Droplet-based microfluidics

Droplet-based microfluidics manipulate discrete volumes of fluids in immiscible phases with low Reynolds number and laminar flow regimes.[1][2] Interest in droplet-based microfluidics systems has been growing substantially in past decades.[3] Microdroplets offer the feasibility of handling miniature volumes (μl to fl) of fluids conveniently, provide better mixing, encapsulation, sorting, sensing and are suitable for high throughput experiments.[4][1] Two immiscible phases used for the droplet based systems are referred to as the continuous phase (medium in which droplets flow) and dispersed phase (the droplet phase).[5]

Droplet formation methods

In order for droplet formation to occur, two immiscible phases, referred to as the continuous phase (medium in which droplets are generated) and dispersed phase (the droplet phase), must be used.[5] The size of the generated droplets is mainly controlled by the flow rate ratio of the continuous phase and dispersed phase, interfacial tension between two phases, and the geometry of the channels used for droplet generation.[6] Droplets can be formed both passively and actively.[7] Active droplet formation (electric, magnetic, centrifugal) often uses similar devices to passive formation but requires an external energy input for droplet manipulation.[7] Passive droplet formation tends to be more common than active as it produces similar results with simpler device designs. Generally, three types of microfluidic geometries are utilized for passive droplet generation: (i) Cross-Flowing, (ii) Flow Focusing, and (iii) Co-Flowing.[7] Droplet based microfluidics often operate under low Reynold’s numbers to ensure laminar flow within the system.[8] Droplet size is often quantified with coefficient of variation (CV) as a description of the standard deviation from the mean droplet size. Each of the listed methods provide a way to generate microfluidic droplets in a controllable and tunable manner with proper variable manipulation.

Cross-flowing droplet formation

Cross-flowing is a passive formation method that involves the continuous and aqueous phases running at an angle to each other.[9] Most commonly, the channels are perpendicular in a T-shaped junction with the dispersed phase intersecting the continuous phase; other configurations such as a Y-junction are also possible.[7][10] The dispersed phase extends into the continuous and is stretched until shear forces break off a droplet.[11][12] In a T-junction, droplet size and formation rate are determined by the flow rate ratio and capillary number.[13] The capillary number relates the viscosity of the continuous phase, the superficial velocity of the continuous phase, and the interfacial tension.[6] Typically, the dispersed phase flow rate is slower than the continuous flow rate. T-junction formation can be further applied by adding additional channels, creating two T-junctions at one location. By adding channels, different dispersed phases can be added at the same point to create alternating droplets of different compositions.[14] Droplet size, usually above 10 μm, is limited by the channel dimensions and often produces droplets with a CV of less than 2% with a rate of up to 7 kHz[4].

Flow focusing droplet formation

Flow focusing is a usually passive formation method that involves the dispersed phase flowing to meet the continuous phase typically at an angle (nonparallel streams) then undergoing a constraint that creates a droplet.[15] This constraint is generally a narrowing in the channel to create the droplet though symmetric shearing, followed by a channel of equal or greater width.[16] As with cross-flowing, the continuous phase flow rate is typically higher than the dispersed phase flow rate. Decreasing the flow of the continuous phase can increase the size of the droplets.[4] Flow focusing can also be an active method with the constraint point being adjustable using pneumatic side chambers controlled by compressed air.[17] The movable chambers act to pinch the flow, deforming the stream and creating a droplet with a changeable driving frequency. Droplet size is usually around several hundred nanometers with a CV of less than 3% and a rate of up to several hundred Hz to tens of kHz.[7]

Co-flowing droplet formation

Co-flowing is a passive droplet formation method where the dispersed phase channel is enclosed inside a continuous phase channel.[18] At the end of the dispersed phase channel, the fluid is stretched until it breaks from shear forces and forms droplets either by dripping or jetting.[19] Dripping occurs when capillary forces dominate the system and droplets are created at the channel endpoint.[19] Jetting occurs, by widening or stretching, when the continuous phase is moving slower, creating a stream from the dispersed phase channel opening. Under the widening regime, the dispersed phase is moving faster than the continuous phase causing a deceleration of the dispersed phase, widening the droplet and increasing the diameter.[20] Under the stretching regime, viscous drag dominates causing the stream to narrow creating a smaller droplet.[20] The effect of the continuous phase flow rate on the droplet size depends on whether the system is in a stretching or widening regime thus different equations must be used to predict droplet size.[19] Droplet size is usually around several hundred nanometers with a CV of less than 5% and a rate of up to tens of kHz.[7]

