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Microfluidics Devices as Miniaturized Analytical Modules for Cancer Diagnosis
Published in Raju Khan, Chetna Dhand, S. K. Sanghi, Shabi Thankaraj Salammal, A. B. P. Mishra, Advanced Microfluidics-Based Point-of-Care Diagnostics, 2022
Niraj K. Vishwakarma, Parul Chaurasia, Pranjal Chandra, Sanjeev Kumar Mahto
An anti-epithelial cell adhesion molecule (anti-EpCAM) is known as the most commonly employed antibody for CTCs isolation via antibody-based cell capture.77–79 In such a system, the isolated CTCs are stained with fluorescent markers for enumeration and counting. However, the method is restricted to limited capture capacity because of the small surface area for ligating antibodies into the microfluidic channel. Nevertheless, various types of microfluidics channels have been developed for better ligation. The first antibody-based CAMC system was reported by Du et al.80 Exploiting this system, cervical cancer cells were captured using α6-integrin as a capture antibody bound to the channel surface. The capture rate of tumor cells was controlled by the flow rate and concentration of antibodies used to the microfluidic channel surface. The system demonstrated a cancer cell recovery rate >30%, including 5% normal cells, with cell line mixtures of human cervical stroma, normal human glandular epithelial, and cervical cancer cells with up-regulated α6-integrin cell surface receptors.
Magnetic Separation in Integrated Micro-Analytical Systems
Published in Nguyễn T. K. Thanh, Clinical Applications of Magnetic Nanoparticles, 2018
Wu et al.23 reported on a multi-antibody assay consisting of multifunctional nanoparticles. There have been several studies to develop magnetic nanoparticles suitable for CTC separation. Many CTCs express epithelial cell adhesion molecule (EpCAM), since carcinomas are tumours developed from epithelial cells. However, it is known that cells growing in a tumour may undergo epithelial–mesenchymal transition (EMT). Due to tumour heterogeneity and EMT, metastatic tumour cells often lose their expression of the epithelial cell-specific antigen. The absence of this antigen limits the efficacy of immunomagnetic assay relying on EpCAM. EpCAM-based assays may show low capturing efficiency for CTCs from mesenchymal-like cancer.
Surface Chemistry for Cell Capture in Microfluidic Systems
Published in Iniewski Krzysztof, Integrated Microsystems, 2017
ShuQi Wang, Feng Xu, Alexander Chi Fai Ip, Mrudula Somu, Xiaohu Zhao, Altug Akay, Utkan Demirci
Antibody–ligand-based cell capture is most commonly used to capture target cells from biological samples (e.g., whole blood) (Figure 25.1) [6,11,13,17]. Generally, the antibody against the surface protein of target cells is first immobilized on the microchannel surface of a microfluidic device by covalent linkage. A clinical sample is then flowed through the microchannels at a constant flow rate. If target cells are present in the clinical sample, and they will be captured by the immobilized antibody, enabling isolation and subsequent characterization of target cells (e.g., counting). Three major factors need to be considered for effective capture of target cells in a microfluidic device. First, the antibody/ligand should be specific to the antigen on the surface of target cells, such as monoclonal antibodies (MAbs), to minimize or avoid nonspecific binding. For example, Nouanthong et al. [18] reported that an anti-CD4+ MAb was able to differentiate CD4+ T lymphocytes from monocytes, which also express CD4+ molecules on the cell surface. The use of such MAb can potentially increase the specificity of isolating CD4+ T lymphocytes in the presence of monocytes. Second, the level of surface antigen on the target cells needs to be significantly higher than on other types of cells so that the antibody can bind most efficiently to the target cells [19,20]. For example, the expression of the epithelial cell adhesion molecule (EpCAM) on tumor-derived epithelial cells (one type of CTCs) is upregulated compared to normal epithelial cells [21]. This forms the basis for isolating CTCs from normal blood cells via anti-EpCAM antibody [3]. Third, the flow rate and corresponding shear stress need to be optimized. Because increased flow rate can increase the shear stress on the captured cells, this may detach the captured cells from the immobilized antibody. In addition, high flow rate decreases the antigen–antibody interaction time, resulting in reduced capture efficiency [3,20].
Atmospheric fine particulate matter and epithelial mesenchymal transition in pulmonary cells: state of the art and critical review of the in vitro studies
Published in Journal of Toxicology and Environmental Health, Part B, 2020
Margaux Cochard, Frédéric Ledoux, Yann Landkocz
Clinical biomarkers are crucial to assist with the diagnostic of pathologies, especially cancers. Some EMT epithelial and mesenchymal markers have been associated with prognostic in NSCLC, the most common type of lung cancer. HIF-1α, E-cadherin, Snail and Twist were notably linked to a poor prognosis (Mittal 2016). E-cadherin decreased expression in NSCLC was reported in several studies. However, only the reduction in E-cadherin expression is not sufficient for a diagnosis (Yang et al. 2014). ZO-1, another epithelial surface marker, is found in NSCLC patients when it is located in the nucleus. Lesage et al. (2017) noted 15 out of 44 cancer cases exhibited an increase of more than 10% in the expression of cytonuclear ZO-1, which is not sufficient to consider ZO-1 as a reliable biomarker. Another potential biomarker is the epithelial cell adhesion molecule (EpCAM); however, EpCAM dependent strategies suffer from low sensitivity for detection of circulating tumor cells (CTC). This deficiency might lead to an underestimation of CTC and a mis-treatment (Milano et al. 2018).
