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Microfluidics

Microfluidics refers to a system that manipulates a small amount of fluids (10−9 to 10−18 liters) using small channels with sizes ten to hundreds micrometres. It is a multidisciplinary field that involves molecular analysis, molecular biology, and microelectronics.[1] It has practical applications in the design of systems that process low volumes of fluids to achieve multiplexing, automation, and high-throughput screening. Microfluidics emerged in the beginning of the 1980s and is used in the development of inkjet printheads, DNA chips, lab-on-a-chip technology, micro-propulsion, and micro-thermal technologies.

NIST researchers have combined a glass slide, plastic sheets and double-sided tape to create an inexpensive and simple-to-build microfluidic device for exposing an array of cells to different concentrations of a chemical.

Typically, micro means one of the following features:

  • Small volumes (μL, nL, pL, fL)
  • Small size
  • Low energy consumption
  • Microdomain effects

Typically microfluidic systems transport, mix, separate, or otherwise process fluids. Various applications rely on passive fluid control using capillary forces, in the form of capillary flow modifying elements, akin to flow resistors and flow accelerators. In some applications, external actuation means are additionally used for a directed transport of the media. Examples are rotary drives applying centrifugal forces for the fluid transport on the passive chips. Active microfluidics refers to the defined manipulation of the working fluid by active (micro) components such as micropumps or microvalves. Micropumps supply fluids in a continuous manner or are used for dosing. Microvalves determine the flow direction or the mode of movement of pumped liquids. Often, processes normally carried out in a lab are miniaturised on a single chip, which enhances efficiency and mobility, and reduces sample and reagent volumes.

Microscale behaviour of fluids edit

 
Silicone rubber and glass microfluidic devices. Top: a photograph of the devices. Bottom: Phase contrast micrographs of a serpentine channel ~15 μm wide.

The behaviour of fluids at the microscale can differ from "macrofluidic" behaviour in that factors such as surface tension, energy dissipation, and fluidic resistance start to dominate the system. Microfluidics studies how these behaviours change, and how they can be worked around, or exploited for new uses.[2][3][4][5][6]

At small scales (channel size of around 100 nanometers to 500 micrometers) some interesting and sometimes unintuitive properties appear. In particular, the Reynolds number (which compares the effect of the momentum of a fluid to the effect of viscosity) can become very low. A key consequence is co-flowing fluids do not necessarily mix in the traditional sense, as flow becomes laminar rather than turbulent; molecular transport between them must often be through diffusion.[7]

High specificity of chemical and physical properties (concentration, pH, temperature, shear force, etc.) can also be ensured resulting in more uniform reaction conditions and higher grade products in single and multi-step reactions.[8][9]

Various kinds of microfluidic flows edit

Microfluidic flows need only be constrained by geometrical length scale – the modalities and methods used to achieve such a geometrical constraint are highly dependent on the targeted application.[10] Traditionally, microfluidic flows have been generated inside closed channels with the channel cross section being in the order of 10 μm x 10 μm. Each of these methods has its own associated techniques to maintain robust fluid flow which have matured over several years.[citation needed]

Open microfluidics edit

The behavior of fluids and their control in open microchannels was pioneered around 2005[11] and applied in air-to-liquid sample collection[12][13] and chromatography.[14] In open microfluidics, at least one boundary of the system is removed, exposing the fluid to air or another interface (i.e. liquid).[15][16][17] Advantages of open microfluidics include accessibility to the flowing liquid for intervention, larger liquid-gas surface area, and minimized bubble formation.[18][15][17][19] Another advantage of open microfluidics is the ability to integrate open systems with surface-tension driven fluid flow, which eliminates the need for external pumping methods such as peristaltic or syringe pumps.[20] Open microfluidic devices are also easy and inexpensive to fabricate by milling, thermoforming, and hot embossing.[21][22][23][24] In addition, open microfluidics eliminates the need to glue or bond a cover for devices, which could be detrimental to capillary flows. Examples of open microfluidics include open-channel microfluidics, rail-based microfluidics, paper-based, and thread-based microfluidics.[15][20][25] Disadvantages to open systems include susceptibility to evaporation,[26] contamination,[27] and limited flow rate.[17]

Continuous-flow microfluidics edit

Continuous flow microfluidics rely on the control of a steady state liquid flow through narrow channels or porous media predominantly by accelerating or hindering fluid flow in capillary elements.[28] In paper based microfluidics, capillary elements can be achieved through the simple variation of section geometry. In general, the actuation of liquid flow is implemented either by external pressure sources, external mechanical pumps, integrated mechanical micropumps, or by combinations of capillary forces and electrokinetic mechanisms.[29][30] Continuous-flow microfluidic operation is the mainstream approach because it is easy to implement and less sensitive to protein fouling problems. Continuous-flow devices are adequate for many well-defined and simple biochemical applications, and for certain tasks such as chemical separation, but they are less suitable for tasks requiring a high degree of flexibility or fluid manipulations. These closed-channel systems are inherently difficult to integrate and scale because the parameters that govern flow field vary along the flow path making the fluid flow at any one location dependent on the properties of the entire system. Permanently etched microstructures also lead to limited reconfigurability and poor fault tolerance capability. Computer-aided design automation approaches for continuous-flow microfluidics have been proposed in recent years to alleviate the design effort and to solve the scalability problems.[31]

 
micro fluid sensor

Process monitoring capabilities in continuous-flow systems can be achieved with highly sensitive microfluidic flow sensors based on MEMS technology, which offers resolutions down to the nanoliter range.[32]

Droplet-based microfluidics edit

High frame rate video showing microbubble pinch-off formation in a flow-focusing microfluidic device[33]

Droplet-based microfluidics is a subcategory of microfluidics in contrast with continuous microfluidics; droplet-based microfluidics manipulates discrete volumes of fluids in immiscible phases with low Reynolds number and laminar flow regimes. Interest in droplet-based microfluidics systems has been growing substantially in past decades. Microdroplets allow for handling miniature volumes (μL to fL) of fluids conveniently, provide better mixing, encapsulation, sorting, and sensing, and suit high throughput experiments.[34] Exploiting the benefits of droplet-based microfluidics efficiently requires a deep understanding of droplet generation[35] to perform various logical operations[36][37] such as droplet manipulation,[38] droplet sorting,[39] droplet merging,[40] and droplet breakup.[41]

Digital microfluidics edit

Alternatives to the above closed-channel continuous-flow systems include novel open structures, where discrete, independently controllable droplets are manipulated on a substrate using electrowetting. Following the analogy of digital microelectronics, this approach is referred to as digital microfluidics. Le Pesant et al. pioneered the use of electrocapillary forces to move droplets on a digital track.[42] The "fluid transistor" pioneered by Cytonix[43] also played a role. The technology was subsequently commercialised by Duke University. By using discrete unit-volume droplets,[35] a microfluidic function can be reduced to a set of repeated basic operations, i.e., moving one unit of fluid over one unit of distance. This "digitisation" method facilitates the use of a hierarchical and cell-based approach for microfluidic biochip design. Therefore, digital microfluidics offers a flexible and scalable system architecture as well as high fault-tolerance capability. Moreover, because each droplet can be controlled independently, these systems also have dynamic reconfigurability, whereby groups of unit cells in a microfluidic array can be reconfigured to change their functionality during the concurrent execution of a set of bioassays. Although droplets are manipulated in confined microfluidic channels, since the control on droplets is not independent, it should not be confused as "digital microfluidics". One common actuation method for digital microfluidics is electrowetting-on-dielectric (EWOD).[44] Many lab-on-a-chip applications have been demonstrated within the digital microfluidics paradigm using electrowetting. However, recently other techniques for droplet manipulation have also been demonstrated using magnetic force,[45] surface acoustic waves,[46] optoelectrowetting, mechanical actuation,[47] etc.

