Overflow sensor for open port sampling probe

Abstract

In a sampling interface for mass spectrometry, a method and apparatus for preventing liquid from spilling from a sampling probe into the sample are proposed. The apparatus includes: a substrate adapted to retain liquid droplets when they form at an open end of the sampling probe; and a sensor located on a sample-opposite surface of the substrate, the sensor adapted to detect the liquid droplets and generate a signal for controlling the liquid droplets before they spill into the sample.

Description

[0001] Related US applications

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 029,216, filed May 22, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to a sampling interface for a mass spectrometry system, and more specifically, to a method and apparatus for preventing liquid from spilling from an open-port sampling probe into the sample. Background Technology

[0004] Mass spectrometry (MS) is an analytical technique used to determine the elemental composition of a substance being tested, with both qualitative and quantitative applications. MS can be used to identify unknown compounds, determine the isotopic composition of elements in a molecule, determine the structure of a specific compound by observing its fragmentation, and quantify the amount of a specific compound in a sample. Given its sensitivity and selectivity, MS is particularly important in life science applications.

[0005] In the analysis of complex sample matrices (e.g., biological, environmental, and food samples), many current MS techniques require extensive pretreatment steps before MS detection / analysis of the analyte of interest. These preanalytical steps can include sampling (i.e., sample collection) and sample preparation (separation from the matrix, concentration, fractionation, and, if necessary, derivatization). For example, it is estimated that over 80% of the entire analytical process can be spent on sample collection and preparation to enable MS detection of analytes or to eliminate potential sources of interference within the sample matrix; however, each stage of sample preparation adds potential sources of dilution and / or error.

[0006] Ideally, sample preparation and introduction techniques for MS should be rapid, reliable, reproducible, inexpensive, and, in some respects, acceptablely automated. For example, various ionization methods have been developed that can desorb / ionize analytes from condensed-phase samples with minimal sample handling. An example of improved sample introduction techniques is the sampling probe, such as the “open-port” sampling interface (OPI), in which a relatively untreated sample can be introduced into a continuously flowing solvent that is delivered to the ion source of the MS system, as described, for example, in the article entitled “Open-port sampling interface for liquid-introduced atmospheric pressure ionization mass spectrometry” by Van Berkel et al., published in Rapid Communications in Mass Spectrometry Letters, Vol. 29 (19), pp. 1749–1756 (2015), which is incorporated herein by reference in its entirety.

[0007] In cases of insufficient aspiration, solvent droplets may accumulate at the open end of the sampling probe. The surface tension of the solvent causes the droplets to suspend from the bottom of the sampling probe, forming a hanging object. When the droplet exceeds a certain weight, it becomes unstable and detaches itself, falling into the sample below under gravity, thus causing contamination. Summary of the Invention

[0008] One aspect of the present invention is to provide an improved method and apparatus for preventing liquid from spilling from a sampling probe into a sample.

[0009] The above aspects can be achieved by a device for preventing liquid from spilling from a sampling probe into the sample, the device comprising: a substrate adapted to retain liquid droplets when liquid droplets form at the open end of the sampling probe; and a sensor located on a sample-opposite surface of the substrate, the sensor being adapted to detect the retained liquid droplets and generate a signal to control the liquid droplets before they spill into the sample.

[0010] In some aspects, controlling the liquid droplets may include stopping the liquid supply to the sampling probe. In some aspects, controlling the liquid droplets may include increasing suction at the sampling probe to draw liquid droplets from the substrate. Liquid flows to the sampling probe. In some aspects, controlling the liquid droplets may include reducing the liquid supply to the sampling probe. In some aspects, control includes a combination of increasing suction of liquid from the sampling probe and reducing or stopping the liquid supply to the sampling probe.

[0011] In some respects, the device can be further manipulated to increase the suction applied to the sampling probe to draw droplets of the held liquid from the substrate.

[0012] In one embodiment, the substrate includes an aperture adapted to accumulate and retain droplets under tension as they grow from the sample-facing surface of the substrate (e.g., the bottom or lower surface) toward the sample-opposite surface of the substrate (e.g., the upper or top surface), thus bringing the droplets into contact with the sensor for detection.