A magnetophoretic microdevice for multi-magnetic particles separation based on size: a numerical simulation study
Published in Engineering Applications of Computational Fluid Mechanics, 2022
Jia Ruan, Weiwei Zhang, Chi Zhang, Na Li, Jian Jiang, Huilan Su
Miniaturization has progressed significantly in the last decade which in turn enabled the development of microfluidic devices. Microfluidic devices can handle small volumes of liquids (10−9–10−18 L) within an area with dimensions of tens to hundreds of micrometers. The separation process can be carried out in a short time with low sample and reagent consumption. Thanks to these features, the microfluidic device has been a satisfactory method for the separation of magnetic particles and has gained significant attention from the researchers (Cao et al., 2020; Zhao et al., 2016). Many groups performed intensive works in both experimental and numerical areas and presented various microfluidic devices for magnetic particles or biomagnetic particles separation during the last few years (Khashan et al., 2013; Kwak et al., 2017; Poudineh et al., 2016; Su et al., 2021; Sun et al., 2020). For example, Kwak et al. (2017) designed a Mag-Gradient Chip, which used a serpentine channel with five straight channel segments parallel to the magnet surface. The magnetically labeled circulating tumor cells (CTCs) were captured in a series of small chambers on the side of a microfluidic channel by application of a magnetic field gradient across the channel breadth. The cells could be separated according to their epithelial cell adhesion molecule (EpCAM) expressing level. Other microfluidic device, like the magnetic ranking cytometry (MagRC) device, was also developed for separating CTCs carrying immunomagnetic beads (Poudineh et al., 2016). The MagRC device contains 100 distinct zones with varied magnetic capture zones. An array of X-shaped structures in the channel generates regions of locally low velocity and circular nickel micromagnets patterned within the channel enhance the externally applied magnetic field. Increasing the size of the micro magnets along the channel increases their region of influence, where high magnetic field gradients lead to efficient CTCs capture. Apart from these microfluidic devices, more and more studies employ the technology of free-flow magnetophoresis to separate magnetic particles in recent years.
Numerical simulation of inertial microfluidics: a review
Published in Engineering Applications of Computational Fluid Mechanics, 2023
In the 1990s, Manz et al. (Manz et al., 1990) proposed the concept of a micro-total analysis system and produced a microfluidic chip, which was gradually developed into a microfluidic technology for controlling fluids in micro-nano-scale structures (Kulrattanarak et al., 2008). Due to the advantages of integration, automation and high throughput, microfluidic technology has shown considerable promise in point-of-care diagnostics and clinical studies. Isolation, enrichment, and purification of cells using microfluidic platforms have been a flourishing area of development in recent years with many successful translations into commercial products. Microfluidic technology enriches circulating tumour cells (CTCs) based on biochemical or physical properties, requiring small sample volumes, controllable flow rates, and the ability to capture live cells. Microfluidic technology based on biochemical properties can effectively sort different types of cells with similar shape or size in a short period of time. The phenotypes of CTCs are diverse, including epithelial, mesenchymal and other cell phenotypes, and the phenotypes are prone to dynamic changes with the microenvironment (Cheng et al., 2018 Miao & Tang, 2019;). At present, in most commercial technology platforms, epithelial cell adhesion molecule (EpCAM) is used as the only surface-specific antigen, ignoring the extremely aggressive mesenchymal phenotype CTC that has undergone epithelial–mesenchymal transition (EMT). The label-free CTC microfluidic separation techniques based on physical properties have developed rapidly. According to the technical mechanism, it can be broadly classified as active and passive separation techniques. Active techniques rely on external force fields (e.g. acoustic (Collins et al., 2016), optical (Hu et al., 2019), and dielectrophoresis (Cheng et al., 2015)), while passive techniques (e.g. microfluidic filters (Liu et al., 2018), deterministic lateral displacement (Loutherback et al., 2012), and inertial microfluidics (Kwak et al., 2018)) only rely on the channel geometry and inherent hydrodynamic forces for separating. Among all existing microfluidic systems, inertial microfluidics has emerged as a promising way for particle and cell separation due to its capabilities in high-volume and high-throughput sample processing (Cruz et al., 2019; Gou et al., 2018; Shen et al., 2017; Stoecklein & Di Carlo, 2018; Zhang et al., 2020). The flow channel structure of the inertial microfluidic system can be divided into straight and curved forms. In addition to the inertial forces, the Dean forces in transverse Dean flow arose from curved channel structure not only provide a compact design, but also allow the exquisite control of particle migration (Warkiani et al., 2016). In 2015, Clearbridge BioMedics developed the ClearCell® FX system based on a microfluidic chip with a single curved channel, which has successfully achieved high-activity separation of heterogeneous CTCs using inertial focusing technology. The system was approved as a Class I medical device by the US Food and Drug Administration in 2018, which provides reliable liquid biopsy solutions for clinical research used in vitro diagnostics.