Paper-based microfluidics edit

Paper-based microfluidic devices fill a growing niche for portable, cheap, and user-friendly medical diagnostic systems.[48] Paper based microfluidics rely on the phenomenon of capillary penetration in porous media.[49] To tune fluid penetration in porous substrates such as paper in two and three dimensions, the pore structure, wettability and geometry of the microfluidic devices can be controlled while the viscosity and evaporation rate of the liquid play a further significant role. Many such devices feature hydrophobic barriers on hydrophilic paper that passively transport aqueous solutions to outlets where biological reactions take place.[50] Paper-based microfluidics are considered as portable point-of-care biosensors used in a remote setting where advanced medical diagnostic tools are not accessible.[51] Current applications include portable glucose detection[52] and environmental testing,[53] with hopes of reaching areas that lack advanced medical diagnostic tools.

Particle detection microfluidics edit

One application area that has seen significant academic effort and some commercial effort is in the area of particle detection in fluids. Particle detection of small fluid-borne particles down to about 1 μm in diameter is typically done using a Coulter counter, in which electrical signals are generated when a weakly-conducting fluid such as in saline water is passed through a small (~100 μm diameter) pore, so that an electrical signal is generated that is directly proportional to the ratio of the particle volume to the pore volume. The physics behind this is relatively simple, described in a classic paper by DeBlois and Bean,[54] and the implementation first described in Coulter's original patent.[55] This is the method used to e.g. size and count erythrocytes (red blood cells [wiki]) as well as leukocytes (white blood cells) for standard blood analysis. The generic term for this method is resistive pulse sensing (RPS); Coulter counting is a trademark term. However, the RPS method does not work well for particles below 1 μm diameter, as the signal-to-noise ratio falls below the reliably detectable limit, set mostly by the size of the pore in which the analyte passes and the input noise of the first-stage amplifier.[citation needed]

The limit on the pore size in traditional RPS Coulter counters is set by the method used to make the pores, which while a trade secret, most likely[according to whom?] uses traditional mechanical methods. This is where microfluidics can have an impact: The lithography-based production of microfluidic devices, or more likely the production of reusable molds for making microfluidic devices using a molding process, is limited to sizes much smaller than traditional machining. Critical dimensions down to 1 μm are easily fabricated, and with a bit more effort and expense, feature sizes below 100 nm can be patterned reliably as well. This enables the inexpensive production of pores integrated in a microfluidic circuit where the pore diameters can reach sizes of order 100 nm, with a concomitant reduction in the minimum particle diameters by several orders of magnitude.

As a result, there has been some university-based development of microfluidic particle counting and sizing[56][57][58][59][60][61][62][63][64][65] [excessive citations]with the accompanying commercialization of this technology. This method has been termed microfluidic resistive pulse sensing (MRPS).

Microfluidic-assisted magnetophoresis edit

One major area of application for microfluidic devices is the separation and sorting of different fluids or cell types. Recent developments in the microfluidics field have seen the integration of microfluidic devices with magnetophoresis: the migration of particles by a magnetic field.[66] This can be accomplished by sending a fluid containing at least one magnetic component through a microfluidic channel that has a magnet positioned along the length of the channel. This creates a magnetic field inside the microfluidic channel which draws magnetically active substances towards it, effectively separating the magnetic and non-magnetic components of the fluid. This technique can be readily utilized in industrial settings where the fluid at hand already contains magnetically active material. For example, a handful of metallic impurities can find their way into certain consumable liquids, namely milk and other dairy products.[67] Conveniently, in the case of milk, many of these metal contaminants exhibit paramagnetism. Therefore, before packaging, milk can be flowed through channels with magnetic gradients as a means of purifying out the metal contaminants.

Other, more research-oriented applications of microfluidic-assisted magnetophoresis are numerous and are generally targeted towards cell separation. The general way this is accomplished involves several steps. First, a paramagnetic substance (usually micro/nanoparticles or a paramagnetic fluid)[68] needs to be functionalized to target the cell type of interest. This can be accomplished by identifying a transmembranal protein unique to the cell type of interest and subsequently functionalizing magnetic particles with the complementary antigen or antibody.[67][69][70][71][72] Once the magnetic particles are functionalized, they are dispersed in a cell mixture where they bind to only the cells of interest. The resulting cell/particle mixture can then be flowed through a microfluidic device with a magnetic field to separate the targeted cells from the rest.

Conversely, microfluidic-assisted magnetophoresis may be used to facilitate efficient mixing within microdroplets or plugs. To accomplish this, microdroplets are injected with paramagnetic nanoparticles and are flowed through a straight channel which passes through rapidly alternating magnetic fields. This causes the magnetic particles to be quickly pushed from side to side within the droplet and results in the mixing of the microdroplet contents.[71] This eliminates the need for tedious engineering considerations that are necessary for traditional, channel-based droplet mixing. Other research has also shown that the label-free separation of cells may be possible by suspending cells in a paramagnetic fluid and taking advantage of the magneto-Archimedes effect.[73][74] While this does eliminate the complexity of particle functionalization, more research is needed to fully understand the magneto-Archimedes phenomenon and how it can be used to this end. This is not an exhaustive list of the various applications of microfluidic-assisted magnetophoresis; the above examples merely highlight the versatility of this separation technique in both current and future applications.

Key application areas edit

Microfluidic structures include micropneumatic systems, i.e. microsystems for the handling of off-chip fluids (liquid pumps, gas valves, etc.), and microfluidic structures for the on-chip handling of nanoliter (nl) and picoliter (pl) volumes.[75] To date, the most successful commercial application of microfluidics is the inkjet printhead.[76] Additionally, microfluidic manufacturing advances mean that makers can produce the devices in low-cost plastics[77] and automatically verify part quality.[78]

Advances in microfluidics technology are revolutionizing molecular biology procedures for enzymatic analysis (e.g., glucose and lactate assays), DNA analysis (e.g., polymerase chain reaction and high-throughput sequencing), proteomics, and in chemical synthesis.[28][79] The basic idea of microfluidic biochips is to integrate assay operations such as detection, as well as sample pre-treatment and sample preparation on one chip.[80][81]

An emerging application area for biochips is clinical pathology, especially the immediate point-of-care diagnosis of diseases.[82] In addition, microfluidics-based devices, capable of continuous sampling and real-time testing of air/water samples for biochemical toxins and other dangerous pathogens,[83] can serve as an always-on "bio-smoke alarm" for early warning.

Microfluidic technology has led to the creation of powerful tools for biologists to control the complete cellular environment, leading to new questions and discoveries. Many diverse advantages of this technology for microbiology are listed below:

  • General single cell studies including growth[84][34]
  • Cellular aging: microfluidic devices such as the "mother machine" allow tracking of thousands of individual cells for many generations until they die[84]
  • Microenvironmental control: ranging from mechanical environment[85] to chemical environment[86][87]
  • Precise spatiotemporal concentration gradients by incorporating multiple chemical inputs to a single device[88]
  • Force measurements of adherent cells or confined chromosomes: objects trapped in a microfluidic device can be directly manipulated using optical tweezers or other force-generating methods[89]
  • Confining cells and exerting controlled forces by coupling with external force-generation methods such as Stokes flow, optical tweezer, or controlled deformation of the PDMS (Polydimethylsiloxane) device[89][90][91]
  • Electric field integration[91]
  • Plant on a chip and plant tissue culture[92]
  • Antibiotic resistance: microfluidic devices can be used as heterogeneous environments for microorganisms. In a heterogeneous environment, it is easier for a microorganism to evolve. This can be useful for testing the acceleration of evolution of a microorganism / for testing the development of antibiotic resistance.

Some of these areas are further elaborated in the sections below:

DNA chips (microarrays) edit

Early biochips were based on the idea of a DNA microarray, e.g., the GeneChip DNAarray from Affymetrix, which is a piece of glass, plastic or silicon substrate, on which pieces of DNA (probes) are affixed in a microscopic array. Similar to a DNA microarray, a protein array is a miniature array where a multitude of different capture agents, most frequently monoclonal antibodies, are deposited on a chip surface; they are used to determine the presence and/or amount of proteins in biological samples, e.g., blood. A drawback of DNA and protein arrays is that they are neither reconfigurable nor scalable after manufacture. Digital microfluidics has been described as a means for carrying out Digital PCR.