[0013] In the embodiments, the sensor is one of a conductive trace, a wire, or a temperature sensor located on the surface of the substrate opposite to the sample.

[0014] In a further embodiment, the temperature sensor is either a thermocouple or a resistance thermometer.

[0015] In some embodiments, a device is provided for preventing liquid from spilling from a sampling probe into a sample. The device includes: a substrate adapted to retain a droplet of liquid as it forms at an open end of the sampling probe; and a sensor located on a sample-opposite surface of the substrate, the sensor adapted to detect the retained liquid droplet and generate a signal to control the liquid droplet before it spills into the sample. The substrate may include an orifice adapted to accumulate and retain the droplet under tension as it grows from a sample-facing surface (e.g., a bottom or lower surface) of the substrate toward a sample-opposite surface (e.g., an upper or top surface), thus contacting the sensor for detection. In some aspects, the substrate may be positioned such that the sampling probe is located within the orifice and the open end of the sampling probe is positioned between the sensor and the sample. In these embodiments, a portion of the sample ejected from the sample travels from the sample to the open end without passing through the sensor on the substrate.

[0016] On the other hand, a method for preventing liquid from spilling from a sampling probe into a sample is proposed, comprising: retaining the liquid droplets as they form at the open end of the sampling probe; detecting the retained liquid droplets; and generating a signal to control the liquid droplets before they spill into the sample.

[0017] In an embodiment, droplets of the held liquid are detected on a substrate surface (e.g., the upper or top surface) opposite the sample.

[0018] In another embodiment, retaining liquid droplets includes the accumulation of droplets under tension as droplets grow from a substrate surface (e.g., bottom or lower surface) facing the sample toward a substrate surface opposite the sample.

[0019] In a further embodiment, a notification signal indicating an overflow condition may be generated.

[0020] In a further embodiment, controlling the liquid droplets includes increasing the suction applied to the sampling probe to draw the held droplets from the substrate. In some aspects, increasing the suction includes increasing the atomizing gas flow rate of the ion source receiving the liquid from the sampling probe.

[0021] These and other aspects and advantages will then become clear in the details of the construction and operation as described more fully and claimed below with reference to the accompanying drawings which form part of the invention, wherein the same reference numerals refer to the same parts throughout. Attached Figure Description

[0022] Figure 1 An embodiment of an exemplary system for preventing liquid from spilling from an open-port sampling probe into a sample in an MS system, based on various aspects of the applicant's teachings, is depicted in the schematic diagram.

[0023] Figure 2 This is a schematic representation of the sampling probe used in the embodiment.

[0024] Figure 3 It shows in Figure 2 The formation of liquid droplets at the open end of the sampling probe.

[0025] Figure 4 An example is shown for use when liquid droplets are in Figure 3 A device for detecting liquid droplets formed at the open end of a sampling probe.

[0026] Figure 5 The illustration depicts the holding of liquid droplets according to embodiments. Figure 4 On the lower surface of the substrate of the device.

[0027] Figure 6 According to the embodiments Figure 5 Details of the substrate shown.

[0028] Figure 7 A method for preventing liquid from spilling from the sampling probe into the sample, according to an embodiment, is described. Detailed Implementation

[0029] Figure 1 An embodiment of an exemplary system 10 for ionization and mass analysis of an analyte received within the open end of a sampling probe 30, according to various aspects of the applicant's teachings, is schematically depicted. According to one aspect, system 10 includes a feedback-based control system configured to prevent liquid from spilling from the sampling probe 30 into the sample 20. Figure 1 As shown, sampling probe 30 (e.g., an open-port sampling interface (OPI)) is in fluid communication with nebulizer-assisted ion source 60 for discharging liquid containing one or more sample analytes (e.g., via electro-jet electrode 64) into ionization chamber 12, and mass analyzer 70, in fluid communication with ionization chamber 12, is used for downstream processing and / or detection of ions generated by ion source 60. Fluid handling system 40 (e.g., including one or more pumps 43 and one or more conduits) provides liquid flow from reservoir 50 to sampling probe 30 and from sampling probe 30 to ion source 60. For example, as... Figure 1 As shown, reservoir 50 (e.g., containing a liquid such as a desorption solvent (e.g., methanol)) can be fluidly coupled to sampling probe 30 via a supply conduit. The liquid can be delivered through the supply conduit at a selected volumetric rate by pump 43 (e.g., a reciprocating pump, a positive displacement pump (such as a rotary pump, gear pump, plunger pump, piston pump, peristaltic pump, diaphragm pump), or other pumps (such as a gravity pump, pulse pump, pneumatic pump, electric pump, and centrifugal pump)). These are all non-limiting examples.

