Droplet based microfluidics
Centrifugal microfluidic systems typically comprise a polymeric substrate with the size of a compact disk incorporating a planar microchannel network and an actuation unit exhibiting a rotational drive, a detection unit and/or a dispenser (Fig. 1). Most applications aim for the process integration, automation, parallelization and miniaturization of analytical, diagnostic and preparative protocols in life sciences.4
The field of centrifugal microfluidics began in the late 1960s with the development of the centrifugal analyzer. N. Anderson, from Oak Ridge National Labs (ORNL), developed a clinical chemistry analyzer, which incorporated a rotating disc with a multicuvette assembly, and a stationary optical detector designed for use with a computer. The design and operation of the system was simple: the disc was fabricated such that channels and risers (i.e. 3D physical barriers) along the radial axis kept samples and reagents separated during fluid loading. During spinning, centrifugal forces drove fluids over the barriers into optical cuvettes positioned on the periphery of the disc. As reactions took place, absorbance changes were monitored with a light source and a photomultiplier tube arranged above and below the cuvettes, respectively. The system was initially used for kinetic assay development.5
Centrifugal microfluidic technologies use the inertial pseudo forces experienced in a rotating reference frame to transport and manipulate fluids, overwhelmingly liquids, through networks of microchannels and chambers on substrates which are often in the format of a disk.4
In centrifugal microfluidic systems, the Navier–Stokes equation is most conveniently expressed within the reference frame where the substrate rotating at a frequency ω= 2πν is at rest.4 In order to understand the unit operations used in centrifugal microfluidics, we hereby introduce the forces that are exploited on this platform, as illustrated in Fig. 2 .
In general, we differentiate between intrinsic forces—sub-classified into pseudo-forces and non-pseudo forces—that are induced merely by the presence or absence of centrifugation, and extrinsic forces resulting from the use of external means.1 Centrifugal force, which acts radially outward on the disc, provides centripetal acceleration during the rotation process.6
Figure 2: Pseudo-forces acting in centrifugal microfluidics. While the centrifugal force always acts radially outward, the Coriolis force acts perpendicular to both ω and the fluid velocity, and the Euler force is proportional to the angular acceleration.1
The centrifugal force is:
Eq.1
Where m is the mass of the sample in the channel, r is the position on the disc, and ω is the angular rotational frequency. The pressure at the far end of a radial column of incompressible fluid (density ρ) extending from radius r1 to r2 is:
Eq.2
In centrifugal microfluidics, there are two forces based on rotation: the Coriolis force (fco) and Euler force (fe). The Coriolis force is velocity dependent and given by:
Eq.3
The Euler force is given by:
Eq.4
It is proportional to the angular acceleration and exists only when the rotation acceleration is not zero. In addition to these three forces, viscous, capillary, and fluidic inertia force are not based on rotation but play important roles in centrifugal microfluidics.6 The pressure corresponding to these three forces Δpvi, Δpca, and Δpin are given by :
Eq.5
Rhyd is the hydraulic resistance and is proportional to the dynamic viscosity, q is the volumetric flow rate, σ denotes the surface tension of a processed liquid, ĸ denotes the curvature of its meniscus, l is the length of a fluidic channel filled with the liquid, and a is the acceleration of the liquid.6
In the case of particle transport in fluids, such as in sedimentation processes, the particles are subject to a viscous force: the drag force (Fd).1 It is given by:
Eq.6
where ρfluid and u are the density and velocity of the fluid relative to a particle, respectively; Aparticle is the particle’s cross-sectional area; and Cd is the drag coefficient.
Centrifugal microfluidics has become a robust system for diverse biomedical uses because of its capacity to effectively manage numerous fluids on a solitary disc. This technology has been a subject of interest in academic and industrial investigations for nearly four decades, with a primary emphasis on biomedical applications. While a variety of assays have been integrated into this platform, its commercial viability as a research or clinical instrument has been somewhat restricted. 5
Circulating tumor cells (CTCs) have been linked to patient outcomes in different types of cancers, and the extraction of these cells from blood samples has garnered significant research interest (Fig. 3).6
Park et al. presented an innovative centrifugal microfluidic system for the isolation of rare cells from a large volume of whole blood. The researchers developed a fully automated disc platform capable of processing 5 mL of blood. This platform featured a blood chamber designed with a triangular obstacle structure (TOS) oriented in the lateral direction. In order to ensure high purity of the isolated circulating tumor cells (CTCs) for subsequent molecular analysis, the CTCs were captured by microbeads coated with anti-EpCAM. This coating facilitated the differentiation in density between CTCs and other blood cells, with the heavier CTCs settling only beneath a layer of density gradient medium (DGM).7
A portable, disc-based, and fully automated enzyme-linked immuno-sorbent assay (ELISA) system was developed to test infectious diseases from whole blood. ELISA is a technique that is used to detect an antigen (or antibody) by using an enzyme-labeled antibody (or antigen) and is based on colorimetry in the presence of a substrate.8 Lee et al. from Samsung reported on a fully integrated ELISA on a disc for biomarkers of the Hepatitis B virus (HBV) starting from whole blood. The centrifugal microfluidic system utilized the laser irradiated ferrowax microvalves (LIFM) to hold reagents and transfer fluids. After isolating HBV antibodies in plasma from whole blood, the sample was passed into a reaction chamber that contained a bed of functionalized polystyrene beads functionalized with capture antigens and separate antigens labeled with enzyme. The bead bed served to improve capture efficiency, increasing surface area and improving mass transport efficiency. The solution was mixed under rotation, then subsequent washing steps were performed, and the substrate was added. Finally, the fluid was moved to a detection chamber and absorbance measurements were taken by a custom built detection unit.9