Molecular biology edit

In addition to microarrays, biochips have been designed for two-dimensional electrophoresis,[93] transcriptome analysis,[94] and PCR amplification.[95] Other applications include various electrophoresis and liquid chromatography applications for proteins and DNA, cell separation, in particular, blood cell separation, protein analysis, cell manipulation and analysis including cell viability analysis[34] and microorganism capturing.[81]

Evolutionary biology edit

By combining microfluidics with landscape ecology and nanofluidics, a nano/micro fabricated fluidic landscape can be constructed by building local patches of bacterial habitat and connecting them by dispersal corridors. The resulting landscapes can be used as physical implementations of an adaptive landscape,[96] by generating a spatial mosaic of patches of opportunity distributed in space and time. The patchy nature of these fluidic landscapes allows for the study of adapting bacterial cells in a metapopulation system. The evolutionary ecology of these bacterial systems in these synthetic ecosystems allows for using biophysics to address questions in evolutionary biology.

Cell behavior edit

The ability to create precise and carefully controlled chemoattractant gradients makes microfluidics the ideal tool to study motility,[97] chemotaxis and the ability to evolve / develop resistance to antibiotics in small populations of microorganisms and in a short period of time. These microorganisms including bacteria[98] and the broad range of organisms that form the marine microbial loop,[99] responsible for regulating much of the oceans' biogeochemistry.

Microfluidics has also greatly aided the study of durotaxis by facilitating the creation of durotactic (stiffness) gradients.

Cellular biophysics edit

By rectifying the motion of individual swimming bacteria,[100] microfluidic structures can be used to extract mechanical motion from a population of motile bacterial cells.[101] This way, bacteria-powered rotors can be built.[102][103]

Optics edit

The merger of microfluidics and optics is typical known as optofluidics. Examples of optofluidic devices are tunable microlens arrays[104][105] and optofluidic microscopes.

Microfluidic flow enables fast sample throughput, automated imaging of large sample populations, as well as 3D capabilities.[106][107] or superresolution.[108]

Photonics Lab on a Chip (PhLOC) edit

Due to the increase in safety concerns and operating costs of common analytic methods (ICP-MS, ICP-AAS, and ICP-OES[109]), the Photonics Lab on a Chip (PhLOC) is becoming an increasingly popular tool for the analysis of actinides and nitrates in spent nuclear waste. The PhLOC is based on the simultaneous application of Raman and UV-Vis-NIR spectroscopy,[110] which allows for the analysis of more complex mixtures which contain several actinides at different oxidation states.[111] Measurements made with these methods have been validated at the bulk level for industrial tests,[109][112] and are observed to have a much lower variance at the micro-scale.[113] This approach has been found to have molar extinction coefficients (UV-Vis) in line with known literature values over a comparatively large concentration span for 150 μL[111] via elongation of the measurement channel, and obeys Beer's Law at the micro-scale for U(IV).[114] Through the development of a spectrophotometric approach to analyzing spent fuel, an on-line method for measurement of reactant quantities is created, increasing the rate at which samples can be analyzed and thus decreasing the size of deviations detectable within reprocessing.[112]

Through the application of the PhLOC, flexibility and safety of operational methods are increased. Since the analysis of spent nuclear fuel involves extremely harsh conditions, the application of disposable and rapidly produced devices (Based on castable and/or engravable materials such as PDMS, PMMA, and glass[115]) is advantageous, although material integrity must be considered under specific harsh conditions.[114] Through the usage of fiber optic coupling, the device can be isolated from instrumentation, preventing irradiative damage and minimizing the exposure of lab personnel to potentially harmful radiation, something not possible on the lab scale nor with the previous standard of analysis.[111] The shrinkage of the device also allows for lower amounts of analyte to be used, decreasing the amount of waste generated and exposure to hazardous materials.[111]

Expansion of the PhLOC to miniaturize research of the full nuclear fuel cycle is currently being evaluated, with steps of the PUREX process successfully being demonstrated at the micro-scale.[110] Likewise, the microfluidic technology developed for the analysis of spent nuclear fuel is predicted to expand horizontally to analysis of other actinide, lanthanides, and transition metals with little to no modification.[111]

High Performance Liquid Chromatography (HPLC) edit

HPLC in the field of microfluidics comes in two different forms. Early designs included running liquid through the HPLC column then transferring the eluted liquid to microfluidic chips and attaching HPLC columns to the microfluidic chip directly.[116] The early methods had the advantage of easier detection from certain machines like those that measure fluorescence.[117] More recent designs have fully integrated HPLC columns into microfluidic chips. The main advantage of integrating HPLC columns into microfluidic devices is the smaller form factor that can be achieved, which allows for additional features to be combined within one microfluidic chip. Integrated chips can also be fabricated from multiple different materials, including glass and polyimide which are quite different from the standard material of PDMS used in many different droplet-based microfluidic devices.[118][119] This is an important feature because different applications of HPLC microfluidic chips may call for different pressures. PDMS fails in comparison for high-pressure uses compared to glass and polyimide. High versatility of HPLC integration ensures robustness by avoiding connections and fittings between the column and chip.[120] The ability to build off said designs in the future allows the field of microfluidics to continue expanding its potential applications.

The potential applications surrounding integrated HPLC columns within microfluidic devices have proven expansive over the last 10–15 years. The integration of such columns allows for experiments to be run where materials were in low availability or very expensive, like in biological analysis of proteins. This reduction in reagent volumes allows for new experiments like single-cell protein analysis, which due to size limitations of prior devices, previously came with great difficulty.[121] The coupling of HPLC-chip devices with other spectrometry methods like mass-spectrometry allow for enhanced confidence in identification of desired species, like proteins.[122] Microfluidic chips have also been created with internal delay-lines that allow for gradient generation to further improve HPLC, which can reduce the need for further separations.[123] Some other practical applications of integrated HPLC chips include the determination of drug presence in a person through their hair[124] and the labeling of peptides through reverse phase liquid chromatography.[125]

Acoustic droplet ejection (ADE) edit

Acoustic droplet ejection uses a pulse of ultrasound to move low volumes of fluids (typically nanoliters or picoliters) without any physical contact. This technology focuses acoustic energy into a fluid sample to eject droplets as small as a millionth of a millionth of a litre (picoliter = 10−12 litre). ADE technology is a very gentle process, and it can be used to transfer proteins, high molecular weight DNA and live cells without damage or loss of viability. This feature makes the technology suitable for a wide variety of applications including proteomics and cell-based assays.

Fuel cells edit

Microfluidic fuel cells can use laminar flow to separate the fuel and its oxidant to control the interaction of the two fluids without the physical barrier that conventional fuel cells require.[126][127][128]

Astrobiology edit

To understand the prospects for life to exist elsewhere in the universe, astrobiologists are interested in measuring the chemical composition of extraplanetary bodies.[129] Because of their small size and wide-ranging functionality, microfluidic devices are uniquely suited for these remote sample analyses.[130][131][132] From an extraterrestrial sample, the organic content can be assessed using microchip capillary electrophoresis and selective fluorescent dyes.[133] These devices are capable of detecting amino acids,[134] peptides,[135] fatty acids,[136] and simple aldehydes, ketones,[137] and thiols.[138] These analyses coupled together could allow powerful detection of the key components of life, and hopefully inform our search for functioning extraterrestrial life.[139]

Food science edit

Microfluidic techniques such as droplet microfluidics, paper microfluidics, and lab-on-a-chip are used in the realm of food science in a variety of categories.[140] Research in nutrition,[141][142] food processing, and food safety benefit from microfluidic technique because experiments can be done with less reagents.[140]

Food processing requires the ability to enable shelf stability in foods, such as emulsions or additions of preservatives. Techniques such as droplet microfluidics are used to create emulsions that are more controlled and complex than those created by traditional homogenization due to the precision of droplets that is achievable. Using microfluidics for emulsions is also more energy efficient compared to homogenization in which “only 5% of the supplied energy is used to generate the emulsion, with the rest dissipated as heat” .[143] Although these methods have benefits, they currently lack the ability to be produced at large scale that is needed for commercialization.[144] Microfluidics are also used in research as they allow for innovation in food chemistry and food processing.[140][144] An example in food engineering research is a novel micro-3D-printed device fabricated to research production of droplets for potential food processing industry use, particularly in work with enhancing emulsions.[145]