[0030] As discussed in detail below, liquid inflow and outflow from the sampling probe 30 occur within a sample space accessible at the open end, allowing one or more analytes to be introduced into the liquid within the sample space and subsequently delivered to the ion source 60. According to one aspect of the applicant's teachings, the system 10 includes means 90 for detecting liquid droplets when they form at the open end of the sampling probe 30, and a controller 80 operatively coupled to the means 90 to receive a signal indicating droplet formation and, in response, to control the liquid droplets before they overflow into the sample 20. In some embodiments, the liquid droplets can be controlled by reducing or stopping the liquid supply to the sampling probe 30 while maintaining suction to draw liquid droplets into the sampling probe 30. In some aspects, the liquid droplets can be controlled by increasing suction to draw liquid droplets into the sampling probe 30. In some aspects, a combination of increasing suction and reducing or stopping the liquid supply to the sampling probe 30 can be used to control the liquid droplets.

[0031] As a non-limiting example, based on various aspects of this teaching, the control signals generated by the controller 80 can reduce or stop the liquid flow to the sampling probe 30 by controlling the operation of the pump 43, and / or increase suction by controlling the operation of the atomizer gas source 63 supplying atomizer gas to the outlet end of the electro-jet electrode 64. In embodiments, the controller 80 may also generate notification signals (e.g., audible and / or visual alarms) to notify the operator of an overflow condition.

[0032] It should be understood that controller 80 can be implemented in a variety of ways according to this teaching, but generally includes one or more processors configured to generate control signals for the operation of elements of system 10, as discussed elsewhere herein. As a non-limiting example, controller 80 may be in the form of a digital controller configured to process (e.g., via an algorithm) signals provided by device 90 and control the operation of pump 43 and / or atomizer gas source 63 to reduce or stop the liquid flow in sampling probe 30 and / or stop the operation of atomizer gas source 63 and / or increase the supply of atomized gas from atomizer gas source 63. According to certain aspects of this teaching, controller may include a digital processor that executes one or more sequences of instructions contained in memory, which may be read into memory from another computer-readable medium (e.g., floppy disk, floppy disk drive, hard disk, magnetic tape or any other magnetic medium, CD-ROM, digital video disc (DVD), Blu-ray disc, any other optical medium, thumb drive, memory card, RAM, PROM and EPROM, FLASH-EPROM, any other memory chip or cartridge, or any other tangible medium from which a computer can read). The execution of a sequence of instructions contained in memory causes the processor to perform the processes described herein. Alternatively, hardwired circuitry can be used in place of or in combination with software instructions to implement this teaching. Therefore, the implementation of this teaching is not limited to any particular combination of hardware circuitry and software. In various embodiments, controller 80 can be connected across a network to one or more other computer systems to form a networked system. The network can include a private network or a public network (such as the Internet). In a networked system, one or more computer systems can store data and provide data to other computer systems. In a cloud computing scenario, one or more computer systems that store and provide data can be referred to as servers or the cloud. For example, one or more computer systems can include one or more web servers. For example, other computer systems that send data to and receive data from servers or the cloud can be referred to as clients or cloud devices.

