Systems and methods for liquid-to-liquid contact sampling

Abstract

A method of sampling a sample liquid disposed in a receptacle includes forming a meniscus of a transport liquid at a port of an open port interface (OPI). The sample liquid is contacted with the transport liquid, thereby transferring at least some of the contents of the sample liquid to the transport liquid.

Description

[0001] SYSTEMS AND METHODS FOR LIQUID-TO-LIQUID CONTACT SAMPLING

[0002] Cross-Reference To Related Application

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 601,880, filed November 22, 2023, the disclosure of which is incorporated by reference herein in its entirety.

[0004] Background

[0005] Prior approaches to sampling with an open port interface (OPI) probe are based on sample liquid aspiration or inhalation. In both cases, sample liquid is withdrawn or ejected from a well or vial as part of a sampling process. In another prior approach, immersion of a solid phase microextraction (SPME) surface (effectively a solid stationary phase with an affinity towards a chemical liquid target) to retrieve a sample from a liquid. SPME is not a part of direct OPI sampling as the SPME fiber needs to be inserted into a flow of transport liquid, which is a multi-step process in contrast to a direct aspiration sampling with the OPI.

[0006] Summary

[0007] In one aspect, the technology relates to a method of sampling a sample liquid disposed in a receptacle, the method including: forming a meniscus of a transport liquid at a port of an open port interface (OPI); and contacting the sample liquid with the transport liquid, thereby transferring at least some of the contents of the sample liquid to the transport liquid. In an example, forming the meniscus includes balancing a transport liquid supply flow rate into the OPI and a transport liquid extraction flow rate from the OPI. In another example, the meniscus is at least one of flat and domed. In yet another example, the transport liquid supply flow rate is substantially similar to the transport liquid extraction flow rate. In still another example, forming the meniscus includes: delivering the transport liquid to the OPI at a transport liquid supply flow rate; and aspirating the transport liquid from the OPI at a transport liquid extraction flow rate.

[0008] In another example of the above aspect, the meniscus is at least one of flat and domed. In an example, the transport liquid supply flow rate is substantially similar to the transport liquid extraction flow rate. In another example, subsequent to contacting the sample liquid with the transport liquid, mixing at least some of the contents of the sample liquid within a transport liquid capture region of the OPI. In yet another example, at least some of the contents of the sample liquid are soluble in the transport liquid. In still another example, subsequent to contacting the sample liquid with the transport liquid, diffusing at least some of the contents of the sample liquid into the transport liquid.

[0009] In another example of the above aspect, the sample liquid and transport liquid are immiscible and wherein at least some of the contents of the sample liquid partition into the transport liquid. In an example, the method further includes selecting a type of the transport fluid based at least in part on a component of the sample liquid. In another example, the method further includes contacting the sample liquid with the OPI. In yet another example, the OPI includes a hydrophobic surface. In still another example, the method further includes analyzing at least some of the contents of the sample liquid.

[0010] In another example of the above aspect, the method further includes terminating contact between the sample liquid and the transport liquid, wherein a volume of the sample liquid in the receptacle prior to and after contact of the transport liquid with the surface of the sample liquid is substantially the same. In an example, contact of the surface of the sample liquid with the transport liquid is terminated after a predetermined amount of time.

[0011] In another aspect, the technology relates to a system for sampling a sample liquid disposed in a receptacle, the system including: an open port interface (OPI); a transport liquid pump coupled to the OPI; a mass analysis device fluidically coupled to the OPI; a sample stage; a moving mechanism coupled to at least one of the OPI and the sample stage, for moving the OPI relative to the sample stage; at least one controller operatively coupled to the transport liquid pump, the mass analysis device, and the moving mechanism; and a memory coupled to the at least one controller, the memory storing instructions that, when executed by the controller, performs a set of operations including: delivering a flow of transport liquid to the OPI, thereby forming a meniscus of the transport liquid at a port of the OPI; activating the moving mechanism in a first direction, thereby contacting a sample liquid disposed on the sample stage with the transport liquid, thereby transferring at least some of the contents of the sample liquid to the transport liquid; and analyzing the transferred at least some of the contents of the sample liquid with the mass analysis device. In an example, the operations further include activating the moving mechanism in a second direction, thereby terminating contact between the sample liquid and the transport liquid. In another example, activating the moving mechanism in the second direction is performed after a predetermined time elapses.