Paper and droplet microfluidics allow for devices that can detect small amounts of unwanted bacteria or chemicals, making them useful in food safety and analysis.[146] Paper-based microfluidic devices are often referred to as microfluidic paper-based analytical devices (μPADs) and can detect such things as nitrate,[147] preservatives,[148] or antibiotics[149] in meat by a colorimetric reaction that can be detected with a smartphone. These methods are being researched because they use less reactants, space, and time compared to traditional techniques such as liquid chromatography. μPADs also make home detection tests possible, which is of interest to those with allergies and intolerances.[147] In addition to paper-based methods, research demonstrates droplet-based microfluidics shows promise in drastically shortening the time necessary to confirm viable bacterial contamination in agricultural waters in the domestic and international food industry.[146]

Future directions edit

Microfluidics for personalized cancer treatment edit

Personalized cancer treatment is a tuned method based on the patient's diagnosis and background. Microfluidic technology offers sensitive detection with higher throughput, as well as reduced time and costs. For personalized cancer treatment, tumor composition and drug sensitivities are very important.[150]

A patient's drug response can be predicted based on the status of biomarkers, or the severity and progression of the disease can be predicted based on the atypical presence of specific cells.[151] Drop-qPCR is a droplet microfluidic technology in which droplets are transported in a reusable capillary and alternately flow through two areas maintained at different constant temperatures and fluorescence detection. It can be efficient with a low contamination risk to detect Her2.[150] A digital droplet‐based PCR method can be used to detect the KRAS mutations with TaqMan probes, to enhance detection of the mutative gene ratio.[152] In addition, accurate prediction of postoperative disease progression in breast or prostate cancer patients is essential for determining post-surgery treatment. A simple microfluidic chamber, coated with a carefully formulated extracellular matrix mixture is used for cells obtained from tumor biopsy after 72 hours of growth and a thorough evaluation of cells by imaging.[153]

Microfluidics is also suitable for circulating tumor cells (CTCs) and non-CTCs liquid biopsy analysis. Beads conjugate to anti‐epithelial cell adhesion molecule (EpCAM) antibodies for positive selection in the CTCs isolation chip (iCHIP).[154] CTCs can also be detected by using the acidification of the tumor microenvironment and the difference in membrane capacitance.[155][156] CTCs are isolated from blood by a microfluidic device, and are cultured on-chip, which can be a method to capture more biological information in a single analysis. For example, it can be used to test the cell survival rate of 40 different drugs or drug combinations.[157] Tumor‐derived extracellular vesicles can be isolated from urine and detected by an integrated double‐filtration microfluidic device; they also can be isolated from blood and detected by electrochemical sensing method with a two‐level amplification enzymatic assay.[158][159]

Tumor materials can directly be used for detection through microfluidic devices. To screen primary cells for drugs, it is often necessary to distinguish cancerous cells from non-cancerous cells. A microfluidic chip based on the capacity of cells to pass small constrictions can sort the cell types, metastases.[160] Droplet‐based microfluidic devices have the potential to screen different drugs or combinations of drugs, directly on the primary tumor sample with high accuracy. To improve this strategy, the microfluidic program with a sequential manner of drug cocktails, coupled with fluorescent barcodes, is more efficient.[161] Another advanced strategy is detecting growth rates of single-cell by using suspended microchannel resonators, which can predict drug sensitivities of rare CTCs.[162]

Microfluidics devices also can simulate the tumor microenvironment, to help to test anticancer drugs. Microfluidic devices with 2D or 3D cell cultures can be used to analyze spheroids for different cancer systems (such as lung cancer and ovarian cancer), and are essential for multiple anti-cancer drugs and toxicity tests. This strategy can be improved by increasing the throughput and production of spheroids. For example, one droplet-based microfluidic device for 3D cell culture produces 500 spheroids per chip.[163] These spheroids can be cultured longer in different surroundings to analyze and monitor. The other advanced technology is organs‐on‐a‐chip, and it can be used to simulate several organs to determine the drug metabolism and activity based on vessels mimicking, as well as mimic pH, oxygen... to analyze the relationship between drugs and human organ surroundings.[163]

A recent strategy is single-cell chromatin immunoprecipitation (ChiP)‐Sequencing in droplets, which operates by combining droplet‐based single cell RNA sequencing with DNA‐barcoded antibodies, possibly to explore the tumor heterogeneity by the genotype and phenotype to select the personalized anti-cancer drugs and prevent the cancer relapse.[164]

See also edit

References edit

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Further reading edit

Review papers edit

  • Yetisen AK, Akram MS, Lowe CR (June 2013). "Paper-based microfluidic point-of-care diagnostic devices". Lab on a Chip. 13 (12): 2210–2251. doi:10.1039/C3LC50169H. PMID 23652632. S2CID 17745196.
  • Whitesides GM (July 2006). "The origins and the future of microfluidics". Nature. 442 (7101): 368–373. Bibcode:2006Natur.442..368W. doi:10.1038/nature05058. PMID 16871203. S2CID 205210989.
  • Seemann R, Brinkmann M, Pfohl T, Herminghaus S (January 2012). "Droplet based microfluidics". Reports on Progress in Physics. 75 (1): 016601. Bibcode:2012RPPh...75a6601S. doi:10.1088/0034-4885/75/1/016601. PMID 22790308. S2CID 5206697.
  • Squires TM, Quake SR (2005). "Microfluidics: Fluid physics at the nanoliter scale" (PDF). Reviews of Modern Physics. 77 (3): 977–1026. Bibcode:2005RvMP...77..977S. doi:10.1103/RevModPhys.77.977.
  • Yetisen AK, Volpatti LR (July 2014). "Patent protection and licensing in microfluidics". Lab on a Chip. 14 (13): 2217–2225. doi:10.1039/C4LC00399C. PMID 24825780. S2CID 8669721.
  • Chen K (2011). . Journal of Undergraduate Life Sciences. 5 (1): 66–69. Archived from the original on 2012-03-31. Retrieved 2011-08-30.
  • Angell JB, Terry SC, Barth PW (April 1983). "Silicon Micromechanical Devices". Scientific American. 248 (4): 44–55. Bibcode:1983SciAm.248d..44A. doi:10.1038/scientificamerican0483-44.
  • Carugo D, Bottaro E, Owen J, Stride E, Nastruzzi C (May 2016). "Liposome production by microfluidics: potential and limiting factors". Scientific Reports. 6: 25876. Bibcode:2016NatSR...625876C. doi:10.1038/srep25876. PMC 4872163. PMID 27194474.
  • Chossat JB, Park YL, Wood RJ, Duchaine V (September 2013). "A Soft Strain Sensor Based on Ionic and Metal Liquids". IEEE Sensors Journal. 13 (9): 3405–3414. Bibcode:2013ISenJ..13.3405C. CiteSeerX 10.1.1.640.4976. doi:10.1109/JSEN.2013.2263797. S2CID 14492585.
  • Tseng TM, Li M, Freitas DN, Mongersun A, Araci IE, Ho TY, Schlichtmann U (2018). (PDF). Proceedings of the 55th Annual Design Automation Conference. p. 163. Archived from the original (PDF) on April 9, 2023.

Books edit

  • Bruus H (2008). Theoretical Microfluidics. Oxford University Press. ISBN 978-0199235094.
  • Folch, Albert. Hidden in Plain Sight: The History, Science, and Engineering of Microfluidic Technology (MIT Press, 2022) online review
  • Herold KE, Rasooly A (2009). Lab-on-a-Chip Technology: Fabrication and Microfluidics. Caister Academic Press. ISBN 978-1-904455-46-2.
  • Kelly R, ed. (2012). Advances in Microfluidics. Richland, Washington, USA: Pacific Northwest National Laboratory. ISBN 978-953-510-106-2.
  • Jenkins G, Mansfield CD (2012). Microfluidic Diagnostics. Humana Press. ISBN 978-1-62703-133-2.
  • Li X, Zhou Y, eds. (2013). Microfluidic devices for biomedical applications. Woodhead Publishing. ISBN 978-0-85709-697-5.
  • Tabeling P (2006). Introduction to Microfluidics. Oxford UP. ISBN 978-0-19-856864-3.