[0033] Continue to refer to Figure 1 The ion source 60 can have a variety of configurations, but is typically configured to generate analytes contained within a liquid (e.g., a desorption solvent) received from the sampling probe 30. Figure 1In the depicted exemplary embodiment, the electrojet electrode 64 may include a capillary fluidly coupled to the sampling probe 30, terminating at an outlet end that extends at least partially into the ionization chamber 12 and discharges the desorbed solvent therein. As those skilled in the art will understand from this teaching, the outlet end of the electrojet electrode 64 may atomize, aerosolize, nebulize, or otherwise discharge the desorbed solvent (e.g., by nozzle spraying) into the ionization chamber 12 to form a sample plume comprising a plurality of microdroplets generally directed toward the curtain plate orifice 14b and the vacuum chamber sampling orifice 16b (e.g., in the vicinity of the curtain plate orifice 14b and the vacuum chamber sampling orifice 16b). As is known in the art, the analyte contained within the microdroplets may be ionized (i.e. charged) by the ion source 60, for example, during sample plume generation. As a non-limiting example, the outlet of the electrojet electrode 64 may be made of a conductive material and electrically coupled to one pole of a voltage source (not shown), while the other pole of the voltage source may be grounded. The microdroplets contained within the sample plume can thus be charged by the voltage applied to the outlet, such that when the liquid or desorbed solvent within the droplets evaporates during desolvation in the ionization chamber 12, these bare charged analyte ions are released and drawn toward and through orifices 14b, 16b, and focused (e.g., via one or more ion lenses) into the mass analyzer 70. While the ion source probe is generally described herein as the electrojet electrode 64, it should be understood that any number of different ionization techniques known in the art for ionizing liquid samples and modified according to this teaching can be used as the ion source 60. As a non-limiting example, the ion source 60 may be an electrojet ionization device, a nebulizer-assisted electrojet device, a chemical ionization device, a nebulizer-assisted atomization device, a photoionization device, a laser ionization device, a thermal jet ionization device, or an acoustic jet ionization device.

[0034] like Figure 1As shown, the exemplary ion source 60 may optionally include a pressurized gas source 63 (e.g., nitrogen, air, or an inert gas) supplying a high-speed atomizing gas stream that surrounds the outlet end of the electro-jet electrode 64 and interacts with the liquid exiting from the outlet end of the electro-jet electrode 64, thereby enhancing the formation of the sample plume and the release of ions within the sample plume for sampling at 14b and 16b, for example, through the interaction of the high-speed atomizing stream and the liquid sample jet. The nebulizer gas can be supplied at various flow rates, for example, in the range from about 0.1 L / min to about 20 L / min, which can also be controlled under the influence of the controller 80 (e.g., via opening and / or closing valve 65). Based on various aspects of this teaching, it should be understood that the flow rate of the nebulizer gas can be adjusted (e.g., under the influence of controller 80) so that the flow rate of the liquid drawn from sampling probe 30 can be adjusted based on the suction / draft force generated, for example, by the interaction between the nebulizer gas and the desorbed solvent being discharged from electro-jet electrode 64 (e.g., due to the Venturi effect). In this way, controller 80 can additionally or alternatively control the flow rate of the desorbed solvent drawn from sampling probe 30 by adjusting one or more of the pump and / or valve 65 used to control the pressure or flow rate of the nebulizer gas. As a non-limiting example, controller 80 can be configured to maintain the supply flow rate of the liquid provided by pump 43 as substantially constant by adjusting the flow of the nebulizer gas provided from nebulizer source 63, thereby adjusting the flow of the liquid drawn from sampling probe 30, while taking into account variations in experimental conditions (e.g., temperature effects, instability of pump 43, variations in solvent / sample composition, thus causing, for example, variations in solvent / sample viscosity, and the rate / volume of liquid sample introduction into the sample space).

[0035] In the depicted embodiments, the ionization chamber 12 can be maintained at atmospheric pressure, but in some embodiments, the ionization chamber 12 can be evacuated to a pressure below atmospheric pressure. Analytes desorbed from the sample 20 can be ionized within the ionization chamber 12 when the desorbing solvent is discharged from the electrojet electrode 64. The ionization chamber 12 is separated from the gas curtain chamber 14 by a plate 14a having a curtain plate orifice 14b. As shown, the vacuum chamber 16 housing the mass analyzer 70 is separated from the curtain chamber 14 by a plate 16a having a vacuum chamber sampling orifice 16b. Evacuation through one or more vacuum pump ports 18 can maintain the curtain chamber 14 and the vacuum chamber 16 at one or more selected pressures (e.g., the same or different subatmospheric pressures, below the pressure of the ionization chamber).

