Human Lung Non-Invasive Anomaly Detection through UWB Microwave Imaging and Diagnosis of COVID-19: A Possible Application

This study shows a prototype for detecting lung effects using microwave imaging. Continuous monitoring of pulmonary fluid levels is one of the most successful approaches for detecting fluid in the lung;early Chest X-rays, computational tomography (CT)-scans, and magnetic resonance imaging (MRI) are the most commonly used instruments for fluid detection. Nonetheless, they lack sensitivity to ionizing radiation and are inaccessible to the general public. This research focuses on the development of a low-cost, portable, and noninvasive device for detecting Covid-19 or lung damage. The simulation of the system involved the antenna design, a 3D model of the human lung, the building of a COMSOL model, and image processing to estimate the lung damage percentage. The simulation consisted of three components. The primary element requires mode switching for four array antennas (transmit and receive). In the paper, microwave tomography was used. Using microwave near-field imaging, the second component of the simulation analyses the lung's bioheat and electromagnetic waves as well as examines the image creation under various conditions;many electromagnetic factors seen at the receiving device are investigated. The final phase of the simulation shows the affected area of the lung phantom and the extent of the damage. © 2023 IEEE.

Pre-Trained Xception Model-based COVID Detection using CXR Images

Providing the essential medical resources for COVID-19 diagnosis is a challenge on a worldwide scale. They should be cutting-edge tools that can rapidly identify and analyze the virus using a sequence of tests, and it should also be reasonably priced. A chest X-ray scan is an excellent screening tool, but if several exams are taken, the images produced by the devices must be reviewed swiftly and accurately. Predicting the progression of COVID-19-induced longitudinal lung parenchymal ground glass and the resulting consolidation of pulmonary opacity is highly challenging. Sometimes, COVID-19 will cause pulmonary opacity to consolidate, giving it a rounded appearance and a distribution on the periphery of the lungs. This study introduces the Xception model for predicting COVID-19 in chest x-rays. Chest x-rays may predict the presence of Covid-19 with an accuracy of around 97.83%. © 2022 IEEE

Lung-on-chip: Its current and future perspective on pharmaceutical and biomedical applications

Organ-on-a-chip is a three-dimensional microfluidic system that simulates the cellular structure and biological milieu of an organ, that seemed to be constructed and studied substantially in the last decade. Microchips can be configured to suit disease states in a variety of organs, including the lung. When contrasted to traditional in vitro models like monolayer cell lineages, lung-on-a-chip models lays out a pragmatic portrayal of disease pathophysiology and pharmaceuticals' mode of action, and this is especially more prevailing in connection with the COVID-19 pandemic. Animal models have typically been used in pharmaceutical drug screening to assess pharmacological and toxicological reactions to a new entity. These adaptations, on the other hand, do not precisely represent biological reactions in humans. Present and prospective uses of the lung-on-a-chip model in the pulmonary system are highlighted in this overview. In addition, the constraints of existing in vitro systems for respiratory disease simulation and therapeutic discovery would be emphasized. Attributes of lung-on-a-chip transformative features in biomedical applications will be addressed to illustrate the relevance of this lung-on-chip model for medical science.Copyright © 2022

Cilgavimab/Tixagevimab as alternative therapeutic approach for BA.2 infections.

Objectives: The identification of the SARS-CoV-2 Omicron variants BA.1 and BA.2 immediately raised concerns about the efficacy of currently used monoclonal antibody therapies. Here, we analyzed the activity of Sotrovimab and Regdanvimab, which are used in clinics for treatment of moderate to severe SARS-CoV-2 infections, and Cilgavimab/Tixagevimab, which are approved for prophylactic use, against BA.1 and BA.2 in a 3D model of primary human bronchial epithelial cells. Methods: Primary human airway epithelia (HAE) cells in a 3D tissue model were infected with clinical isolates of SARS-CoV-2 Delta, BA.1 or BA.2. To mimic the therapeutic use of mAbs, we added Regdanvimab, Sotrovimab or Cilgavimab/Tixagevimab 6 h after infection. In order to mirror the prophylactic use of Cilgavimab/Tixagevimab, we added this compound 6 h prior to infection to the fully differentiated, pseudostratified epithelia cultured in air-liquid interphase (ALI). Results: We observed that Sotrovimab, but not Regdanvimab, is active against BA.1; however, both antibodies lose their efficacy against BA.2. In contrast, we found that BA.2 was sensitive to neutralization by the approved prophylactic administration and the therapeutic use, which is not yet permitted, of Cilgavimab/Tixagevimab. Conclusion: Importantly, while the use of Tixagevimab/Cilgavimab is effective in controlling BA.2 but not BA.1 infection, monoclonal antibodies (mAbs) with efficacy against BA.1 are ineffective to reduce BA.2 virus replication in a human lung model. Our data may have implications on the variant specific clinical use of monoclonal antibodies.

