (NAb) concentration. NAbs deactivate the virus by attaching to the viral receptor-binding domain (RBD), which interacts with angiotensin-converting enzyme 2 (ACE2) on the human cell. This paper introduces inexpensive, rapid, sensitive, and quantifiable impedance-based immunosensors to evaluate the NAb. The sensor limit of detection is experimentally determined in different buffer dilutions using bovine IgG-anti-bovine IgG interaction. The dominance of AC electrokinetic transport and molecular diffusion in the sensor is investigated using scaling analysis and numerical simulations. The results demonstrated that the sensor detection mechanism is mainly based on the diffusion of the biomolecules onto the electrode surface. After evaluating the sensor working principles, viral RBD buffers, including different NAb concentrations, are applied to the sensor, immobilized with the human ACE2 (hACE2). Results demonstrate that the sensor is capable of NAb detection in the analytical measuring interval between 45 ng/mL and 185 ng/mL. Since the present sensor provides fast test results with lower costs, it can be used to assess the NAb in people's blood serum before receiving further COVID vaccine doses.

A Microfluidic Dielectric Spectroscopy System for Characterization of Biological Cells in Physiological Media.

Dielectric spectroscopy (DS) is a promising cell screening method that can be used for diagnostic and drug discovery purposes. The primary challenge of using DS in physiological buffers is the electrode polarization (EP) that overwhelms the impedance signal within a large frequency range. These effects further amplify with the miniaturization of the measurement electrodes. In this study, we present a microfluidic system and the associated equivalent circuit models for real-time measurements of cell membrane capacitance and cytoplasm resistance in physiological buffers with 10 s increments. The current device captures several hundreds of biological cells in individual microwells through gravitational settling and measures the system's impedance using microelectrodes covered with dendritic gold nanostructures. Using PC-3 cells (a highly metastatic prostate cancer cell line) suspended in cell growth media (CGM), we demonstrate stable measurements of cell membrane capacitance and cytoplasm resistance in the device for over 15 min. We also describe a consistent application of the equivalent circuit model, starting from the reference measurements used to determine the system parameters. The circuit model is tested using devices with varying dimensions, and the obtained cell parameters between different devices are nearly identical. Further analyses of the impedance data have shown that accurate cell membrane capacitance and cytoplasm resistance can be extracted using a limited number of measurements in the 5 MHz to 10 MHz range. This will potentially reduce the timescale required for real-time DS measurements below 1 s. Overall, the new microfluidic device can be used for the dielectric characterization of biological cells in physiological buffers for various cell screening applications.

Manipulation of micro- and nanoparticles in viscoelastic fluid flows within microfluid systems.

Manipulation of micro- and nanoparticles in complex biofluids is highly demanded in most biological and biomedical applications. A significant number of microfluidic platforms have been developed for inexpensive, rapid, accurate, and efficient particle manipulation. Due to the enormous potential of viscoelastic fluids (VEFs) for particle manipulation, various emerging microfluidic-based VEFs techniques have been presented over the last decade. This review provides an intuitive understanding of VEF physics for particle separation in different microchannel geometries. Besides, active and passive VEF methods are critically reviewed, highlighting the potential and practical challenges of each technique for particle/cell focusing, sorting, and separation. The outcome of this study could enable recognizing deliverable VEF technology with the promising prospect in the manipulation of submicron biological samples (e.g., exosomes, DNA, and proteins).

Changes in Electrical Capacitance of Cell Membrane Reflect Drug Partitioning-Induced Alterations in Lipid Bilayer.

The plasma membrane is a lipid bilayer that establishes the outer boundary of a living cell. The composition of the lipid bilayer influences the membrane's biophysical properties, including fluidity, thickness, permeability, phase behavior, charge, elasticity, and formation of flat sheet or curved structures. Changes in the biophysical properties of the membrane can be occasioned when new entities, such as drug molecules, are partitioned in the bilayer. Therefore, assessing drugs for their effect on the biophysical properties of the lipid bilayer of a cell membrane is critical to understanding specific and non-specific drug action. Previously, we reported a non-invasive technique for real-time characterization of cellular dielectric properties, such as membrane capacitance and cytoplasmic conductivity. In this study, we discuss the potential application of the technique in assessing the biophysical properties of the cell membrane in response to interaction with amiodarone compared to aspirin/acetylsalicylic acid and glucose. Amiodarone is a potent drug used to treat cardiac arrhythmia, but it also exerts various non-specific effects. Compared to aspirin and glucose, we measured a rapid and higher magnitude increase in membrane capacitance on cells under amiodarone treatment. Increased membrane capacitance induced by aspirin and glucose quickly returned to baseline in 15 s, while amiodarone-induced increased capacitance sustained and decreased slowly, approaching baseline or another asymptotic limit in ~2.5 h. Because amiodarone has a strong lipid partitioning property, we reason that drug partitioning alters the lipid bilayer context and subsequently reduces bilayer thickness, leading to an increase in the electrical capacitance of the cell membrane. The presented microfluidic system promises a new approach to assess drug-membrane interactions and delineate specific and non-specific actions of the drug on cells.