[0012] Brief Description of the Drawings

[0013] FIG. 1 is a schematic view of an example system utilizing an open port interface (OPI) sampling interface and electrospray ionization (ESI) source.

[0014] FIGS. 2A-2C depict partial cross-sectional views of a system depicting an OPI in a liquid-to-liquid contact sampling operation with a sample liquid.

[0015] FIG. 3A depicts a mass spectrometer (MS) signal associated with conventional OPI operation, when a sample liquid is aspirated into the OPI.

[0016] FIG. 3B depicts an MS signal associated with liquid-to-liquid contact sampling, when no sample liquid is aspirated in the OPI.

[0017] FIG. 4 depicts a method of contact sampling a sample liquid.

[0018] FIG. 5 depicts an example of a suitable operating environment in which one or more of the present examples can be implemented.

[0019] Detailed Description

[0020] The technologies described herein contemplate sampling a sample liquid via direct liquid-liquid contact, e.g., between a transport liquid in an open port interface (OPI) and a liquid sample. This direct liquid-to-liquid contact obtains at least some of the contents of the sample liquid for analysis, but in some embodiments without removal of an appreciable amount of sample liquid from the container in which the sample liquid is contained. This would result in only a minor reduction in volume of sample liquid remaining in the sample well after liquid-to-liquid contact sampling. The contents of the sample liquid may be obtained via diffusion, local mixing within the capture area of the OPI, or via other methods that do not require removal (e.g., ejection or aspiration) of the sample liquid from the sample container. Such sampling may be based on differences in a target concentration between the two liquids and solubility. Thus, the sampling technologies described herein use the OPI for in-situ sample “extraction” without any sample liquid removal from the container.

[0021] One problem inherent in direct sampling (e.g., based on aspiration of a sample) comes from so-called “complex” matrices (dirty matrices), where endogenous material (such as salts, lipids, or biomolecules) in the matrix suppress signal through ionization suppression and analyte trapping. Known methods for analyzing such samples include passing the samples through a liquid chromatography (LC) column, where organic compounds are slowed down within the column depending on their affinity for column stationary phase, while salts pass through the column. Processing samples using LC columns, however, can be notoriously slow and expensive. Other processes for cleaning complex matrices are known but are similarly labor- and time-intensive. The technologies described herein, however, allow on-line sample extraction, for mass spectrometer analysis, from complex matrices, without removal of the matrix or sample liquid from the container. In this case, the ionization suppression is reduced or obviated by “cleaning up” the sample through the liquid-to-liquid contact process.

[0022] If an OPI is operated at balanced flow, flow entering the OPI is matched to the flow exiting the OPI. Under this condition, the OPI probe, when immersed in a sample vial, is not aspirating any liquid from the vial, but a surface bead of transport liquid surface is present at the OPI inlet. The liquid inside this surface bead is continuously refreshed by the transport flow. When the surface bead contacts or is submerged into a sample liquid in a sample container, certain contents of the sample are extracted from the sample liquid by diffusion and / or diffusion-driven local mixing within the capture area of the OPI. Either of these processes introduce a “clean” sample dissolved in a “clean” transport liquid for mass spectrometer analysis. As used herein, the term “sample liquid” or “target liquid” includes a matrix, which are components of the sample liquid that are unwanted, such as interfering proteins, salts, lipids, etc., as well as “organic compounds” or “components of interest”. These organic compounds may be small and / or large molecules. In examples, proteins and peptides could also be components of interest, and can be discriminated in the MS. One of those small or large molecules is the analyte of interest. Organic, solvable components may diffuse into the transport liquid or be mixed into the transport liquid when applying the methods described herein. In the case of the liquid-to-liquid contact sampling described herein, interfering proteins, salts, and water remain in the container holding the sample liquid. Transport liquid may include additives to enhance target compound selection, processing, or ionization. In examples, chemical tags may be added to enhance identification, and the transport liquid may provide better ionizable adducts to the target compounds. For biomolecule targets, detergent may be added to transport liquid to improve the detection process by preventing non-specific binding, controlling crystallization, release from substrate, and improve solubility.