Droplet manipulation

The benefits of microfluidics can be scaled up to higher throughput using larger channels to allow more droplets to pass or by increasing droplet size.[21] Droplet size can be tuned by adjusting the rate of flow of the continuous and disperse phases, but droplet size is limited by the need to maintain the concentration, inter-analyte distances, and stability of microdroplets.[22] Thus, increased channel size becomes attractive due to the ability to create and transport a large number of droplets,[21] though dispersion[23] and stability of droplets[24] become a concern. Finally, thorough mixing of droplets to expose the greatest possible number of reagents is necessary to ensure the maximum amount of starting materials react.[21] This can be accomplished by using a windy channel to facilitate unsteady laminar flow within the droplets.[25]

Reagent addition

Microscale reactions performed in droplet-based applications conserve reagents and reduce reaction time all at kilohertz rates.[26][27] Reagent addition to droplet microreactors has been a focus of research due to the difficulty of achieving reproducible additions at kilohertz rates without droplet-to-droplet contamination.[28]

Reagent coflow prior to droplet formation

Reagents can be added at the time of droplet formation through a “co-flow” geometry.[29] Reagent streams are pumped in separate channels and join at the interface with a channel containing the continuous phase, which shears and creates droplets containing both reagents. By changing the flow rates in reagent channels, reagent ratios within a droplet can be controlled.[30][31]

Droplet fusion

The fusion of droplets with different contents can also be exploited for reagent addition. Electro-coalescence merges pairs of droplets by applying an electric field to temporarily destabilize the droplet-droplet interface to achieve reproducible droplet fusion in surfactant-stabilized emulsions.[32][33] Electro-coalescence requires droplets (which are normally separated by the continuous phase) to come into contact. By manipulating droplet size in separate streams, differential flow of droplet sizes can bring droplets into contact before merging.[34]

Injection of reagents into existing droplets

Reagent co-flow and droplet fusion methods are tied to droplet formation events which lack downstream flexibility. To decouple reagent addition from droplet creation, a setup where reagent stream flows through a channel perpendicular to the droplet stream is utilized.[35][36] An injection droplet is then merged with the plug as it passes the channel. Reagent volume is controlled by the flow rate of the perpendicular reagent channel.

An early challenge for such systems is that reagent droplet merging was not reproducible for stable emulsions.[37] By adapting the use of an actuated electric field into this geometry, Abate et al. achieved sub-picoliter control of reagent injection.[37] This approach, termed picoinjection, controls injection volume through reagent stream pressure and droplet velocity. Further work on this method has aimed to reduce pressure fluctuations that impede reproducible injections.[38]

Droplet-to-droplet contamination is a challenge of many injection methods.[39] To combat this, Doonan et al. developed a multifunctional K-channel, which flows reagent streams opposite the path of the droplet stream.[40] Utilizing an interface between the two channels, injection is achieved similarly to picoinjection, but any bilateral contamination washed away through continuous reagent flow. Contamination is avoided at the expense of potentially wasting precious reagent.

Droplet incubation

In order to make droplet-based microfluidics a viable technique for carrying out chemical reactions or working with living cells on the microscale, it is necessary to implement methods allowing for droplet incubation.[41] Chemical reactions often need time to occur, and living cells similarly require time to grow, multiply, and carry out metabolic processes. Droplet incubation can be accomplished either within the device itself (on-chip) or externally (off-chip), depending on the parameters of the system.[42] Off-chip incubation is useful for incubation times of a day or more or for incubation of millions of droplets at a time.[42] On-chip incubation allows for integration of droplet manipulation and detection steps in a single device.[42]

Off-chip incubation

Droplets containing cells can be stored off-chip in PTFE tubing for up to several days while maintaining cell viability and allowing for reinjection onto another device for analysis.[43] Evaporation of aqueous and oil-based fluids has been reported with droplet storage in PTFE tubing, so for storage longer than several days, glass capillaries are also used.[44] Finally, following formation in a microfluidic device, droplets may also be guided through a system of capillaries and tubing leading to a syringe. Droplets can be incubated in the syringe and then directly injected onto another chip for further manipulation or detection and analysis.[45]

On-chip incubation

Delay lines are used to incubate droplets on-chip. After formation, droplets can be introduced into a serpentine channel with length of up to a meter or more.[46][47] Increasing the depth and width of the delay line channel (as compared to channels used to form and transport droplets) enables longer incubation times while minimizing channel back pressure.[47] Because of the larger channel size, droplets fill up the delay line channel[48] and incubate in the time it takes the droplets to traverse this channel.