Construction of Human Three-Dimensional Lung Model Using Layer-by-Layer Method.

The respiratory tract is one of the frontline barriers for biological defense. Lung epithelial intercellular adhesions provide protection from bacterial and viral infections and prevent invasion into deep tissues by pathogens. Dysfunction of lung epithelial intercellular adhesion caused by pathogens is associated with development of several diseases, such as acute respiratory distress syndrome, pneumonia, and asthma. To elucidate the pathological mechanism of respiratory infections, two-dimensional cell cultures and animal models are commonly used, although are not useful for evaluating host specificity or human biological response. With the rapid progression and worldwide spread of severe acute respiratory syndrome coronavirus-2, there is increasing interest in the development of a three-dimensional (3D) in vitro lung model for analyzing interactions between pathogens and hosts. However, some models possess unclear epithelial polarity or insufficient barrier functions and need the use of complex technologies, have high cost, and long cultivation terms. We previously reported about the fabrication of 3D cellular multilayers using a layer-by-layer (LbL) cell coating technique with extracellular matrix protein, fibronectin (FN), and gelatin (G). In the present study, such a LbL cell coating technique was utilized to construct a human 3D lung model in which a monolayer of the human lower airway epithelial adenocarcinoma cell line Calu-3 cells was placed on 3D-cellular multilayers composed of FN-G-coated human primary pulmonary fibroblast cells. The 3D lung model thus constructed demonstrated an epithelial-fibroblast layer that maintained uniform thickness until 7 days of incubation. Moreover, expressions of E-cadherin, ZO-1, and mucin in the epithelial layer were observed by immunohistochemical staining. Epithelial barrier integrity was evaluated using transepithelial electrical resistance values. The results indicate that the present constructed human 3D lung model is similar to human lung tissues and also features epithelial polarity and a barrier function, thus is considered useful for evaluating infection and pathological mechanisms related to pneumonia and several pathogens. Impact statement A novel in vitro model of lung tissue was established. Using a layer-by-layer cell coating technique, a three-dimensional cultured lung model was constructed. The present novel model was shown to have epithelial polarity and chemical barrier functions. This model may be useful for investigating interaction pathogens and human biology.

Generation Of Macro-scale And Mature Lung Organoids Through Engineering Cell Microenvironment

Purpose/Objectives: <Most used lower respiratory tract models consist of cell monolayers which lack of tissue and organ level response and of in-vivo phenotype. Ex-vivo lung tissues have short viability and limited availability. Lung organoids, which recapitulates better the 3D cellular complex structures, architecture, and in-vivo function, fail to reach maturity even after 85 -185 days of culture. Therefore, these models have a limited use to study fetal lung diseases. Other lung models, consist of only one structure of the lower track, such as bronchial tubes or alveoli, but fail to recapitulate the whole organ structure. In this work, cell microenvironment was used to promote the self-organization of epithelial and mesenchymal cells into macro-structures, aiming to mimic the whole and adult lower respiratory tract model> Methodology: <Different parts of the microenvironment were considered to create a compliant matrix. Alginate-Gelatin hydrogels were used for 3D encapsulation of mesenchymal origin cells. This hydrogel provided a stiffness like the one on the lung. Base membrane zone proteins were used to induce the attachment and guidance of epithelial cells into 3D structures. The interactions between both cell types, further guided them into lung fate. The morphology of resulting organoids was analyzed using immunostaining and confocal microscopy, LSM710, with the purpose of evaluate polarization, protein markers, and different cell populations. Quantitative PCR was performed to evaluate and compare the expression of lung fate genes with traditional cell monocultures.> Results: <The engineered microenvironment and protocol development done in this work resulted in macro-scale structures, in which branching morphogenesis occurred at day 21. Different structures were identified in the organoid including bronchial tube, bronchioles, and alveoli. Polarization of the organoids was confirmed by visualization of E-cadherin, and ZO-1. Expression of Surfactant Protein B and C into the organoids confirmed the presence of alveolar type II cells, which are only present in the later development stage. Surfactant Protein B, Transmembrane protease, serine 2, TMPRSS-2, and Angiotensin-converting enzyme 2, ACE2 were found to be significantly higher expressed into the organoids in comparison with traditional epithelial cells monolayers.> Conclusion/Significance: <Growth factors are normally used to induce the fate of stem cells into lung organoids;however, these fail to reach maturity. Here, we developed a new methodology to induce the formation of the organoids based on the cell microenvironment. The resulting organoids require less time for development. The initial stage of adult cells can be modulated through culture conditions induce a 3D structure like the adult lung. As such, these organoids have the potential to be used for modeling adult diseases and to develop specific models from patient cells, which is one step forward to personalized medicine. SFTPB is one of the main proteins which facilitates the breathing process. Its high expression into our model may indicate that breathing occurs into our lung organoids. The higher expression of TMPRSS-2 and ACE2 into the organoids has a major significance in the field of virology since both proteins are the mainly entrance of SARS-CoV-2, and influenza H1N1.>.