[0023] FIG. 1 is a schematic view of an example system 100 that may be utilized with the sampling methods described herein. The example system 100 combines an OPI sampling interface 104 and ESI source 114. The system 100 may be a mass analysis instrument such as a mass spectrometry device that is for ionizing and mass analyzing analytes received within an open end of a sampling OPI 104. Such a system 100 is described, for example, in U.S. Pat. No. 10,770,277, the disclosure of which is incorporated by reference herein in its entirety. Sample liquids are contained within individual wells 110 of a well plate 112 another container, which may be moved via a moveable stage 134. Movement may be enabled via one or more motors or other actuators (depicted generally at 132a). Such movement may include movement of the stage 134 and well plate 112 relative to and towards the OPI 104, so as to enable contact between the OPI 104 and the sample liquids in the various wells 110, as described in further detail herein. Alternatively, or additionally, another set of motors / actuators 132b may move the OPI 104 relative to and towards the well plate 112.

[0024] As shown in FIG. 1, the example system 100 generally includes the sampling OPI 104 in liquid communication with the ESI source 114 for discharging a liquid containing one or more sample analytes (e.g., via electrospray electrode 116) into an ionization chamber 118, and a mass analyzer detector (depicted generally at 120) in communication with the ionization chamber 118 for downstream processing and / or detection of ions generated by the ESI source 114. Due to the configuration of the nebulizer probe 138 and electrospray electrode 116 of the ESI source 114, samples ejected therefrom are in a nebulized plume that desolvates to the gas phase. A liquid handling system 122 (e.g., including one or more pumps 124 and one or more transfer conduits 125) provides for the flow of liquid from a solvent reservoir 126 to the sampling OPI 104 and from the sampling OPI 104 to the ESI source 114. The solvent reservoir 126 (e.g., containing a liquid, desorption solvent such as methanol) can be fluidly coupled to the sampling OPI 104 via a supply conduit 127 through which the liquid can be delivered at a selected volumetric rate by the pump 124 (e.g., a reciprocating pump, a positive displacement pump such as a rotary, gear, plunger, piston, peristaltic, diaphragm pump, or other pump such as a gravity, impulse, pneumatic, electrokinetic, and centrifugal pump), all by way of non-limiting example. Examples of sampling OPIs are known in the art.

[0025] As discussed in detail below, the flow of liquid into and out of the sampling OPI 104 occurs within a sample space accessible at the open end. This enables contents of the sample liquid to be introduced into the port inlet 128 at the OPI 104 tip and subsequently delivered to the ESI source 114, by being drawn first into a sample removal conduit 131 within the OPI 104. A controller 130 may be operatively coupled to the various components depicted herein. Controller 130 can be, but is not limited to, a microcontroller, a computer, a microprocessor, or any device capable of sending and receiving control signals and data. Wired or wireless connections between the controller 130 and the remaining elements of the system 100 are not depicted but would be apparent to a person of skill in the art.

[0026] As shown in FIG. 1, the ESI source 114 can include a source 136 of pressurized gas (e.g., nitrogen, air, or a noble gas) that supplies a high velocity nebulizing gas flow to the nebulizer probe 138 that surrounds the outlet end of the electrospray electrode 116. As depicted, the electrospray electrode 116 protrudes from a distal end of the nebulizer probe 138. The pressurized gas interacts with the liquid discharged from the electrospray electrode 116 to enhance the formation of the sample plume and the ion release within the plume for sampling by mass analyzer detector 120, e.g., via the interaction of the high-speed nebulizing flow and jet of liquid sample (e.g., analytesolvent dilution). The liquid discharged may include diluted volumes of sample liquid LS obtained from each reservoir 110 of the well plate 112, or from another container, as described herein. The diluted volumes of sample liquid LS may be separated from each other by volumes of the solvent S (hence, as flow of the solvents moves the sample liquid LS from the OPI 104 to the ESI source 114, the solvent may also be referred to herein as a transport liquid). The nebulizer gas can be supplied at a variety of flow rates, for example, in a range from about 0.1 L / min to about 20 L / min, which can also be controlled under the influence of controller 130 (e.g., via opening and / or closing valve 140).

[0027] It will be appreciated that the flow rate of the nebulizer gas can be adjusted (e.g., under the influence of controller 130) such that the flow rate of liquid within the sampling OPI 104 can be adjusted based, for example, on suction / aspiration force generated by the interaction of the nebulizer gas and the analyte-solvent dilution as it is being discharged from the electrospray electrode 116 (e.g., due to the Venturi effect). The ionization chamber 118 can be maintained at atmospheric pressure, though in some examples, the ionization chamber 118 can be evacuated to a pressure lower than atmospheric pressure.