Delay lines were originally designed for incubating droplets containing chemical reaction mixtures and were capable of achieving delay times of up to one hour.[47][49][50] These devices make use of delay line channels tens of centimeters in length. Increasing the total length of the delay line channels to one or more meters made incubation times of 12 or more hours possible.[46][51] Delay lines have been shown to maintain droplet stability for up to 3 days,[51] and cell viability has been demonstrated using on-chip delay lines for up to 12 hours.[46] Prior to the development of delay lines, on-chip incubation was performed by directing droplets into large reservoirs (several millimeters in both length and width), which offers high storage capacity and lower complexity of device construction and operation if precise time control of droplets is not required.[52]

If it is important to have a uniform distribution of incubation times for the droplets, the delay line channel may contain regularly-spaced constrictions.[47] Droplets flowing through a channel of uniform diameter travel at different speeds based on their radial position; droplets closer to the center of the channel move faster than those near the edges.[47] By narrowing the channel width to a fraction of its original size, droplets with higher velocities are forced to equilibrate with slower-moving droplets because the constriction allows fewer droplets to pass through at a time.[47] Another manipulation to the geometry of the delay line channel involves introducing turns to the droplets' trajectory. This increases the extent to which any reagents contained within the droplets are mixed via chaotic advection.[25] For systems requiring the incubation of 100 to 1000 droplets, traps can be fabricated in the delay line channel that store droplets separately from one another.[53][54] This provides for finer control and monitoring of individual droplets.

Magnetic droplets

The micro-magnetofluidic method is the control of magnetic fluids by an applied magnetic field on a microfluidic platform,[55] offering wireless and programmable control of the magnetic droplets.[56] Hence, the magnetic force can also be used to perform various logical operations, in addition to the hydrodynamic force and the surface tension force. The magnetic field strength, type of the magnetic field (gradient, uniform or rotating), magnetic susceptibility, interfacial tension, flow rates, and flow rate ratios determine the control of the droplets on a micro-magnetofluidic platform.[57]

Key applications

Cell culture

One of the key advantages of droplet-based microfluidics is the ability to use droplets as incubators for single cells.[58][59]

Devices capable of generating thousands of droplets per second opens new ways characterize cell population, not only based on a specific marker measured at a specific time point but also based on cells' kinetic behavior such as protein secretion, enzyme activity or proliferation. Recently, a method was found to generate a stationary array of microscopic droplets for single-cell incubation that does not require the use of a surfactant.

Biological macromolecule characterization

Protein crystallization

Droplet-based devices have also been used to investigate the conditions necessary for protein crystallization.[60][61]

Droplet-based PCR

Polymerase chain reaction (PCR) has been a vital tool in genomics and biological endeavors since its inception as it has greatly sped up production and analysis of DNA samples for a wide range of applications.[62] The technological advancement of microdroplet scale PCR has enabled the construction of single-molecule PCR-on-a-chip device.[63] Early single molecule DNA replication, including what occurs in microdroplet or emulsion PCR, was more difficult than larger scale PCR so much higher concentrations of components were usually used.[64] However, fully optimized conditions have minimized this overload by insuring single molecules have an appropriate concentration of replication components distributed throughout the reaction cell.[64] Non-droplet based microfluidic PCR also faces challenges with reagent absorption into the device channels, but droplet-based systems lessen this problem with decreased channel contact.[65]

Using water-in-oil systems, droplet PCR operates by assembling ingredients, forming droplets, combining droplets, thermocycling, and then processing results much like normal PCR. This technique is capable of running in excess of 2 million PCR reactions in addition to a 100,000-fold increase in the detection of wild-type alleles over mutant alleles.[66] Droplet-based PCR greatly increases the multiplexing capabilities of normal PCR – allowing for fast production of mutation libraries. Without proofreading, DNA replication is inherently somewhat error-prone, but by introducing error-prone polymerases, droplet-based PCR utilizes higher than normal mutation output to build a mutation library more quickly and efficiently than normal.[67] This makes droplet-based PCR more attractive than slower, traditional PCR.[68] In a similar application, highly multiplexed, microdroplet PCR has been developed that allows for the screening of large numbers of target sequences enabling applications such as bacterial identification.[69] On-chip PCR allows for an excess of 15 x 15 multiplexing, which means that multiple target DNA sequences could be run on the same device at the same time.[70] This multiplexing was made possible with immobilized DNA primer fragments placed in the base of the individual wells of the chips.[71]