PCL- And Gelatin-based Electrospun Biological Scaffolds For In Vitro Lung Tissue Engineering

Purpose/Objectives: Acute and chronic respiratory diseases constitute a substantial socioeconomic burden on a global scale, as made abundantly clear in the last two years with the rampant coronavirus disease 2019 (COVID-19) pandemic. Alas, the development of new therapies for pathological respiratory conditions has been hindered by the inadequacy of current preclinical models, which often fail to provide reliable predictions on drug safety and efficacy in humans. In particular, considerable anatomical and physiological differences between the respiratory systems of commonly used animal models and humans are one of the main issues leading to high drug attrition and clinical failure rates. Accordingly, the generation of physiologically relevant preclinical lung models for early drug development and pharmaceutical research is urgently needed. In this work, poly(ϵ-caprolactone) (PCL) and gelatin were used as raw materials to produce electrospun scaffolds for in vitro lung tissue engineering, in order to generate human biomimetic platforms for preclinical drug safety and efficacy testing. Methodology: PCL and gelatin were mixed at varying volume ratios: 1:0 (PP), 6:1 (PPG61), 4:1 (PPG41), and 2:1 (PPG21), so as to determine the optimal gelatin concentration for cell adhesion and growth. Poly(vinylpyrrolidone) (PVP) was added to every polymer mixture to facilitate the electrospinning process, and electrospun fibrous matrices were fabricated using a needleless electrospinning technique. Scaffold morphology, chemical composition, and wettability were characterized with scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and water contact angle analysis, respectively. Biocompatibility testing was performed using human bronchial (16HBE) and alveolar (A549) epithelial cell lines, consisting of cell metabolic activity, proliferation, and adhesion evaluation over two weeks of in vitro culture. Results: All polymer blends resulted in the formation of electrospun scaffolds with a nanofibrous structure. The addition of gelatin in PPG61 scaffolds improved fiber morphology compared to PP formulations, but increasing proportions of this polymer in PPG41 and PPG21 mats caused a larger number of defects, such as beading and branching. FTIR analysis confirmed the presence of PCL and PVP in PP scaffolds, as well as the addition of gelatin in all PPG blends. Moreover, as expected, all scaffolds were hydrophilic, with water contact angles below 90°, being suitable for protein adsorption and cell adhesion. Regarding 16HBE and A549 cell viability, surprisingly, no major differences were found between the different formulations over the two-week culture period, showing that all polymer blends were equally capable of promoting cell adhesion and growth. While PP scaffolds significantly outperformed PPG electrospun mats in early timepoints, no such differences were identified at the end of the experimental period. Conclusion/Significance: These results suggested that PCL, PVP, and/or gelatin blend electrospun scaffolds are conducive to lung epithelial cell adhesion and proliferation. Nevertheless, further studies investigating epithelial cell differentiation and function should be conducted to fully assess the suitability of these biomaterials as platforms for in vitro lung tissue engineering.

3D tissue-engineered lung models to study immune responses following viral infections of the small airways.