[0028] It will also be appreciated by a person skilled in the art and in light of the teachings herein that the mass analyzer detector 120 can have a variety of configurations. Generally, the mass analyzer detector 120 is configured to process (e.g., filter, sort, dissociate, detect, etc.) sample ions generated by the ESI source 114. By way of non-limiting example, the mass analyzer detector 120 can be a triple quadrupole mass spectrometer, or any other mass analyzer known in the art and modified in accordance with the teachings herein. Other non-limiting, exemplary mass spectrometer systems that can be modified in accordance with various aspects of the systems, devices, and methods disclosed herein can be found, for example, in an article entitled "Product ion scanning using a Q-q-Q linear ion trap (Q TRAP) mass spectrometer," authored by James W. Hager and J. C. Yves Le Blanc and published in Rapid Communications in Mass Spectrometry (2003; 17: 1056-1064); and U.S. Pat. No. 7,923,681, entitled "Collision Cell for Mass Spectrometer," the disclosures of which are hereby incorporated by reference herein in their entireties.

[0029] Other configurations, including but not limited to those described herein and others known to those skilled in the art, can also be utilized in conjunction with the systems, devices, and methods disclosed herein. For instance, other suitable mass spectrometers include single quadrupole, triple quadrupole, ToF, trap, and hybrid analyzers. It will further be appreciated that any number of additional elements can be included in the system 100 including, for example, an ion mobility spectrometer (e.g., a differential mobility spectrometer) that is disposed between the ionization chamber 118 and the mass analyzer detector 120 and is configured to separate ions based on their mobility difference under high-field and low-field conditions. Additionally, it will be appreciated that the mass analyzer detector 120 can comprise a detector that can detect the ions that pass through the analyzer detector 120 and can, for example, supply a signal indicative of the number of ions per second that are detected.

[0030] An OPI 104, such as depicted above in FIG. 1, provides a mechanism to introduce contents of a sample liquid to the mass spectrometer 120. Such introduction into the transport stream in the OPI 104 occurs at atmospheric pressure, a significant difference from more conventional introduction into a pressurized transport stream via a high-pressure valve. The OPI 104 offers a control of a ratio of transport liquid supply flow rate into the OPI 104 (e.g., via the transport liquid pump 124) versus the transport liquid evacuation flow rate (e.g., via the ESI source 114). The OPI 104 is evacuated by a pull generated by the rapidly expanding nebulizer gas. Hence the pull can be controlled via the nebulizer gas flow. The transport supply flow is delivered to the OPI 104 by the pump 124, which controls the flowrate entering the OPI 104. Hence the OPI 104 can be made to operate in a “starved” (or “over-pumped”) condition where the transport liquid supply flow rate entering the OPI 104 is much less than the transport liquid evacuation flow rate; or at a “balanced” (or “closed”) flow where the flowrate entering the OPI 104 matches the evacuation rate; or at an “overflow” (or “underpumped”) mode where more flow enters the OPI 104 than is evacuated. To simplify further discussion, balanced (or closed) flow is abbreviated as cflow. Hence, the overpumped mode, where the OPI 104 is starved of incoming liquid, is expressed as flow < cflow. Further, the under-pumped mode, wherein more liquid enters the OPI 104 than can be evacuated, is expressed as flow > cflow. The technologies described herein may be practiced in any OPI flow condition where drips of transport liquid from the OPI 104 do not occur. Such conditions may be described as domed, flat, and other shapes of the transport liquid where capture region mixing and / or diffusion may occur without aspirating or actively withdrawing target liquid into the OPI.