Combining droplet-based PCR with polydimethylsiloxane (PDMS) devices has allowed for novel enhancements of droplet PCR as well as remedying some preexisting problems with droplet PCR including high liquid loss due to evaporation.[72] Droplet-based PCR is highly sensitive to air bubbles as they create temperature differentials hindering DNA replication while also dislodging reagents from the replication chamber.[65] Now, droplet-based PCR has been carried out in PDMS devices to transfer reagents into droplets through a PDMS layer in a more controlled manner that better maintains replication progress and stability than traditional valves.[73] A recent droplet-PCR PDMS device allowed for higher accuracy and amplification of small copy numbers in comparison to traditional quantitative PCR experiments.[74] This higher accuracy was due to surfactant-doped PDMS as well as a sandwiched glass-PDMS-glass device design. These device properties have allowed for more streamlined priming of DNA and less water evaporation during PCR cycling.[74]

DNA sequencing

DNA sequence information gathered from healthy and diseased tissues is highly valuable in the medical field as mutations can be identified, individualized medical care can be administered, and organisms identified and cataloged.[75][76] First demonstrated on an integrated microchip by Mathies et al.,[77] droplet-based microfluidics has become an important, cost-effective approach to DNA sequencing that provides high throughput and high accuracy sequencing information.[78] DNA sequencing via droplets gained popularity with the utilization of fluorescent probes for high sensitivity and region specificity.[79][80]

Most microfluidic DNA sequencing focuses on single nucleobase reading.[81][82] Commercially available devices utilizing cyclic-array sequencing of DNA, and tag sequences with intermediate fluorophore attachment; these devices provide adequate sample throughput but suffer from photobleaching and complications with multi-component biomolecules.[83] Real-time DNA sequencing provides the means of single-molecule processing within even smaller environments.[84] This method uses various fluorophores which can attach to specific nucleobases and eliminate the need for cyclic-array sequencing.[85] Multi-dye methods produce an increased accuracy at a decreased throughput. However, this method can be hindered by proximity limitations, biased detection, and labeling efficiencies.[78]

Chemical synthesis

Droplet-based microfluidics has become an important tool in chemical synthesis due to several attractive features. Microscale reactions allow for cost reduction through the usage of small reagent volumes, rapid reactions in the order of milliseconds, and efficient heat transfer that leads to environmental benefits when the amount of energy consumed per unit temperature rise can be extremely small.[86] The degree of control over local conditions within the devices often makes it possible to select one product over another with high precision.[86][87] With high product selectivity and small sizes of reagents and reaction environments come less stringent reaction clean-up and smaller footprint.[86] Microdispersed droplets created by droplet-based chemistry are capable of acting as environments in which chemical reactions occur, as reagent carriers in the process of generating complex nanostructures.[88] Droplets are also capable of being transformed into cell-like structures which can be used to mimic humans' biological components and processes.[88][87]

As a method of chemical synthesis, Droplets in microfluidics devices act as individual reaction chambers protected from contamination through device fouling by the continuous phase. Benefits of synthesis using this regime (compared to batch processes) include high throughput, continuous experiments, low waste, portability, and a high degree of synthetic control.[88] Some examples of possible syntheses are the creation of semiconductor microspheres[89] and nanoparticles.[90] Chemical detection is integrated into the device to ensure careful monitoring of reactions, NMR spectroscopy, microscopy, electrochemical detection, and chemiluminescent detection are used. Often, measurements are taken at different points along the microfluidic device to monitor the progress of the reaction.[88]

Increased rate of reactions using microdroplets is seen in the aldol reaction of silyl enol ethers and aldehydes. Using a droplet-based microfluidic device, reaction times were shortened to twenty minutes versus the twenty-four hours required for a batch process.[22] Other experimenters were able to show a high selectivity of cis-stilbene to the thermodynamically favored trans-stilbene compared to the batch reaction, showing the high degree of control afforded by microreactor droplets. This stereocontrol is beneficial to the pharmaceutical industry.[91] For instance, L-Methotrexate, a drug used in chemotherapy, is more readily absorbed than the D isomer.