Education edit

microfluidics, refers, system, that, manipulates, small, amount, fluids, liters, using, small, channels, with, sizes, hundreds, micrometres, multidisciplinary, field, that, involves, molecular, analysis, molecular, biology, microelectronics, practical, applica. Microfluidics refers to a system that manipulates a small amount of fluids 10 9 to 10 18 liters using small channels with sizes ten to hundreds micrometres It is a multidisciplinary field that involves molecular analysis molecular biology and microelectronics 1 It has practical applications in the design of systems that process low volumes of fluids to achieve multiplexing automation and high throughput screening Microfluidics emerged in the beginning of the 1980s and is used in the development of inkjet printheads DNA chips lab on a chip technology micro propulsion and micro thermal technologies NIST researchers have combined a glass slide plastic sheets and double sided tape to create an inexpensive and simple to build microfluidic device for exposing an array of cells to different concentrations of a chemical Typically micro means one of the following features Small volumes mL nL pL fL Small size Low energy consumption Microdomain effects Typically microfluidic systems transport mix separate or otherwise process fluids Various applications rely on passive fluid control using capillary forces in the form of capillary flow modifying elements akin to flow resistors and flow accelerators In some applications external actuation means are additionally used for a directed transport of the media Examples are rotary drives applying centrifugal forces for the fluid transport on the passive chips Active microfluidics refers to the defined manipulation of the working fluid by active micro components such as micropumps or microvalves Micropumps supply fluids in a continuous manner or are used for dosing Microvalves determine the flow direction or the mode of movement of pumped liquids Often processes normally carried out in a lab are miniaturised on a single chip which enhances efficiency and mobility and reduces sample and reagent volumes Contents 1 Microscale behaviour of fluids 2 Various kinds of microfluidic flows 2 1 Open microfluidics 2 2 Continuous flow microfluidics 2 3 Droplet based microfluidics 2 4 Digital microfluidics 2 5 Paper based microfluidics 2 6 Particle detection microfluidics 2 7 Microfluidic assisted magnetophoresis 3 Key application areas 3 1 DNA chips microarrays 3 2 Molecular biology 3 3 Evolutionary biology 3 4 Cell behavior 3 5 Cellular biophysics 3 6 Optics 3 7 Photonics Lab on a Chip PhLOC 3 8 High Performance Liquid Chromatography HPLC 3 9 Acoustic droplet ejection ADE 3 10 Fuel cells 3 11 Astrobiology 3 12 Food science 3 13 Future directions 3 13 1 Microfluidics for personalized cancer treatment 4 See also 5 References 6 Further reading 6 1 Review papers 6 2 Books 6 3 EducationMicroscale behaviour of fluids edit nbsp Silicone rubber and glass microfluidic devices Top a photograph of the devices Bottom Phase contrast micrographs of a serpentine channel 15 mm wide The behaviour of fluids at the microscale can differ from macrofluidic behaviour in that factors such as surface tension energy dissipation and fluidic resistance start to dominate the system Microfluidics studies how these behaviours change and how they can be worked around or exploited for new uses 2 3 4 5 6 At small scales channel size of around 100 nanometers to 500 micrometers some interesting and sometimes unintuitive properties appear In particular the Reynolds number which compares the effect of the momentum of a fluid to the effect of viscosity can become very low A key consequence is co flowing fluids do not necessarily mix in the traditional sense as flow becomes laminar rather than turbulent molecular transport between them must often be through diffusion 7 High specificity of chemical and physical properties concentration pH temperature shear force etc can also be ensured resulting in more uniform reaction conditions and higher grade products in single and multi step reactions 8 9 Various kinds of microfluidic flows editMicrofluidic flows need only be constrained by geometrical length scale the modalities and methods used to achieve such a geometrical constraint are highly dependent on the targeted application 10 Traditionally microfluidic flows have been generated inside closed channels with the channel cross section being in the order of 10 mm x 10 mm Each of these methods has its own associated techniques to maintain robust fluid flow which have matured over several years citation needed Open microfluidics edit The behavior of fluids and their control in open microchannels was pioneered around 2005 11 and applied in air to liquid sample collection 12 13 and chromatography 14 In open microfluidics at least one boundary of the system is removed exposing the fluid to air or another interface i e liquid 15 16 17 Advantages of open microfluidics include accessibility to the flowing liquid for intervention larger liquid gas surface area and minimized bubble formation 18 15 17 19 Another advantage of open microfluidics is the ability to integrate open systems with surface tension driven fluid flow which eliminates the need for external pumping methods such as peristaltic or syringe pumps 20 Open microfluidic devices are also easy and inexpensive to fabricate by milling thermoforming and hot embossing 21 22 23 24 In addition open microfluidics eliminates the need to glue or bond a cover for devices which could be detrimental to capillary flows Examples of open microfluidics include open channel microfluidics rail based microfluidics paper based and thread based microfluidics 15 20 25 Disadvantages to open systems include susceptibility to evaporation 26 contamination 27 and limited flow rate 17 Continuous flow microfluidics edit Continuous flow microfluidics rely on the control of a steady state liquid flow through narrow channels or porous media predominantly by accelerating or hindering fluid flow in capillary elements 28 In paper based microfluidics capillary elements can be achieved through the simple variation of section geometry In general the actuation of liquid flow is implemented either by external pressure sources external mechanical pumps integrated mechanical micropumps or by combinations of capillary forces and electrokinetic mechanisms 29 30 Continuous flow microfluidic operation is the mainstream approach because it is easy to implement and less sensitive to protein fouling problems Continuous flow devices are adequate for many well defined and simple biochemical applications and for certain tasks such as chemical separation but they are less suitable for tasks requiring a high degree of flexibility or fluid manipulations These closed channel systems are inherently difficult to integrate and scale because the parameters that govern flow field vary along the flow path making the fluid flow at any one location dependent on the properties of the entire system Permanently etched microstructures also lead to limited reconfigurability and poor fault tolerance capability Computer aided design automation approaches for continuous flow microfluidics have been proposed in recent years to alleviate the design effort and to solve the scalability problems 31 nbsp micro fluid sensor Process monitoring capabilities in continuous flow systems can be achieved with highly sensitive microfluidic flow sensors based on MEMS technology which offers resolutions down to the nanoliter range 32 Droplet based microfluidics edit Main article Droplet based microfluidics source source source source High frame rate video showing microbubble pinch off formation in a flow focusing microfluidic device 33 Droplet based microfluidics is a subcategory of microfluidics in contrast with continuous microfluidics droplet based microfluidics manipulates discrete volumes of fluids in immiscible phases with low Reynolds number and laminar flow regimes Interest in droplet based microfluidics systems has been growing substantially in past decades Microdroplets allow for handling miniature volumes mL to fL of fluids conveniently provide better mixing encapsulation sorting and sensing and suit high throughput experiments 34 Exploiting the benefits of droplet based microfluidics efficiently requires a deep understanding of droplet generation 35 to perform various logical operations 36 37 such as droplet manipulation 38 droplet sorting 39 droplet merging 40 and droplet breakup 41 Digital microfluidics edit Main article Digital microfluidics Alternatives to the above closed channel continuous flow systems include novel open structures where discrete independently controllable droplets are manipulated on a substrate using electrowetting Following the analogy of digital microelectronics this approach is referred to as digital microfluidics Le Pesant et al pioneered the use of electrocapillary forces to move droplets on a digital track 42 The fluid transistor pioneered by Cytonix 43 also played a role The technology was subsequently commercialised by Duke University By using discrete unit volume droplets 35 a microfluidic function can be reduced to a set of repeated basic operations i e moving one unit of fluid over one unit of distance This digitisation method facilitates the use of a hierarchical and cell based approach for microfluidic biochip design Therefore digital microfluidics offers a flexible and scalable system architecture as well as high fault tolerance capability Moreover because each droplet can be controlled independently these systems also have dynamic reconfigurability whereby groups of unit cells in a microfluidic array can be reconfigured to change their functionality during the concurrent execution of a set of bioassays Although droplets are manipulated in confined microfluidic channels since the