[0036] Those skilled in the art will also understand, and in accordance with the teachings herein, that mass analyzer 70 can have a wide variety of configurations. Typically, mass analyzer 70 is configured to process (e.g., filter, classify, dissociate, detect, etc.) sample ions generated by ion source 60. As a non-limiting example, mass analyzer 70 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 according to various aspects of the systems, apparatuses, and methods disclosed herein can be, for example, those entitled “Using a QqQ linear ion trap” written by James W. Hager and J.C.Y. LeBlanc and published in Mass Spectrometry Letters (2003; 17: 1056-1064). The information can be found in the article “Product Ion Scanning with Mass Spectrometer” and in U.S. Patent No. 7,923,681 entitled “Collision Chamber for Mass Spectrometer,” which is incorporated herein by reference in its entirety. Other configurations, including but not limited to those described herein and others known to those skilled in the art, may also be used in conjunction with the systems, apparatus, and methods disclosed herein. For example, other suitable mass spectrometers may include single quadrupole, triple quadrupole, ToF, trap, and hybrid analyzers. It should also be understood that any number of additional elements may be included in system 10, including, for example, an ion mobility spectrometer (e.g., a differential mobility spectrometer) disposed between ionization chamber 12 and mass analyzer 70 and configured to separate ions based on the mobility of ions through drift gases in high and low fields rather than on their mass-to-charge ratio. Additionally, it should be understood that mass analyzer 70 may include a sensor that can detect ions passing through analyzer 70 and may, for example, provide a signal indicating the number of ions detected per second.

[0037] The sampling probe 30 can have a variety of configurations, but typically includes an open end through which the liquid delivered from the reservoir 50 is exposed to the atmosphere, thus presenting a liquid-air interface for capturing the sample, such as... Figure 2 As illustrated schematically. In some embodiments, the sampling probe 30 may include a first cylindrical member 205 for discharging liquid and an open end 215 disposed within a second cylindrical member 210 for supplying liquid to an open end, the first cylindrical member 205 and the second cylindrical member 210 being arranged coaxially, and the open end 215 being configured to receive molecules of a sample 20 containing or suspected to contain one or more analytes.

[0038] During operation, sample 20 can be dispensed from sample container 310 ( Figure 3 The ejection (e.g., acoustic ejection) enters the open end 215 of the sampling probe 30. Figure 2As depicted by the arrows defining the fluid path, within the sampling probe 30, the captured fluid (e.g., an organic solvent) travels through the annular space 220 between the two cylindrical members toward the end 215, and then exits the end and travels through the inner cylinder. As discussed above, the captured fluid and molecules of sample 20 flow from end 215 to ionization chamber 12.

[0039] As a non-limiting example, in some embodiments, sample 20 may include a liquid sample that can be acoustically ejected from sample container 310 directly into the liquid present in the sample space at end 215. Those skilled in the art will also understand that, in accordance with the teachings herein, any liquid (e.g., a solvent) suitable for, for example, directly receiving a liquid sample and capable of undergoing ionization processes can be provided by reservoir 50 according to various aspects of these teachings. In other embodiments, the sample may include a solid sample that can be directly introduced into the liquid present in the sample space for dissolution. In some embodiments, the solid sample may include a solid-phase substrate having a binding affinity for selected proteins of a drug molecule, such as solid-phase microextraction (SPME) fibers or magnetic particles.

[0040] return Figure 3 The external physical structure of the sampling probe 30 is described. Figure 2 This is a schematic diagram. Liquid droplets 300 are shown forming at the open end 215 due to insufficient suction, for example, at the open end 215. As discussed above, when a certain weight is exceeded, liquid droplets 300 detach from the sampling probe 30 and fall into the sample container 310 (e.g., a sample well plate) under gravity, thus contaminating the sample 20. The inventors' experiments have shown that the viscosity characteristics of organic solvents cause them to "slowly climb" up the conical region of the sampling probe before sufficient weight is available to form droplets. Based on a flow rate of 200 μL / min, droplet formation has been observed in approximately 30 milliseconds due to the imbalance between the solvent supply to the sampling probe 30 and the solvent removal via suction caused by the flow of atomized gas at the open end.