Nanoparticle synthesis

Advanced particles and particle-based materials, such as polymer particles, microcapsules, nanocrystals, and photonic crystal clusters or beads can be synthesized with the assistance of droplet-based microfluidics.[92] Nanoparticles, such as colloidal CdS and CdS/CdSe core-shell nanoparticles, can also be synthesized through multiple steps on a millisecond time scale in a microfluidic droplet-based system.[93]

Extraction and phase transfer using droplet microfluidics

Liquid-liquid extraction is a method used to separate an analyte from a complex mixture; with this method compounds separate based on their relative solubility in different immiscible liquid phases.[94][95] To overcome some of the disadvantages associated with common bench top methods such as the shake-flask method,[96] microfluidic liquid-liquid extraction methods have been employed. Microfluidic droplet-based systems have demonstrated the capability to manipulate discrete volumes of fluids in immiscible phases with low Reynolds numbers[97] and laminar flow regimes.[98] Microscale methods reduce time required, reduce sample and reagent volume, and allow for automation and integration.[99][100] In some studies, the performance of droplet-based microfluidic extraction compares closely with the shake-flask method.[101] A study which compared the shake-flask and microfluidic liquid-Liquid extrication methods for 26 compounds and found a close correlation between the values obtained (R2= 0.994).[102]

It has also been demonstrated that microfluidic liquid-liquid extraction devices can be integrated with other instruments for detection of the extracted analytes[103][104] For example, microfluidic extraction could be used to extract an analyte initially in an aqueous phase such as cocaine in saliva then interfaced with on-chip IR spectroscopy for detection[105] Microfluidic liquid-liquid extraction has shown to be advantageous in numerous applications such as pharmacokinetic drug studies where only small cell numbers are needed,[106][107] and in additional studies where smaller reagent volumes are required.[108]

Droplet detection

Separation methods

Droplet-based microfluidic systems can be coupled to separation methods for specific tasks. Common separation techniques coupled to droplet-based microfluidic systems include High Performance Liquid Chromatography (HPLC) and electrophoresis.

High performance liquid chromatography

Chemical separation on the microscale can be used in both biological and chemical analysis.[109][110][111] As an analytical tool, a chemical separation technique, like HPLC, can be coupled to a microfluidic device. Droplet-based microfluidic devices coupled to HPLC have high detection sensitivity, use low volumes of reagents, have short analysis times, and minimal cross-contamination of analytes, which make them efficient in many aspects.[112] One basic use of HPLC in droplet-based microfluidics is chemical separation by HPLC, which is then connected to a device that creates microliter sized droplets of each eluted compound. With this system, it is possible to create large droplet libraries of different compounds in a centralized location.[109] However, there are problems associated with microscale chromatography, like HPLC. These problems include dispersion of separated bands, diffusion, and “dead volume” in channels after separation.[110] One way to bypass these issues is the use of droplets to compartmentalize separation bands, which combats diffusion and the loss of separated analytes.[111] An advantage to using HPLC coupled to a microfluidic device is that more than one separation can be coupled. For example, 2D separation (two-dimensional chromatography) is possible with these devices (i.e. HPLC x LC, LC x LC, and HPLC x HPLC).[113]

Electrophoresis

Capillary electrophoresis (CE) and microcapillary gel electrophoresis (μCGE) are well-recognized microchip electrophoresis (MCE) methods that can provide numerous analytical advantages including high resolution, high sensitivity, and effective coupling to mass spectrometry (MS).[114][115][116] Microchip electrophoresis can be applied generally as a method for high-throughput screening processes that help discover and evaluate drugs.[115] Using MCE, specifically CE, microcapillary gel electrophoresis (μCGE) devices are created to perform high-number DNA sample processing, which makes it a good candidate for DNA analysis.[116][117] μCGE devices are also practical for separation purposes because they use online separation, characterization, encapsulation, and selection of differing analytes originating from a composite sample.[116] All of these advantages of MCE methods translate to microfluidic devices. The reason MCE methods are coupled to droplet-based microfluidic devices is because of the ability to analyze samples on the nanoliter scale.[118] Using MCE methods on a small scale reduces cost and reagent use.[116] Similarly to HPLC, fluorescence based detection techniques are used for capillary electrophoresis, which make these methods practical and can be applied to fields such as biotechnology, analytical chemistry, and drug development.[119] These MCE and other electrophoresis based methods began to develop once capillary electrophoresis gained popularity in the 1980s and gained even more attention in the early 1990s, as it was reviewed nearly 80 times by the year 1992.[120]