control on droplets is not independent it should not be confused as digital microfluidics One common actuation method for digital microfluidics is electrowetting on dielectric EWOD 44 Many lab on a chip applications have been demonstrated within the digital microfluidics paradigm using electrowetting However recently other techniques for droplet manipulation have also been demonstrated using magnetic force 45 surface acoustic waves 46 optoelectrowetting mechanical actuation 47 etc Paper based microfluidics edit Main article Paper based microfluidics Paper based microfluidic devices fill a growing niche for portable cheap and user friendly medical diagnostic systems 48 Paper based microfluidics rely on the phenomenon of capillary penetration in porous media 49 To tune fluid penetration in porous substrates such as paper in two and three dimensions the pore structure wettability and geometry of the microfluidic devices can be controlled while the viscosity and evaporation rate of the liquid play a further significant role Many such devices feature hydrophobic barriers on hydrophilic paper that passively transport aqueous solutions to outlets where biological reactions take place 50 Paper based microfluidics are considered as portable point of care biosensors used in a remote setting where advanced medical diagnostic tools are not accessible 51 Current applications include portable glucose detection 52 and environmental testing 53 with hopes of reaching areas that lack advanced medical diagnostic tools Particle detection microfluidics edit One application area that has seen significant academic effort and some commercial effort is in the area of particle detection in fluids Particle detection of small fluid borne particles down to about 1 mm in diameter is typically done using a Coulter counter in which electrical signals are generated when a weakly conducting fluid such as in saline water is passed through a small 100 mm diameter pore so that an electrical signal is generated that is directly proportional to the ratio of the particle volume to the pore volume The physics behind this is relatively simple described in a classic paper by DeBlois and Bean 54 and the implementation first described in Coulter s original patent 55 This is the method used to e g size and count erythrocytes red blood cells wiki as well as leukocytes white blood cells for standard blood analysis The generic term for this method is resistive pulse sensing RPS Coulter counting is a trademark term However the RPS method does not work well for particles below 1 mm diameter as the signal to noise ratio falls below the reliably detectable limit set mostly by the size of the pore in which the analyte passes and the input noise of the first stage amplifier citation needed The limit on the pore size in traditional RPS Coulter counters is set by the method used to make the pores which while a trade secret most likely according to whom uses traditional mechanical methods This is where microfluidics can have an impact The lithography based production of microfluidic devices or more likely the production of reusable molds for making microfluidic devices using a molding process is limited to sizes much smaller than traditional machining Critical dimensions down to 1 mm are easily fabricated and with a bit more effort and expense feature sizes below 100 nm can be patterned reliably as well This enables the inexpensive production of pores integrated in a microfluidic circuit where the pore diameters can reach sizes of order 100 nm with a concomitant reduction in the minimum particle diameters by several orders of magnitude As a result there has been some university based development of microfluidic particle counting and sizing 56 57 58 59 60 61 62 63 64 65 excessive citations with the accompanying commercialization of this technology This method has been termed microfluidic resistive pulse sensing MRPS Microfluidic assisted magnetophoresis edit One major area of application for microfluidic devices is the separation and sorting of different fluids or cell types Recent developments in the microfluidics field have seen the integration of microfluidic devices with magnetophoresis the migration of particles by a magnetic field 66 This can be accomplished by sending a fluid containing at least one magnetic component through a microfluidic channel that has a magnet positioned along the length of the channel This creates a magnetic field inside the microfluidic channel which draws magnetically active substances towards it effectively separating the magnetic and non magnetic components of the fluid This technique can be readily utilized in industrial settings where the fluid at hand already contains magnetically active material For example a handful of metallic impurities can find their way into certain consumable liquids namely milk and other dairy products 67 Conveniently in the case of milk many of these metal contaminants exhibit paramagnetism Therefore before packaging milk can be flowed through channels with magnetic gradients as a means of purifying out the metal contaminants Other more research oriented applications of microfluidic assisted magnetophoresis are numerous and are generally targeted towards cell separation The general way this is accomplished involves several steps First a paramagnetic substance usually micro nanoparticles or a paramagnetic fluid 68 needs to be functionalized to target the cell type of interest This can be accomplished by identifying a transmembranal protein unique to the cell type of interest and subsequently functionalizing magnetic particles with the complementary antigen or antibody 67 69 70 71 72 Once the magnetic particles are functionalized they are dispersed in a cell mixture where they bind to only the cells of interest The resulting cell particle mixture can then be flowed through a microfluidic device with a magnetic field to separate the targeted cells from the rest Conversely microfluidic assisted magnetophoresis may be used to facilitate efficient mixing within microdroplets or plugs To accomplish this microdroplets are injected with paramagnetic nanoparticles and are flowed through a straight channel which passes through rapidly alternating magnetic fields This causes the magnetic particles to be quickly pushed from side to side within the droplet and results in the mixing of the microdroplet contents 71 This eliminates the need for tedious engineering considerations that are necessary for traditional channel based droplet mixing Other research has also shown that the label free separation of cells may be possible by suspending cells in a paramagnetic fluid and taking advantage of the magneto Archimedes effect 73 74 While this does eliminate the complexity of particle functionalization more research is needed to fully understand the magneto Archimedes phenomenon and how it can be used to this end This is not an exhaustive list of the various applications of microfluidic assisted magnetophoresis the above examples merely highlight the versatility of this separation technique in both current and future applications Key application areas editMicrofluidic structures include micropneumatic systems i e microsystems for the handling of off chip fluids liquid pumps gas valves etc and microfluidic structures for the on chip handling of nanoliter nl and picoliter pl volumes 75 To date the most successful commercial application of microfluidics is the inkjet printhead 76 Additionally microfluidic manufacturing advances mean that makers can produce the devices in low cost plastics 77 and automatically verify part quality 78 Advances in microfluidics technology are revolutionizing molecular biology procedures for enzymatic analysis e g glucose and lactate assays DNA analysis e g polymerase chain reaction and high throughput sequencing proteomics and in chemical synthesis 28 79 The basic idea of microfluidic biochips is to integrate assay operations such as detection as well as sample pre treatment and sample preparation on one chip 80 81 An emerging application area for biochips is clinical pathology especially the immediate point of care diagnosis of diseases 82 In addition microfluidics based devices capable of continuous sampling and real time testing of air water samples for biochemical toxins and other dangerous pathogens 83 can serve as an always on bio smoke alarm for early warning Microfluidic technology has led to the creation of powerful tools for biologists to control the complete cellular environment leading to new questions and discoveries Many diverse advantages of this technology for microbiology are listed below General single cell studies including growth 84 34 Cellular aging microfluidic devices such as the mother machine allow tracking of thousands of individual cells for many generations until they die 84 Microenvironmental control ranging from mechanical environment 85 to chemical environment 86 87 Precise spatiotemporal concentration gradients by incorporating multiple chemical inputs to a single device 88 Force measurements of adherent cells or confined chromosomes objects trapped in a microfluidic device can be directly manipulated using optical tweezers or other force generating methods 89 Confining cells and exerting controlled forces by coupling with external force generation methods such as Stokes flow optical tweezer or controlled deformation of the PDMS Polydimethylsiloxane device 89 90 91 Electric field integration 91 Plant on a chip and plant tissue culture 92 Antibiotic resistance microfluidic devices can be used as heterogeneous environments for microorganisms In a heterogeneous environment it is easier for a microorganism to evolve This can be useful for testing the acceleration of evolution of a microorganism for testing the development of antibiotic resistance Some of these areas are further elaborated in the sections below