[0031] FIGS. 2A-2C depict partial cross-sectional views of a system 200 depicting an OPI 204 in a liquid-to-liquid sampling operation with a sample liquid 202. More specifically, the system 200 introduces contents of a sample liquid 202 to an OPI 204 in a liquid-to-liquid contact sampling operation from a sample liquid container 206 (such as a well of a well plate). The OPI 204 includes a housing 205 defining at a lower end thereof an inlet port 207. The housing 205 defines therein a transport liquid supply conduit 210, in which is disposed a sample removal conduit 208. A surface of the housing 205 and / or sample removal conduit 208 may be treated or coated so as to display one of or combination of hydrophobic, hydrophilic, lipophilic, lipophobic, or so-called “omni-phobic” properties to control the shape of the meniscus and interaction of the surface with sample and / or transport liquid. A coated surface may enhance meniscus shape by controlling the contact angle the liquid forms with its solid substrate. It may also be used to prevent sample liquids from adhering to the OPI port. Transport liquid (depicted by dashed arrows) is delivered via the transport liquid supply conduit 210 and forms a meniscus 212 proximate the inlet 207. In FIG. 2A, two menisci 212 are depicted. A first meniscus 212a corresponds to a balanced or closed flow condition, and results in a liquid surface proximate the inlet port 207 of the OPI 204. The first meniscus 212a may be even with the port 207, or distend slightly therefrom. A second meniscus 212b corresponds to a balanced or closed flow condition that has been achieved by approach from an overflow or under-pumped condition, and results in a liquid surface that distends farther from the inlet port 207 of the OPI 204, but without forming a droplet that releases from the OPI 204. During operation, the meniscus shape may change from that of the first meniscus 214a to that of the second meniscus 214b. In the process of changing or growing the meniscus when using the overflow or underpumped condition, once a droplet of sufficient size is formed, the flow conditions revert to the balanced or closed flow conditions. In some embodiments, sampling can take place during the overflow or underpumped condition (e.g., as the droplet is growing) as long as the droplet does not grow to such a size that it disengages from the OPI 204. If the OPI 204 is operated with transport flow entering the OPI 204 at or slightly above the cflow, then there will be no net aspiration of sample liquid 202 through the OPI 204 when the OPI 204 comes into contact with the sample liquid 202. With the OPI 204 operating at the closed flow or just above it, a dome meniscus will be formed, this may be stretched to an attached droplet, which offers an increased surface area over the dome meniscus.

[0032] The liquid-to-liquid contact sampling technologies of the present disclosure may operate efficiently in either condition, though a larger meniscus (such as the second meniscus 212b, as compared to the first meniscus 212a) provides a greater surface area, which may aid in increasing diffusion or other processes. The contents of a sample liquid that are diffused or absorbed into the transport liquid may be mixed in a capture region 214 of the of the transport liquid, which is at least partially defined by the housing 205, the sample removal conduit 208, and the meniscus 212. The transport liquid and any contents of the sample liquid that may have entered the capture region 214 by any mechanism are aspirated into the sample removal conduit 208.

[0033] In FIG. 2B, the OPI 204 has moved in a first direction relative to the liquid sample container 206. This movement may be movement Mo of the OPI 204 or may be movement Ms of the sample liquid source 206, or a combination of both. In FIG. 2B, at least the transport liquid (defined by either menisci 212), or in certain examples, the menisci 212 and the inlet port 207 of the OPI 204, contacts the sample liquid 202. The menisci 212 are still depicted in FIG. 2B for illustrative purposes, but in effect, the menisci 212 would disappear, as the transport liquid mixes in the capture region 214 with contents of the sample liquid 202. It has been observed that while operating the OPI 204 in this mode and immersing it in a sample liquid 202, a sample signal is generated and detected by a mass spectrometer. Since the OPI 204 is operating at balanced flow or above no sample liquid 202 was removed from the sample container 206. As such, the signal is due to diffusion or adhesion of contents of the sample liquid 202 to the transport liquid circulating through the OPI 204. It has been observed that an MS connected to the OPI 204 nevertheless detects components of the sample liquid 202. The transport liquid, as well as the OPI 204 itself in certain cases, may remain immersed in the sample liquid 202 for up to about 1 second, up to about 3 seconds, up to about 5 seconds, up to about 10 seconds, up to about 15 seconds, up to about 20 seconds, up to about 25 seconds, or up to about 30 seconds.

[0034] As depicted in FIG. 2C, one of the menisci 212 is visible as the OPI 204 is moved in a second direction relative to the sample liquid source 206. As above, the relative movement may be movement of the OPI Mo, movement of the sample source Ms, or both.