Mass spectrometry (MS) is a near universal detection technique that is recognized throughout the world as the gold standard for identification of manycompounds. MS is an analytical technique in which chemical species are ionized and sorted before detection, and the resulting mass spectrum is used to identify the ions' parent molecules. This makes MS, unlike other detection techniques (such as fluorescence), label-free; i.e. there is no need to bind additional ligands or groups to the molecule of interest in order to receive a signal and identify the compound.

There are many cases in which other spectroscopic methods, such as nuclear magnetic resonance (NMR), fluorescence, infrared, or Raman, are not viable as standalone methods due to the particular chemical composition of the droplets. Often, these droplets are sensitive to fluorescent labels,[55] or contain species that are otherwise indeterminately similar, where MS may be employed along with other methods to characterize a specific analyte of interest.[56] [57]However, MS has only recently (in the past decade) gained popularity as a detection method for droplet-based microfluidics (and microfluidics as a whole) due to challenges associated with coupling mass spectrometers with these miniaturized devices.[121][122][123] Difficulty of separation/purification make entirely microfluidic scale systems coupled to mass spectrometry ideal in the fields of proteomics,[124][55] [58] [59] enzyme kinetics,[60] drug discovery,[37] and newborn disease screening.[61] The two primary methods of ionization for mass analysis used in droplet-based microfluidics today are matrix-assisted laser desorption/ionization (MALDI)[62] [63] and electrospray ionization (ESI).[55] Additional methods for coupling, such as (but not limited to) surface acoustic wave nebulization (SAWN),[125] and paper-spray ionization onto miniaturized MS,[126] are being developed as well.[121][64]

Mass spectrometry

Mass spectrometry (MS) is a near universal detection technique that is recognized throughout the world as the gold standard for identification of manycompounds. MS is an analytical technique in which chemical species are ionized and sorted before detection, and the resulting mass spectrum is used to identify the ions' parent molecules. This makes MS, unlike other detection techniques (such as fluorescence), label-free; i.e. there is no need to bind additional ligands or groups to the molecule of interest in order to receive a signal and identify the compound.

There are many cases in which other spectroscopic methods, such as nuclear magnetic resonance (NMR), fluorescence, infrared, or Raman, are not viable as standalone methods due to the particular chemical composition of the droplets. Often, these droplets are sensitive to fluorescent labels,[55] or contain species that are otherwise indeterminately similar, where MS may be employed along with other methods to characterize a specific analyte of interest.[56] [57]However, MS has only recently (in the past decade) gained popularity as a detection method for droplet-based microfluidics (and microfluidics as a whole) due to challenges associated with coupling mass spectrometers with these miniaturized devices.[121][122][123] Difficulty of separation/purification make entirely microfluidic scale systems coupled to mass spectrometry ideal in the fields of proteomics,[124][55] [58] [59] enzyme kinetics,[60] drug discovery,[37] and newborn disease screening.[61] The two primary methods of ionization for mass analysis used in droplet-based microfluidics today are matrix-assisted laser desorption/ionization (MALDI)[62] [63] and electrospray ionization (ESI).[55] Additional methods for coupling, such as (but not limited to) surface acoustic wave nebulization (SAWN),[125] and paper-spray ionization onto miniaturized MS,[126] are being developed as well.[121][64]

Electrospray ionization

One complication offered by the coupling of MS to droplet-based microfluidics is that the dispersed samples are produced at comparatively low flow rates compared to traditional MS-injection techniques. ESI is able to easily accept these low flow rates and is now commonly exploited for on-line microfluidic analysis.[121][127][128][129] ESI and MALDI offer a high throughput answer to the problem of label-free droplet detection, but ESI requires less intensive sample preparation and fabrication elements that are scalable to microfluidic device scale.[124][129][128][68] ESI involves the application of a high voltage to a carrier stream of analyte-containing droplets, which aerosolizes the stream, followed by detection at a potential-differentiated analyser region. The carrier fluid within a droplet-based microfluidic device, typically an oil, is often an obstacle within ESI. The oil, when part of the flow of droplets going into an ESI-MS instrument, can cause a constant background voltage interfering with the detection of sample droplets.[127] This background interference can be rectified by changing the oil used as a carrier fluid and by adjusting the voltage used for the electrospray.[127][124]