Separation of bacteria smaller than 4 µm from other blood components using insulator-based dielectrophoresis: numerical simulation approach.

Bloodstream infection (BSI) is a life-threatening infection that causes more than 80,000 deaths and more than 500,000 infections annually in North America. The rapid diagnosis of infection reduces BSI mortality. We proposed bacterial enrichment and separation approach in the current work that may reduce culturing time and accelerate the diagnosis of infection. Over the last two decades, multiple separation methods have been developed, and among these methods, insulator-based dielectrophoresis (iDEP) is considered a powerful technique for separating biological particles. Bacterial separation in the blood is challenging due to the presence of other blood cells, such as white blood cells, red blood cells, and platelets. In the present study, a model is presented which is capable of blood cells separation and directing each cell to a specific outlet using continuous flows of particles with sizes larger than 8 µm, 8-4 µm, and smaller than 4 µm. Compared to other methods, such as filtration, the main advantage of this model is that particles larger than 8 µm are separated from the flow before other particles, which prevents the accumulation of particles in the channel. The outcomes of simulations demonstrated that the factors such as applied voltage and channel dimensions significantly affect the separation efficiency. If these values are properly selected (for example voltage of 70 V that was causing an electric field of 200 V/cm), the proposed model can completely (100%) separate particles larger than 8 µm and smaller than 4 µm (8-4 µm particles separation efficiency is 95%).

A Novel Electrokinetic-Based Technique for the Isolation of Circulating Tumor Cells.

The separation of rare cells from complex biofluids has attracted attention in biological research and clinical applications, especially for cancer detection and treatment. In particular, various technologies and methods have been developed for the isolation of circulating tumor cells (CTCs) in the blood. Among them, the induced-charge electrokinetic (ICEK) flow method has shown its high efficacy for cell manipulation where micro-vortices (MVs), generated as a result of induced charges on a polarizable surface, can effectively manipulate particles and cells in complex fluids. While the majority of MVs have been induced by AC electric fields, these vortices have also been observed under a DC electric field generated around a polarizable hurdle. In the present numerical work, the capability of MVs for the manipulation of CTCs and their entrapment in the DC electric field is investigated. First, the numerical results are verified against the available data in the literature. Then, various hurdle geometries are employed to find the most effective geometry for MV-based particle entrapment. The effects of electric field strength (EFS), wall zeta potential magnitude, and the particles' diameter on the trapping efficacy are further investigated. The results demonstrated that the MVs generated around only the rectangular hurdle are capable of trapping particles as large as the size of CTCs. An EFS of about 75 V/cm was shown to be effective for the entrapment of above 90% of CTCs in the MVs. In addition, an EFS of 85 V/cm demonstrated a capability for isolating particles larger than 8 µm from a suspension of particles/cells 1-25 µm in diameter, useful for the enrichment of cancer cells and potentially for the real-time and non-invasive monitoring of drug effectiveness on circulating cancer cells in blood circulation.

Magnetic particle targeting for diagnosis and therapy of lung cancers.