DNA chips microarrays edit Early biochips were based on the idea of a DNA microarray e g the GeneChip DNAarray from Affymetrix which is a piece of glass plastic or silicon substrate on which pieces of DNA probes are affixed in a microscopic array Similar to a DNA microarray a protein array is a miniature array where a multitude of different capture agents most frequently monoclonal antibodies are deposited on a chip surface they are used to determine the presence and or amount of proteins in biological samples e g blood A drawback of DNA and protein arrays is that they are neither reconfigurable nor scalable after manufacture Digital microfluidics has been described as a means for carrying out Digital PCR Molecular biology edit In addition to microarrays biochips have been designed for two dimensional electrophoresis 93 transcriptome analysis 94 and PCR amplification 95 Other applications include various electrophoresis and liquid chromatography applications for proteins and DNA cell separation in particular blood cell separation protein analysis cell manipulation and analysis including cell viability analysis 34 and microorganism capturing 81 Evolutionary biology edit By combining microfluidics with landscape ecology and nanofluidics a nano micro fabricated fluidic landscape can be constructed by building local patches of bacterial habitat and connecting them by dispersal corridors The resulting landscapes can be used as physical implementations of an adaptive landscape 96 by generating a spatial mosaic of patches of opportunity distributed in space and time The patchy nature of these fluidic landscapes allows for the study of adapting bacterial cells in a metapopulation system The evolutionary ecology of these bacterial systems in these synthetic ecosystems allows for using biophysics to address questions in evolutionary biology Cell behavior edit Main article Microfluidic cell culture The ability to create precise and carefully controlled chemoattractant gradients makes microfluidics the ideal tool to study motility 97 chemotaxis and the ability to evolve develop resistance to antibiotics in small populations of microorganisms and in a short period of time These microorganisms including bacteria 98 and the broad range of organisms that form the marine microbial loop 99 responsible for regulating much of the oceans biogeochemistry Microfluidics has also greatly aided the study of durotaxis by facilitating the creation of durotactic stiffness gradients Cellular biophysics edit By rectifying the motion of individual swimming bacteria 100 microfluidic structures can be used to extract mechanical motion from a population of motile bacterial cells 101 This way bacteria powered rotors can be built 102 103 Optics edit The merger of microfluidics and optics is typical known as optofluidics Examples of optofluidic devices are tunable microlens arrays 104 105 and optofluidic microscopes Microfluidic flow enables fast sample throughput automated imaging of large sample populations as well as 3D capabilities 106 107 or superresolution 108 Photonics Lab on a Chip PhLOC edit Due to the increase in safety concerns and operating costs of common analytic methods ICP MS ICP AAS and ICP OES 109 the Photonics Lab on a Chip PhLOC is becoming an increasingly popular tool for the analysis of actinides and nitrates in spent nuclear waste The PhLOC is based on the simultaneous application of Raman and UV Vis NIR spectroscopy 110 which allows for the analysis of more complex mixtures which contain several actinides at different oxidation states 111 Measurements made with these methods have been validated at the bulk level for industrial tests 109 112 and are observed to have a much lower variance at the micro scale 113 This approach has been found to have molar extinction coefficients UV Vis in line with known literature values over a comparatively large concentration span for 150 mL 111 via elongation of the measurement channel and obeys Beer s Law at the micro scale for U IV 114 Through the development of a spectrophotometric approach to analyzing spent fuel an on line method for measurement of reactant quantities is created increasing the rate at which samples can be analyzed and thus decreasing the size of deviations detectable within reprocessing 112 Through the application of the PhLOC flexibility and safety of operational methods are increased Since the analysis of spent nuclear fuel involves extremely harsh conditions the application of disposable and rapidly produced devices Based on castable and or engravable materials such as PDMS PMMA and glass 115 is advantageous although material integrity must be considered under specific harsh conditions 114 Through the usage of fiber optic coupling the device can be isolated from instrumentation preventing irradiative damage and minimizing the exposure of lab personnel to potentially harmful radiation something not possible on the lab scale nor with the previous standard of analysis 111 The shrinkage of the device also allows for lower amounts of analyte to be used decreasing the amount of waste generated and exposure to hazardous materials 111 Expansion of the PhLOC to miniaturize research of the full nuclear fuel cycle is currently being evaluated with steps of the PUREX process successfully being demonstrated at the micro scale 110 Likewise the microfluidic technology developed for the analysis of spent nuclear fuel is predicted to expand horizontally to analysis of other actinide lanthanides and transition metals with little to no modification 111 High Performance Liquid Chromatography HPLC edit HPLC in the field of microfluidics comes in two different forms Early designs included running liquid through the HPLC column then transferring the eluted liquid to microfluidic chips and attaching HPLC columns to the microfluidic chip directly 116 The early methods had the advantage of easier detection from certain machines like those that measure fluorescence 117 More recent designs have fully integrated HPLC columns into microfluidic chips The main advantage of integrating HPLC columns into microfluidic devices is the smaller form factor that can be achieved which allows for additional features to be combined within one microfluidic chip Integrated chips can also be fabricated from multiple different materials including glass and polyimide which are quite different from the standard material of PDMS used in many different droplet based microfluidic devices 118 119 This is an important feature because different applications of HPLC microfluidic chips may call for different pressures PDMS fails in comparison for high pressure uses compared to glass and polyimide High versatility of HPLC integration ensures robustness by avoiding connections and fittings between the column and chip 120 The ability to build off said designs in the future allows the field of microfluidics to continue expanding its potential applications The potential applications surrounding integrated HPLC columns within microfluidic devices have proven expansive over the last 10 15 years The integration of such columns allows for experiments to be run where materials were in low availability or very expensive like in biological analysis of proteins This reduction in reagent volumes allows for new experiments like single cell protein analysis which due to size limitations of prior devices previously came with great difficulty 121 The coupling of HPLC chip devices with other spectrometry methods like mass spectrometry allow for enhanced confidence in identification of desired species like proteins 122 Microfluidic chips have also been created with internal delay lines that allow for gradient generation to further improve HPLC which can reduce the need for further separations 123 Some other practical applications of integrated HPLC chips include the determination of drug presence in a person through their hair 124 and the labeling of peptides through reverse phase liquid chromatography 125 Acoustic droplet ejection ADE edit Acoustic droplet ejection uses a pulse of ultrasound to move low volumes of fluids typically nanoliters or picoliters without any physical contact This technology focuses acoustic energy into a fluid sample to eject droplets as small as a millionth of a millionth of a litre picoliter 10 12 litre ADE technology is a very gentle process and it can be used to transfer proteins high molecular weight DNA and live cells without damage or loss of viability This feature makes the technology suitable for a wide variety of applications including proteomics and cell based assays Fuel cells edit Further information Electroosmotic pump Microfluidic fuel cells can use laminar flow to separate the fuel and its oxidant to control the interaction of the two fluids without the physical barrier that conventional fuel cells require 126 127 128 Astrobiology edit To understand the prospects for life to exist elsewhere in the universe astrobiologists are interested in measuring the chemical composition of extraplanetary bodies 129 Because of their small size and wide ranging functionality microfluidic devices are uniquely suited for these remote sample analyses 130 131 132 From an extraterrestrial sample the organic content can be assessed using microchip capillary electrophoresis and selective fluorescent dyes 133 These devices are capable of detecting amino acids 134 peptides 135 fatty acids 136 and simple aldehydes ketones 137 and thiols 138 These analyses coupled together could allow powerful detection of the key components of life and hopefully inform our search for functioning extraterrestrial life 139 Food science edit Microfluidic techniques such as droplet microfluidics paper microfluidics and lab on a chip are used in the realm of food science in a variety of categories 140 Research in nutrition 141 142 food processing and food safety benefit from