Droplet size, Taylor cone shape, and flow rate can be controlled by varying the potential differential and the temperature of a drying (to evaporate analyte-surrounding solvent) stream of gas (usually nitrogen).[69] Because ESI allows for online droplet detection, other problems posed by segmented or off-chip detection based systems can be solved, such as the minimizing of sample (droplet) dilution, which is especially critical to microfluidic droplet detection where analyte samples are already diluted to the lowest experimentally relevant concentration.[70]

Matrix-assisted laser desorption/ionization

MALDI is typified by the use of an ultraviolet (UV) laser to trigger ablation of analyte species that are mixed with a matrix of crystallized molecules with high optical absorption.[123] The ions within the resulting ablated gasses are then protonated or deprotonated before acceleration into a mass spectrometer. The primary advantages of MALDI detection over ESI in microfluidic devices are that MALDI allows for much easier multiplexing,[65][130] which even further increases the device's overall throughput,[63] as well as less reliance on moving parts, and the absence of Taylor cone stability problems posed by microfluidic-scale flow rates.[131][66] The speed of MALDI detection, along with the scale of microfluidic droplets, allows for improvements upon macro-scale techniques in both throughput and time-of-flight (TOF) resolution.[60] [63] Where typical MS detection setups often utilize separation techniques such as chromatography, MALDI setups require a sufficiently purified sample to be mixed with pre-determined organic matrices, suited for the specific sample, prior to detection.[58] MALDI matrix composition must be tuned to produce appropriate fragmentation and ablation of analytes.

One method to obtain a purified sample from droplet-based microfluidics is to end the microfluidic channel onto a MALDI plate, with aqueous droplets forming on hydrophilic regions on the plate.[123][130][131][132] Solvent and carrier fluid are then allowed to evaporate, leaving behind only the dried droplets of the sample of interest, after which the MALDI matrix is applied to the dried droplets. This sample preparation has notable limitations and complications, which are not currently overcome for all types of samples. Additionally, MALDI matrices are preferentially in much higher concentrations than the analyte sample, which allows for microfluidic droplet transportation to be incorporated into online MALDI matrix production. Due to the low number of known matrices and trial and error nature of finding appropriate new matrix compositions,[67] this can be the determining factor in the use of other forms of spectroscopy over MALDI.[123][121][133]

Raman spectroscopy

Raman spectroscopy is an optical technique that provides non-destructive analysis with chemical specificity without complex sample preparation, and is capable of detecting components within mixtures. Raman signal corresponds to vibrational excitation of specific molecules within the system based on the scattered visible light emitted from a molecule with a lower energy than the excitation light source. Raman spectroscopy, when coupled with microfluidic devices, can monitor fluid mixing and trapping[134] of liquids and can also detect solid and gas phases[135] within microfluidic platforms. Raman signal can be detected with integrated fiberoptics[136] within the microfluidic chip or by placing the device on Raman microscope.[137]

Raman signal is inherently weak; therefore for short detection times at small sample volumes in microfluidic devices, signal amplification is utilized. Some microfluidic systems utilize metallic colloids[138] or nanoparticles[139] within solution to capitalize on Surface-enhanced Raman spectroscopy (SERS) as a detection technique.[140] Typical confocal Raman microscopy allows for spectroscopic information from small focal volumes less 1 micron cubed, and thus smaller than the microfluidic channel dimensions.[137] Multi-photon Raman spectroscopy, such as stimulated Raman scattering (SRS) or coherent anti-Stokes Raman scattering (CARS) also enhance signal from substances in microfluidic devices.[141]

For droplet-based microfluidics, Raman detection provides online analysis of multiple analytes within droplets or continuous phase. Raman signal is sensitive to concentration changes, therefore solubility and mixing kinetics of a droplet-based microfluidic system can be detected using Raman.[135][137] Considerations include the refractive index difference at the interface of the droplet and continuous phase, as well as between fluid and channel connections.[137][134][142]

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