[0035] FIG. 3A depicts an MS signal associated with conventional OPI operation, when a sample liquid is aspirated into an OPI. FIG. 3A depicts the signal generated during an OPI flow mode of 0.62 cflow, and displays two well-defined peaks. FIG. 3B depicts an MS signal associated with liquid-to-liquid contact sampling, when no sample liquid is aspirated in the OPI. In this example, the OPI under a closed flow condition was immersed in the sample liquid for 10 seconds. Surprisingly, even though no liquid sample is aspirated, while the OPI operates at a flow mode of 1.0 cflow, a signal is nevertheless generated by this method. The peak area is comparable to that depicted in FIG. 3A, above, but peak shape is different (e.g., more Gaussian), and more symmetrical. This suggests a different sample pick-up mechanism from that of advection, encountered at lower cflows. The most likely mechanism is diffusion, but contribution may also be coming from surface adhesion, local mixing, solute concertation equilibration and solubility differences, e.g., within the capture region of the OPI. The diffusion mechanism seems also supported by the time dependence of the sample signal intensity. Further, diffusion may also occur into the transport fluid in the absence of any measurable transport liquid flow into the OPI. That is, a droplet of transport liquid may be held static at the OPI and placed into contact with a sample liquid, such as a sample liquid having very little volume. After sufficient time for diffusion to occur, contact between the transport liquid droplet and the sample liquid may be terminated and the aspiration of the transport liquid and diffused sample out of the OPI may be performed, enabling analysis of the diffused components of the sample.

[0036] If the transport liquid is immiscible with the sample liquid, then sample liquid solute migration between the two liquids will be driven or caused by the difference in the compound solubility in the two liquids. At equilibrium, the ratio of solute concentrations in the two liquids is called a distribution constant or partition coefficient. It is a measure of a selective partitioning of the solute between the two immiscible liquids. If a partition coefficient is sufficiently large, then solute will move from sample liquid to the transport liquid. A transport liquid with a favorable partition coefficient may be selected to enhance extraction, migration, or selection of solute from sample liquid.

[0037] For example, short immersions (e.g., less than about 1 sec) reduce signal, which is in agreement with diffusion as a multi-second process. Thus, this immersion process while at balanced or underpumped flow modes would enable in-situ sampling of “dirty” matrices by utilizing the liquid-liquid contact sampling process and greater affinity of the target molecule for the transport fluid. Affinity may be enhanced by both solubility and concentration, where certain contents of the sample liquid are soluble in the transport liquid. Hence transport liquid delivers a “clean” sample to the ion source.

[0038] FIG. 4 depicts a method 400 of sampling a sample liquid. Example mass spectrometry systems, as well as components thereof, such as OPIs, transport liquid pumps, sample stages, etc., are described therein and may be used to perform one or more operations of the example method 400. The above method 400 may be defined by one or more of the following operations. The method 400 begins with operation 402, by balancing a transport liquid supply flow rate into the OPI and a transport liquid extraction flow rate from the OPI to form a meniscus of a transport liquid at a port of an open port interface (OPI). In an example, the meniscus may be formed, in some examples, by balancing a transport liquid supply flow rate into the OPI and a transport liquid extraction flow rate from the OPI, operation 404. The meniscus may be substantially level with the port of the OPI (e.g., flat or substantially flat) or may distend (e.g., in a domed condition) therefrom, for example, without forming a droplet that would release from the OPI. In examples, when the transport liquid supply flow rate is substantially similar to the transport liquid extraction flow rate, a meniscus is formed at the OPI port. A relatively or substantially flat meniscus is formed when balanced (or closed) flow is approached from over-pumped (flow < cflow) state. If a larger domed meniscus is desired, then balanced flow is approached from underpumped (flow > cflow) state. In this approach, a domed meniscus of the transport liquid is formed at a port of the OPI.

[0039] Thus, menisci of various outer profiles (e.g., flat, substantially flat, or domed) may be formed by delivering the transport liquid to the OPI at a transport liquid supply flow rate, operation 406, while aspirating the transport liquid from the OPI at a transport liquid extraction flow rate, operation 408. The meniscus may then be placed in contact with the sample liquid, operation 410. Contact may be enabled by activating a moving mechanism (either of a sample stage, OPI, or both) in a first direction, thereby placing the two liquids in contact. Movement of the moving mechanism in a second direction terminates this contact. This contact transfers, via mechanisms described herein, at least some of the contents of the sample liquid to the transport liquid. In certain systems, the sample liquid may be contacted by the OPI itself 412. In such examples, it may be advantageous for the OPI to have a hydrophobic outer surface, to prevent sample liquids from adhering thereto.