Small airway infections caused by respiratory viruses are some of the most prevalent causes of illness and death. With the recent worldwide pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is currently a push in developing models to better understand respiratory diseases. Recent advancements have made it possible to create three-dimensional (3D) tissue-engineered models of different organs. The 3D environment is crucial to study physiological, pathophysiological, and immunomodulatory responses against different respiratory conditions. A 3D human tissue-engineered lung model that exhibits a normal immunological response against infectious agents could elucidate viral and host determinants. To create 3D small airway lung models in vitro, resident epithelial cells at the air-liquid interface are co-cultured with fibroblasts, myeloid cells, and endothelial cells. The air-liquid interface is a key culture condition to develop and differentiate airway epithelial cells in vitro. Primary human epithelial and myeloid cells are considered the best 3D model for studying viral immune responses including migration, differentiation, and the release of cytokines. Future studies may focus on utilizing bioreactors to scale up the production of 3D human tissue-engineered lung models. This review outlines the use of various cell types, scaffolds, and culture conditions for creating 3D human tissue-engineered lung models. Further, several models used to study immune responses against respiratory viruses, such as the respiratory syncytial virus, are analyzed, showing how the microenvironment aids in understanding immune responses elicited after viral infections.

Construction and Application of in vitro Alveolar Models Based on 3D Printing Technology

Increasing lung diseases, mutating coronaviruses, and the development of new compounds urgently require biomimetic in vitro lung models for lung pathology, toxicology, and pharmacology. The current construction strategies for lung models mainly include animal models, 2D cell culture, lung-on-a-chip, and lung organoids. However, current models face difficulties in reproducing in vivo-like alveolar size and vesicle-like structures, and are unable to contain multiple cell types. In this study, a strategy for constructing alveolar models based on degradable hydrogel microspheres is proposed. Hydrogel microspheres, 200–250 μm in diameter, were prepared using a self-developed printing technique driven by alternating viscous and inertial forces. Microcapsules were further constructed using a coacervation-based layer-by-layer technique and core liquefaction. Three types of cells were inoculated and co-cultured on hydrogel capsules based on optimized microcapsule surface treatment strategies. Finally, an in vitro three-dimensional endothelial alveolar model with a multicellular composition and vesicle-like structure with a diameter of approximately 230 μm was successfully constructed. Cells in the constructed alveolar model maintained a high survival rate. The LD50 values of glutaraldehyde based on the constructed models were in good agreement with the reference values, validating the potential of the model for future toxicant and drug detection.

Study of UWB Near Field Microwave Imaging System for the Diagnosis of Lungs Damage Due to Fluid Accumulations

Lung damages, which is the leading cause of cancer and Covid-19 related death worldwide, can be better treated, and patients' chances of survival increased with early detection and diagnosis. PET (positron emission tomography), cone beam CT, Low dose helical CT, are advanced lung imaging techniques that allow for early diagnosis of smaller pulmonary nodules than normal chest radiography, but with ionizing radiation effect and being costly. In the field of imaging technology, microwave imaging has long been researched in the field of breast and brain. This study presents a review, conducts a feasibility study, and validates the concept of imaging the lungs in a similar manner to the breast and brain. The analysis includes designing a 3D human lung model, microwaves' various elements and factors inspection through the human body using holographic near field imaging, and image processing to estimate the percentage of lung damage. The safety and ionization exposure were also taken into consideration during the overall experiment. The use of microwave energy in various lung diseases is examined, and the basis for fluid detection utilizing microwave water content accumulation is also addressed compared to normal tissues. © 2022 IEEE.

Desperate measures: An acute respiratory distress syndrome approach to multiplex ventilation

INTRODUCTION/HYPOTHESIS: As the world braces itself against new variants of SARS-CoV-2, less resource-rich facilities must consider what to do when the surge of critically ill COVID-19 patients requiring mechanical ventilation outnumbers the supply of ventilators. One solution is multiplex ventilation, where a single ventilator supports two patients. Previously proposed scenarios sacrifice volume control for pressure control in the name of safety. However, volume control ventilation, low tidal volumes, high positive endexpiratory pressure (PEEP) and high respiratory rate are key for Acute Respiratory Distress Syndrome (ARDS) ventilator management. We offer a proof of concept for an accessible multiplex ventilation model with volume protective settings. METHODS: Using one parent ventilator, two daughter circuits were improved with a 3D-printed splitter fitted with laser-cut mechanical flowmeters. Resistance valves connected to each flowmeter outflow port attach to the inspiratory limb of the daughter circuit. At the patient wye, a Luer lock attaches a dry arterial line transducer and an end-tidal CO2 monitor. A one-way check valve connects each daughter circuit expiratory limb to a T-piece at the expiratory port of the ventilator. Test lungs were used to assess whether lung-protective settings can be maintained and adjusted by measuring plateau and driving pressures with varying lung compliance. RESULTS: The improved sub-circuit flowmeters and valves allowed monitoring and manipulation of flow to correct tidal volume shifts with changes in patient lung compliance. Dry arterial line transducers reliably measured peak pressure, PEEP, stress index and plateau pressure on a GE monitor. One-way valves prevented expiratory gas rebreathing by the more compliant lungs. CONCLUSIONS: We concede that two patients on one ventilator is not a good idea, but as the COVID-19 pandemic rages on, resource-poor facilities will run out of good ideas quickly. With our solution, volume control ventilation can be employed, pressures measured, alarms set, and volumes calculated and adjusted for each patient. In the spirit of Roosevelt's call to “do what you can, with what you've got, where you are”, we submit that this is a relatively low-tech, inexpensive model that allows ARDS settings with just a few simple parts, anywhere in the world.