microfluidic technique because experiments can be done with less reagents 140 Food processing requires the ability to enable shelf stability in foods such as emulsions or additions of preservatives Techniques such as droplet microfluidics are used to create emulsions that are more controlled and complex than those created by traditional homogenization due to the precision of droplets that is achievable Using microfluidics for emulsions is also more energy efficient compared to homogenization in which only 5 of the supplied energy is used to generate the emulsion with the rest dissipated as heat 143 Although these methods have benefits they currently lack the ability to be produced at large scale that is needed for commercialization 144 Microfluidics are also used in research as they allow for innovation in food chemistry and food processing 140 144 An example in food engineering research is a novel micro 3D printed device fabricated to research production of droplets for potential food processing industry use particularly in work with enhancing emulsions 145 Paper and droplet microfluidics allow for devices that can detect small amounts of unwanted bacteria or chemicals making them useful in food safety and analysis 146 Paper based microfluidic devices are often referred to as microfluidic paper based analytical devices mPADs and can detect such things as nitrate 147 preservatives 148 or antibiotics 149 in meat by a colorimetric reaction that can be detected with a smartphone These methods are being researched because they use less reactants space and time compared to traditional techniques such as liquid chromatography mPADs also make home detection tests possible which is of interest to those with allergies and intolerances 147 In addition to paper based methods research demonstrates droplet based microfluidics shows promise in drastically shortening the time necessary to confirm viable bacterial contamination in agricultural waters in the domestic and international food industry 146 Future directions edit Microfluidics for personalized cancer treatment edit Personalized cancer treatment is a tuned method based on the patient s diagnosis and background Microfluidic technology offers sensitive detection with higher throughput as well as reduced time and costs For personalized cancer treatment tumor composition and drug sensitivities are very important 150 A patient s drug response can be predicted based on the status of biomarkers or the severity and progression of the disease can be predicted based on the atypical presence of specific cells 151 Drop qPCR is a droplet microfluidic technology in which droplets are transported in a reusable capillary and alternately flow through two areas maintained at different constant temperatures and fluorescence detection It can be efficient with a low contamination risk to detect Her2 150 A digital droplet based PCR method can be used to detect the KRAS mutations with TaqMan probes to enhance detection of the mutative gene ratio 152 In addition accurate prediction of postoperative disease progression in breast or prostate cancer patients is essential for determining post surgery treatment A simple microfluidic chamber coated with a carefully formulated extracellular matrix mixture is used for cells obtained from tumor biopsy after 72 hours of growth and a thorough evaluation of cells by imaging 153 Microfluidics is also suitable for circulating tumor cells CTCs and non CTCs liquid biopsy analysis Beads conjugate to anti epithelial cell adhesion molecule EpCAM antibodies for positive selection in the CTCs isolation chip iCHIP 154 CTCs can also be detected by using the acidification of the tumor microenvironment and the difference in membrane capacitance 155 156 CTCs are isolated from blood by a microfluidic device and are cultured on chip which can be a method to capture more biological information in a single analysis For example it can be used to test the cell survival rate of 40 different drugs or drug combinations 157 Tumor derived extracellular vesicles can be isolated from urine and detected by an integrated double filtration microfluidic device they also can be isolated from blood and detected by electrochemical sensing method with a two level amplification enzymatic assay 158 159 Tumor materials can directly be used for detection through microfluidic devices To screen primary cells for drugs it is often necessary to distinguish cancerous cells from non cancerous cells A microfluidic chip based on the capacity of cells to pass small constrictions can sort the cell types metastases 160 Droplet based microfluidic devices have the potential to screen different drugs or combinations of drugs directly on the primary tumor sample with high accuracy To improve this strategy the microfluidic program with a sequential manner of drug cocktails coupled with fluorescent barcodes is more efficient 161 Another advanced strategy is detecting growth rates of single cell by using suspended microchannel resonators which can predict drug sensitivities of rare CTCs 162 Microfluidics devices also can simulate the tumor microenvironment to help to test anticancer drugs Microfluidic devices with 2D or 3D cell cultures can be used to analyze spheroids for different cancer systems such as lung cancer and ovarian cancer and are essential for multiple anti cancer drugs and toxicity tests This strategy can be improved by increasing the throughput and production of spheroids For example one droplet based microfluidic device for 3D cell culture produces 500 spheroids per chip 163 These spheroids can be cultured longer in different surroundings to analyze and monitor The other advanced technology is organs on a chip and it can be used to simulate several organs to determine the drug metabolism and activity based on vessels mimicking as well as mimic pH oxygen to analyze the relationship between drugs and human organ surroundings 163 A recent strategy is single cell chromatin immunoprecipitation ChiP Sequencing in droplets which operates by combining droplet based single cell RNA sequencing with DNA barcoded antibodies possibly to explore the tumor heterogeneity by the genotype and phenotype to select the personalized anti cancer drugs and prevent the cancer relapse 164 See also edit nbsp Biology portal nbsp Technology portal Advanced Simulation Library Droplet based microfluidics Fluidics Induced charge electrokinetics Integrated fluidic circuit Lab on a chip Microfluidic cell culture Microfluidic modulation spectroscopy Microphysiometry Micropumps Microvalves uFluids Home Paper based microfluidicsReferences edit Whitesides George M July 2006 The origins and the future of microfluidics Nature 442 7101 368 373 Bibcode 2006Natur 442 368W doi 10 1038 nature05058 ISSN 0028 0836 PMID 16871203 S2CID 205210989 Terry SC Jerman JH Angell JB December 1979 A gas chromatographic air analyzer fabricated on a silicon wafer IEEE Transactions on Electron Devices 26 12 1880 6 Bibcode 1979ITED 26 1880T doi 10 1109 T ED 1979 19791 S2CID 21971431 Kirby BJ 2010 Micro and Nanoscale Fluid Mechanics Transport in Microfluidic Devices Cambridge University Press Archived from the original on 2019 04 28 Retrieved 2010 02 13 Karniadakis GM Beskok A Aluru N 2005 Microflows and Nanoflows Springer Verlag Bruus H 2007 Theoretical Microfluidics Oxford 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Fluid physics at the nanoliter scale PDF Reviews of Modern Physics 77 3 977 1026 Bibcode 2005RvMP 77 977S doi 10 1103 RevModPhys 77 977 Yetisen AK Volpatti LR July 2014 Patent protection and licensing in microfluidics Lab on a Chip 14 13 2217 2225 doi 10 1039 C4LC00399C PMID 24825780 S2CID 8669721 Chen K 2011 Microfluidics and the future of drug research Journal of Undergraduate Life Sciences 5 1 66 69 Archived from the original on 2012 03 31 Retrieved 2011 08 30 Angell JB Terry SC Barth PW April 1983 Silicon Micromechanical Devices Scientific American 248 4 44 55 Bibcode 1983SciAm 248d 44A doi 10 1038 scientificamerican0483 44 Carugo D Bottaro E Owen J Stride E Nastruzzi C May 2016 Liposome production by microfluidics potential and limiting factors Scientific Reports 6 25876 Bibcode 2016NatSR 625876C doi 10 1038 srep25876 PMC 4872163 PMID 27194474 Chossat JB Park YL Wood RJ Duchaine V September 2013 A Soft Strain Sensor Based on Ionic and Metal Liquids IEEE Sensors Journal 13 9 3405 3414 Bibcode 2013ISenJ 13 3405C CiteSeerX 10 1 1 640 4976 doi 10 1109 JSEN 2013 2263797 S2CID 14492585 Tseng TM Li M Freitas DN Mongersun A Araci IE Ho TY Schlichtmann U 2018 Columba S a scalable co layout design automation tool for microfluidic large scale integration PDF Proceedings of the 55th Annual Design Automation Conference p 163 Archived from the original PDF on April 9 2023 Books edit Bruus H 2008 Theoretical Microfluidics Oxford University Press ISBN 978 0199235094 Folch Albert Hidden in Plain Sight The History Science and Engineering of Microfluidic Technology MIT Press 2022 online review Herold KE Rasooly A 2009 Lab on a Chip Technology Fabrication and Microfluidics Caister Academic Press ISBN 978 1 904455 46 2 Kelly R ed 2012 Advances in Microfluidics Richland Washington USA Pacific Northwest National Laboratory ISBN 978 953 510 106 2 Jenkins G Mansfield CD 2012 Microfluidic Diagnostics Humana Press ISBN 978 1 62703 133 2 Li X Zhou Y eds 2013 Microfluidic devices for biomedical applications Woodhead Publishing ISBN 978 0 85709 697 5 Tabeling P 2006 Introduction to Microfluidics Oxford UP ISBN 978 0 19 856864 3 nbsp Wikimedia Commons has media related to Microfluidics Education edit nbsp Wikibooks has a book on the topic of Microfluidics nbsp Scholia has a topic profile for Microfluidics Retrieved from https en wikipedia org w index php title Microfluidics amp oldid 1224163888, wikipedia, wiki, book, books, library,

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