Centrifugal microfluidic systems are also applied in biochemical analysis and diagnostics. Biochemical analysis commonly involves identifying and measuring substances like glucose, electrolytes, creatinine, and biomarkers, encompassing tasks such as separating plasma or blood cells and isolating various biological particles.8 Biochemical analysis can be classified into three categories based on the centrifugal microfluidic platform used: plasma/blood cell separation, extraction, and filtration of biological particles; and qualitative and quantitative detection of other biochemicals.8
In many diagnostic applications, the separation of plasma from whole blood represents a critical first step and aims to reduce noise in subsequent analyses. To this end, centrifugal microfluidic platforms offer an appealing solution. Under a centrifugal force, cells of high density will sediment and separate from whole blood in a straightforward manner (Fig. 4).10-12
Zhang et.al. reported on a lab-on-CD microstructure capable of separating blood cells from the whole blood into different reservoirs directly. A CD platform including a microchannel network consisting of a straight main microchannel, a curved microchannel and a branching microchannel were proposed. A 0.5 μL blood sample was introduced into the inlet reservoir and the lab-on-CD was placed on a spin processor for the subsequent separation experiment (angular frequency of 1550 rpm). In fine, blood separation was obtained within 1 s after the angular frequency reached 1550 rpm.10
In this simple but effective lab-on-CD design, two centrifugal forces and one Coriolis force work together to separate blood cells from plasma. The separation efficiency monotonically increases as the hematocrit decreases. Blood temperature also significantly affects the separation efficiency. This device demonstrated that RBC separation efficiency up to 99% and about 22% plasma recovery rate have been constantly achieved for the diluted blood of 6% hematocrit.10
Centrifugal microfluidic systems have also found applications in environmental monitoring. A monitoring chip-based design and centrifugal cartridge-based platform (Fig. 5) was demonstrated for environmental monitoring. The chip-based platform utilizes a Al-SiO2 interdigitated transducer platform for the detection of Escherichia coli with a reported limit of detection of 1.8×10−15 M.13
Maguire et. al. presented a novel LOCD-based platform, developed to assess one of the most dangerous toxins documented toxins, microcystin-LR (MC-LR) and Domoic acid (DA) toxin levels in situ, with the additional capabilities for deployment as a long-term real-time microcystin monitor (Fig. 6).14 Using recombinant antibody technology, the LOCD platform combines immunofluorescence with centrifugally driven microfluidic liquid handling to achieve a next-generation disposable device for high throughput sampling.14
The main advantage of working with LOCD systems is that multiple testing mechanisms can be incorporated onto one single disc. This means samples can either be tested multiple times on a single disc, with the exact testing condition in each chamber, or multiple analytes can be detected simultaneously. This provides more statistically accurate and repeatable data.15
The merits of this design are its simple structure, less operating time and high separation efficiency because it utilizes multiple separation mechanisms, for instance, two centrifugal forces and Coriolis force.10
Centrifugal microfluidics can easily be integrated with various fully functional microfluidics devices for blood diagnostics.
Brassard et.al. describe the development of an on-chip nucleic acid (NA) extraction assay from whole blood using a centrifugal microfluidic platform that allows for pneumatic actuation of liquids during rotation. The combination of pneumatic and centrifugal forces makes it possible to perform fluidic operations without the need for integrating active control elements on the microfluidic cartridge.16
The platform allows for applying regulated air pressure to a microfluidic cartridge using a pneumatic interface. Each pressure port can be programmed to apply either positive or negative pressure from the pump (in the range of −5 to +10 psi) or normal atmospheric pressure (vent). Pressure differences generated in this way allow for performing a variety of fluidic functions such as valving, flow switching, inward pumping, or on-demand bubble-based mixing without the need for integrating any active element on the cartridge. The pump and the electromechanical valves are controlled by a microcontroller connected to an internal computer using a slip-ring, enabling direct real-time control of the pneumatic pressure through a custom-designed (LabVIEW) user interface. Each of the 8 pressure outlets is surrounded by an O-ring to seal the interface upon contact with the cartridge.16
An important consideration in the design of the cartridge derives from the use of external vials for storing the blood and eluted NA sample. The purpose of these vials is to simplify and automate the process of loading the blood sample and retrieving the prepared NA sample from the cartridge. Off-chip storage involving automated transfer of liquid on demand to and from the cartridge constitutes a novel and unique approach that is made possible through the pneumatic capabilities of the platform. The cap of each vial has been modified for tubing to go in and out and connect with the cartridge to allow for pneumatic actuation and exchange of liquid. During centrifugation, the pneumatic manifold of the platform applies pressure to the sample vial to transfer blood onto the cartridge. To retrieve the eluted NA sample, pressure is applied to the cartridge, thereby pushing the liquid into the vial.
The OB1 flow controller, (Fig. 7), stands out as a versatile instrument that offers extensive customization options to cater to specific experimental needs. Through the selection of the pressure range for the flow controller, the range of motion can be precisely tailored to suit the requirements of the experiment. It can also hold the potential to serve as an external pneumatic pressure controller, delivering consistent and regulated pressure for applications such as the centrifugal microfluidics systems.
Lab-on-a-Chip and Disk (LOCD) techniques predominantly execute all operations internally on the disk without necessitating external components except for centrifugal forces. Nevertheless, studies have indicated the feasibility of incorporating additional microfluidic devices to enhance functionalities within LOCD systems. Elveflow products emerge as a promising avenue for such integrations, offering potential synergies and expanded capabilities within microfluidic platforms.
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