Valsartan protects both cardiac and lung cells from sars-cov-2 infection

Background: Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) disease (COVID19) mainly affects the respiratory system, but cardiac complications occur very often. SARS-CoV-2 entry in host cells is mediated by the interaction between the viral Spike (S) glycoprotein and the host angiotensin-converting enzyme 2 (ACE2). The use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) might influence the expression of ACE2 and viral infection, but not much is known about these interactions. Aim: To evaluate the effects of ACEIs and ARBs during active viraemia. Methods: We tested the ACEI Lisinopril (at 100nM and 500nM) and the ARB Valsartan (at 10uM and 50uM) for one week on two cell types: cardiomyocytes derived from hiPSC (hiPSC-CMs) as heart model and a lung epithelial cancer cell line (16HBE) as pulmonary model. The SARS-CoV-2 wild strain was inoculated in the two treated cell types for one hour. Cell viability was measured 72 hours after infection. Supernatants were collected and titrated to verify the presence of infectious virus using a micro-neutralization assay on VERO-E6 cells. Levels of ACE2 mRNA and protein content on cell lysates were quantified after each treatment by RT-qPCR and western blot, respectively. Results: ACEI and ARB at both concentrations affected the viability of neither hiPSC-CMs nor 16HBE cells in the absence of virus. Vice versa, viral infection significantly decreased viability of both hiPSC-CMs (-46%;p<0,01) and 16HBE (-19%;p<0,05). Viral titration revealed that SARSCoV-2 replicated in both cell lines and was actively released in supernatants. Importantly, pretreatment with Valsartan 50uM increased the viability of both hiPSC-CMs and 16HBE after infection, while Lisinopril and the lower dose of Valsartan had neutral effect. Of note, Valsartan 50uM treatment decrease ACE2 mRNA level in both hiPSC-CMs (-47%, p<0,01) and 16HBE (-37%, p<0,01). Also ACE2 protein levels were reduced in cell lysates of hiPSC-CMs and 16HBE treated with Valsartan 50uM. Conclusion: These data suggest that ACEIs and ARBs do not worsen the SARS-CoV-2 infection. On the contrary, Valsartan seems to be protective against SARS-CoV-2 infection, possibly by reducing ACE2 expression.

Comparison of Geometrical Lung Models to Calculate Tidal Volumes during Spontaneous Breathing

Demographic changes, increasing air pollution and the ongoing Covid-19 pandemic, causing virus-induced respiratory failures, monitoring of respiratory parameters is the focus of international interest. In this study, motioncapture- system data was used to get circumferences of the human thorax while executing different breathing patterns. Four geometric models were used to model tidal volumes of the tracked person while using spirometry data as a reference. The results show that all four introduced models can be used for tidal volume calculation based on changes in the thoracic circumference. In terms of accuracy, the use-case must be considered © 2021 by Walter de Gruyter Berlin/Boston.

Computational model of trachea-alveoli gas movement during spontaneous breathing.

A computational model of the transport of gases involved in spontaneous breathing, from the trachea inlet to the alveoli was developed for healthy patients. Convective and diffusive transport mechanisms were considered simultaneously, using a diffusion coefficient (D) that has considered the four main species of gases present in the exchange carried out by the human lung, nitrogen (N2), oxygen (O2), carbon dioxide (CO2) and water vapor (H2O). A Matlab® script was programmed to simulate the trachea-alveolus gas exchange model under three respiratory frequencies: 12, 24 and 40 breaths per minute (BPM), each with three diaphragmatic movements of 2 cm, 4 cm, and 6 cm. During the simulations, the CO2 inlet concentrations in the alveoli and the O2 concentration at the inlet of the trachea were kept constant. A simplified but stable model of mass transport between the trachea and alveoli was obtained, allowing the concentrations to be determined dynamically at the selected test points in the airway.