Over the past decade, the growing interest in targeted lung cancer therapy has guided researchers toward the cutting edge of controlled drug delivery, particularly magnetic particle targeting. Targeting of tissues by magnetic particles has tackled several limitations of traditional drug delivery methods for both cancer detection (e.g., using magnetic resonance imaging) and therapy. Delivery of magnetic particles offers the key advantage of high efficiency in the local deposition of drugs in the target tissue with the least harmful effect on other healthy tissues. This review first overviews clinical aspects of lung morphology and pathogenesis as well as clinical features of lung cancer. It is followed by reviewing the advances in using magnetic particles for diagnosis and therapy of lung cancers: (i) a combination of magnetic particle targeting with MRI imaging for diagnosis and screening of lung cancers, (ii) magnetic drug targeting (MDT) through either intravenous injection and pulmonary delivery for lung cancer therapy, and (iii) computational simulations that models new and effective approaches for magnetic particle drug delivery to the lung, all supporting improved lung cancer treatment. The review further discusses future opportunities to improve the clinical performance of MDT for diagnosis and treatment of lung cancer and highlights clinical therapy application of the MDT as a new horizon to cure with minimal side effects a wide variety of lung diseases and possibly other acute respiratory syndromes (COVID-19, MERS, and SARS).

Mathematical and computational modeling of nano-engineered drug delivery systems.

While the advent of nano-engineered drug delivery systems (DDSs) has revived hopes for better management of a wide range of pathologies, critical appraisal of the field has shown that further improvement of nanomedicine demands a paradigmatic shift in design and development approaches currently employed by drug developers. In this review, we portray various theoretical modeling frameworks as influential tools to furnish future design and development of DDSs. The rational design of nanomedicines should be premised on taking into account the sui generis nature of DDSs within a multiplex biological milieu in vivo. Technical limitations, however, remain a bottleneck to the faithful reconstruction of such biomimetic models. Computational and mathematical modeling tools have shown potential as a promising technique to broaden the horizon of nanomedicine by addressing blind spots of current empirical models. Through integration with modern imaging and microfluidic technologies, in silico modeling is expected to expedite the clinical translation of nanomedicine.

Magnetic aerosol drug targeting in lung cancer therapy using permanent magnet.

Primary bronchial cancer accounts for almost 20% of all cancer death worldwide. One of the emerging techniques with tremendous power for lung cancer therapy is magnetic aerosol drug targeting (MADT). The use of a permanent magnet for effective drug delivery in a desired location throughout the lung requires extensive optimization, but it has not been addressed yet. In the present study, the possibility of using a permanent magnet for trapping the particles on a lung tumor is evaluated numerically in the Weibel's model from G0 to G3. The effect of different parameters is considered on the efficiency of particle deposition in a tumor located on a distant position of the lung bronchi and bronchioles. Also, the effective position of the magnetic source, tumor size, and location are the objectives for particle deposition. The results show that a limited particle deposition occurs on the lung branches in passive targeting. However, the incorporation of a permanent magnet next to the tumor enhanced the particle deposition fraction on G2 to up to 49% for the particles of 7 µm diameter. Optimizing the magnet size could also improve the particle deposition fraction by 68%. It was also shown that the utilization of MADT is essential for effective drug delivery to the tumors located on the lower wall of airway branches given the dominance of the air velocity and resultant drag force in this region. The results demonstrated the high competence and necessity of MADT as a noninvasive drug delivery method for lung cancer therapy.

Delivery of magnetic micro/nanoparticles and magnetic-based drug/cargo into arterial flow for targeted therapy.

Magnetic drug targeting (MDT) and magnetic-based drug/cargo delivery are emerging treatment methods which attracting the attention of many researchers for curing different cancers and artery diseases such as atherosclerosis. Herein, computational studies are accomplished by utilizing magnetic approaches for cancer and artery atherosclerosis drug delivery, including nanomagnetic drug delivery and magnetic-based drug/cargo delivery. For the first time, the four-layer structural model of the artery tissue and its porosity parameters are modeled in this study which enables the interaction of particles with the tissue walls in blood flow. The effects of parameters, including magnetic field strength (MFS), magnet size, particle size, the initial position of particles, and the relative magnetic permeability of particles, on the efficacy of MDT through the artery walls are characterized. The magnetic particle penetration into artery layers and fibrous cap (the covering layer over the inflamed part of the artery) is further simulated. The MDT in healthy and diseased arteries demonstrates that some of the particles stuck in these tissues due to the collision of particles or blood flow deviation in the vicinity of the inflamed part of the artery. Therefore the geometry of artery and porosity of its layers should be considered to show the real interaction of particles with the artery walls. Also, the results show that increasing the particles/drug/cargo size and MFS leads to more particles/drug/cargo retention within the tissue. The present work provides insights into the decisive factors in arterial MDT with an obvious impact on locoregional cancer treatment, tissue engineering, and regenerative medicine.