[0040] While the transport liquid is in contact with the sample liquid, at least one of several operations are performed. In operation 414, mixing of at least some of the contents of the sample liquid within a transport liquid capture region of the OPI may occur. In another operation 416, diffusing at least some of the contents of the sample liquid into the transport liquid may occur. In operation 418, at least some of the contents of the sample liquid migrate across the boundary between sample liquid and transport liquid. One, two, or all operations may be performed depending on factors such as immiscibility of the liquids (which may drive partitioning), solubility of target compounds in the liquids, solute concentration, as well as other factors. As such, it may be desirable to select a type of transport fluid based on a component of the sample liquid to ensure the desired contact sampling. The partitioning, diffusion, or mixing with the transport liquid ultimately enables analyzing of at least some of the contents of the sample liquid, operation 420, for example with a mass analysis device. The method may also include operation 422, terminating contact between the sample liquid and the transport liquid, for example after a predetermined period of time. Upon terminating contact, a volume of the sample liquid in the receptacle after contact of the transport liquid with the surface of the sample liquid may be substantially the same as the volume of liquid before contact.

[0041] FIG. 5 depicts one example of a suitable operating environment 500 in which one or more of the present examples can be implemented. This operating environment may be incorporated directly into the controller for a mass spectrometry system, e.g., such as the controller depicted in FIG. 1. This is only one example of a suitable operating environment and is not intended to suggest any limitation as to the scope of use or functionality. Other well- known computing systems, environments, and / or configurations that can be suitable for use include, but are not limited to, personal computers, server computers, hand-held or laptop devices, multiprocessor systems, microprocessor-based systems, programmable consumer electronics such as smart phones, network PCs, minicomputers, mainframe computers, tablets, distributed computing environments that include any of the above systems or devices, and the like.

[0042] In its most basic configuration, operating environment 500 typically includes at least one processing unit 502 and memory 504. Depending on the exact configuration and type of computing device, memory 504 (storing, among other things, instructions to adjust a transport liquid flow rate, control evacuation of the transport liquid from the OPI by activating the ESI, moving the sample stage and / or the OPI, or perform other methods disclosed herein) can be volatile (such as RAM), non-volatile (such as ROM, flash memory, etc.), or some combination of the two. This most basic configuration is illustrated in FIG. 5 by dashed line 506. Further, environment 500 can also include storage devices (removable, 508, and / or non-removable, 510) including, but not limited to, magnetic or optical disks or tape. Similarly, environment 500 can also have input device(s) 514 such as touch screens, keyboard, mouse, pen, voice input, etc., and / or output device(s) 516 such as a display, speakers, printer, etc. Also included in the environment can be one or more communication connections 512, such as LAN, WAN, point to point, Bluetooth, RF, etc.

[0043] Operating environment 500 typically includes at least some form of computer readable media. Computer readable media can be any available media that can be accessed by processing unit 502 or other devices having the operating environment. By way of example, and not limitation, computer readable media can include computer storage media and communication media. Computer storage media includes volatile and nonvolatile, removable and non-removable media implemented in any method or technology for storage of information such as computer readable instructions, data structures, program modules or other data. Computer storage media includes, RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disks (DVD) or other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, solid state storage, or any other tangible medium which can be used to store the desired information. Communication media embodies computer readable instructions, data structures, program modules, or other data in a modulated data signal such as a carrier wave or other transport mechanism and includes any information delivery media. The term "modulated data signal" means a signal that has one or more of its characteristics set or changed in such a manner as to encode information in the signal. By way of example, and not limitation, communication media includes wired media such as a wired network or direct-wired connection, and wireless media such as acoustic, RF, infrared and other wireless media. Combinations of the any of the above should also be included within the scope of computer readable media. A computer-readable device is a hardware device incorporating computer storage media.

[0044] The operating environment 500 can be a single computer operating in a networked environment using logical connections to one or more remote computers. The remote computer can be a personal computer, a server, a router, a network PC, a peer device or other common network node, and typically includes many or all of the elements described above as well as others not so mentioned. The logical connections can include any method supported by available communications media. Such networking environments are commonplace in offices, enterprise-wide computer networks, intranets and the Internet.

[0045] In some examples, the components described herein include such modules or instructions executable by computer system 500 that can be stored on computer storage medium and other tangible mediums and transmitted in communication media. Computer storage media includes volatile and non-volatile, removable and nonremovable media implemented in any method or technology for storage of information such as computer readable instructions, data structures, program modules, or other data. Combinations of any of the above should also be included within the scope of readable media. In some examples, computer system 500 is part of a network that stores data in remote storage media for use by the computer system 500.

