Filtration & fluid control
(for instance, a drop of blood) is introduced into the chip, where specific reactions occur. This enables real-time detection and analysis. At this scale, fluids don’t behave in the same way they would on a macro scale, meaning filtration can also look quite different. Some platforms do incorporate membranes – microporous or nanoporous barriers that enable the filtrate to move into a separate chamber. However, membranes are notorious for clogging, leading to high replacement costs. As a result, we are seeing a rise in membrane- free microfiltration technologies. As described in ‘Membrane-less microfiltration using microfluidics’ in the Microfluidics and Nanofluidics journal, these can be divided into passive, active or hybrid approaches. Passive approaches use the channel structures and intrinsic hydrodynamic forces to sort the particles, whereas active approaches filter the particles via an external force.
One common example of a passive microfluidic system is deterministic lateral displacement, in which arrays of micropillars are arranged in specific patterns within a microchannel. The pillars function like a sieve, deflecting larger particles into a different flow path while allowing smaller ones to continue along the main channel. Other devices use a hydrophoretic separation technique, in which repetitive surface structural grooves are used to relocate and separate particles.
Active microfluidic systems, meanwhile, are operated via electrical, magnetic, acoustic or optical forces. For instance, in fluorescence-activated cell sorting (FACS), cells or particles are identified and separated based on their light-scattering and fluorescence characteristics, most commonly in specialised flow cytometers rather than wearable or benchtop microfluidic chips. In magnetophoresis, cells are labelled with magnetic particles and then separated by an external magnetic field. There are two key emerging applications for techniques of this kind.
Liquid biopsy Within liquid biopsy, a small amount of blood is analysed for cancer-specific biomarkers. These might include circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), tumour-derived extracellular vesicles (EVs), tumour-educated platelets (TEPs) and circulating free RNA (cfRNA). There are various techniques for doing so, and different types of biomarker require different strategies. However, one important approach, especially for CTCs, is filtration based on biophysical properties such as deformability or size. In the simplest case, a membrane might be used for this purpose. The blood sample passes through microscopic pores, big enough to let other blood components through but small enough to trap large CTCs. For reference, red
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blood cells are typically 6–8μm and white blood cells 7–15μm across. Since CTCs commonly measure around 15–25μm, size-based filtration is considered feasible.
The challenge here is that not all CTCs fit the profile: some highly metastatic CTCs are much smaller. Studies such as ‘Strategies for enrichment of circulating tumour cells’ in the journal Translational Cancer Research suggest that as many as 20–50% of CTCs may go undetected by size-based approaches. It may be necessary to apply a size enlargement strategy, such as selective size amplification, in which CTCs are bound to modified microbeads. In a 2018 study, ‘High-purity capture of CTCs based on micro-beads enhanced isolation by size of epithelial tumor cells (ISET) method’, researchers using this strategy were able to isolate up to 91% of target cells from whole blood samples at a flow rate of 1mL per minute. Other researchers have developed microfiltration systems for capturing CTC clusters (groupings of cells). If clustering is induced, the size is increased dramatically, making size-based capture much more effective. Another promising technique for filtering cells is dielectrophoresis (DEP), an example of an active microfluidic system. In a DEP platform, blood passes through regions of non-uniform electric field where forces on different cell types vary with their dielectric properties, creating an electrically controlled trapping or deflection mechanism for target cells. DEP is emerging as an important technique for trapping not only CTCs but also other types of cells, such as cancer stem-like cells (CSCs), that are present during disease progression. It can also be used to isolate exosomes, which are very small and poorly suited to size-based filtration methods.
While liquid biopsy holds great promise for cancer detection, its clinical applications to date remain limited. There are still numerous technical hurdles to overcome, not least a lack of laboratory standardisation, the need for sample enrichment
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Microfluidic platforms are often referred to as a ‘lab on a chip’.
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