[0046] This disclosure described some examples of the present technology with reference to the accompanying drawings, in which only some of the possible examples were shown. Other aspects can, however, be embodied in many different forms and should not be construed as limited to the examples set forth herein. Rather, these examples were provided so that this disclosure was thorough and complete and fully conveyed the scope of the possible examples to those skilled in the art. In addition, some aspects of the present disclosure are described above with reference to block diagrams and / or operational illustrations of systems and methods according to aspects of this disclosure. The functions, operations, and / or acts noted in the blocks may occur out of the order that is shown in any respective flowchart. For example, two blocks shown in succession may in fact be executed or performed substantially concurrently or in reverse order, depending on the functionality and implementation involved.

[0047] Although specific examples were described herein, the scope of the technology is not limited to those specific examples. One skilled in the art will recognize other examples or improvements that are within the scope of the present technology. Therefore, the specific structure, acts, or media are disclosed only as illustrative examples. Examples according to the technology may also combine elements or components of those that are disclosed in general but not expressly exemplified in combination, unless otherwise stated herein. The scope of the technology is defined by the following claims and any equivalents therein.

Claims

Claims1. A method of sampling a sample liquid disposed in a receptacle, the method comprising: forming a meniscus of a transport liquid at a port of an open port interface (OPI); and contacting the sample liquid with the transport liquid, thereby transferring at least some of the contents of the sample liquid to the transport liquid.

2. The method of claim 1, wherein forming the meniscus comprises balancing a transport liquid supply flow rate into the OPI and a transport liquid extraction flow rate from the OPI.

3. The method of any of claims 1-2, wherein the meniscus is at least one of flat and domed.

4. The method of any of claims 2-3, wherein the transport liquid supply flow rate is substantially similar to the transport liquid extraction flow rate.

5. The method of any of claims 1-4, wherein forming the meniscus comprises: delivering the transport liquid to the OPI at a transport liquid supply flow rate; and aspirating the transport liquid from the OPI at a transport liquid extraction flow rate.

6. The method of claim 5, wherein the meniscus is at least one of flat and domed.

7. The method of any of claims 5-6, wherein the transport liquid supply flow rate is substantially similar to the transport liquid extraction flow rate.

8. The method of any of claims 1-7, wherein, subsequent to contacting the sample liquid with the transport liquid, mixing at least some of the contents of the sample liquid within a transport liquid capture region of the OPI.

9. The method of claim 8, wherein at least some of the contents of the sample liquid are soluble in the transport liquid.

10. The method of any of claims 1-9, wherein, subsequent to contacting the sample liquid with the transport liquid, diffusing at least some of the contents of the sample liquid into the transport liquid.

11. The method of claim 10, wherein the sample liquid and transport liquid are immiscible and wherein at least some of the contents of the sample liquid partition into the transport liquid.

12. The method of any of claims 10-11, further comprising selecting a type of the transport fluid based at least in part on a component of the sample liquid.

13. The method of any of claims 1-12, further comprising contacting the sample liquid with the OPI.

14. The method of any of claims 1-13, wherein the OPI comprises a hydrophobic surface.

15. The method of any of claims 1-14, further comprising analyzing at least some of the contents of the sample liquid.

16. The method of any of claims 1-15, further comprising terminating contact between the sample liquid and the transport liquid, wherein a volume of the sample liquid in the receptacle prior to and after contact of the transport liquid with the surface of the sample liquid is substantially the same.

17. The method of claim 16, wherein contact of the surface of the sample liquid with the transport liquid is terminated after a predetermined amount of time.

18. A system for sampling a sample liquid disposed in a receptacle, the system comprising:an open port interface (OPI); a transport liquid pump coupled to the OPI; a mass analysis device fluidically coupled to the OPI; a sample stage; a moving mechanism coupled to at least one of the OPI and the sample stage, for moving the OPI relative to the sample stage; at least one controller operatively coupled to the transport liquid pump, the mass analysis device, and the moving mechanism; and a memory coupled to the at least one controller, the memory storing instructions that, when executed by the controller, performs a set of operations comprising: delivering a flow of transport liquid to the OPI, thereby forming a meniscus of the transport liquid at a port of the OPI; activating the moving mechanism in a first direction, thereby contacting a sample liquid disposed on the sample stage with the transport liquid, thereby transferring at least some of the contents of the sample liquid to the transport liquid; and analyzing the transferred at least some of the contents of the sample liquid with the mass analysis device.

19. The system of claim 18, wherein the operations further comprise activating the moving mechanism in a second direction, thereby terminating contact between the sample liquid and the transport liquid.

20. The system of any of claims 18-19, wherein activating the moving mechanism in the second direction is performed after a predetermined time elapses.

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