[0041] Turning Figures 4-6 According to an embodiment, the device 90 is shown to include a substrate 500 adapted to hold the droplet 300 when it forms at the open end 215 of the sampling probe 30. In an embodiment, as Figure 6As shown, substrate 500 includes an aperture 610 positioned to receive the open end 215 of sampling probe 30 and allow sample to pass through into the open end 215. The aperture 610 is adapted to accumulate droplets 300 under tension as they grow from the lower surface 520 of the substrate (i.e., facing the sample 20) along the wall of the aperture toward the upper surface 510 of the substrate, as shown at 515, thus bringing the droplets into contact with the sensor 600 on the upper surface 510. In some embodiments, the sampling probe 30 extends through the upper surface 510 into the aperture 610 to position the open end 215 between the sample 20 and the sensor 600. In these embodiments, the sample sprayed into the open end 215 is captured before passing through the sensor 600, thereby reducing the likelihood of the sensor 600 interfering with the sample trajectory.

[0042] Sensor 600 is adapted to detect droplets 300 of accumulated liquid and generate a signal to controller 980 for reducing or stopping the liquid flow to sampling probe 30 while continuing aspiration to expel excess liquid from open end 215. In this way, droplets 300 are trapped and removed before overflowing into the sample. In some embodiments, controller 980 may be further operable to increase the atomizing gas flow, thereby correspondingly increasing aspiration at open end. In some aspects, controller 980 may be operable to maintain the liquid flow supplied to sampling probe 30 at a constant flow rate while increasing the atomizing gas flow to increase aspiration and thus aspirate droplets 300 into open end 215.

[0043] In this embodiment, the sensor 600 is positioned on the top surface 510, away from the ejected droplets from the sample container 310, to reduce or eliminate any interference from the electric field emanating from the sensor 600 on the sample ejection trajectory. Acoustically ejected nanodroplets are highly sensitive to charge, and uncontrolled electrostatic charges are known to affect droplet volume and / or trajectory (see, for example, U.S. Patent No. 7,070,260). In embodiments where the sensor 600 does not generate sufficient charge from the acoustic ejection to affect the sample droplets, it may be convenient to locate the sensor 600 at its bottom or within the orifice wall of the orifice 610 itself.

[0044] Experiments have shown that the time it takes for the device 90 to retain the spilled solvent and drip the actual liquid into the sample has increased from approximately 30 milliseconds to approximately 30 seconds. This time is sufficient to stop the collection process and generate a notification signal to warn the operator of the spill and / or correct the problem by aspirating the spilled liquid.

[0045] In other embodiments, sensor 600 is one of the following: a conductive trace or wire located, for example, on the upper surface 510, for detecting changes in resistance upon contact with a solvent; or a temperature sensor, such as a thermocouple or resistance thermometer, for detecting changes in temperature upon contact with a solvent. In other embodiments, an auxiliary capillary fitting may be positioned to aspirate any spilled liquid from sensor 600 before it drips into the sample.

[0046] On the other hand, such as Figure 7 As shown, a method for preventing liquid from spilling from a sampling probe 30 into a sample 20 is proposed. In an embodiment, the method includes: retaining a liquid droplet 300 (700) when it forms at the open end 215 of the sampling probe; detecting the retained liquid droplet (710); and generating a signal to reduce or stop the liquid flow supplied to the sampling probe 30 before the retained droplet spills into the sample 20 (720). In some embodiments, a notification signal may also be generated to indicate an spill condition to an operator (730). In some aspects, the method may include at least one of: adjusting the flow rate of a solvent supply to control the fluid supply to the open end of the sampling probe 30 and / or adjusting the flow rate of an atomizing gas to control the discharge of fluid from the open end of the sampling probe 30.

[0047] In one embodiment, a droplet 300 of liquid is detected on the upper surface 510 opposite to the sample 20. In another embodiment, retaining the droplet 300 (700) includes accumulating the droplet under tension as it grows from the bottom surface 520 of the substrate 500.

[0048] Many features and advantages of the present invention are apparent from the detailed description; therefore, the appended claims are intended to cover all such features and advantages of the invention that fall within its scope. Furthermore, since many modifications and variations will readily occur to those skilled in the art, it is not intended to limit the invention to the exact constructions and operations shown and described, and therefore all suitable modifications and equivalents fall within the scope of the invention.

Claims

1. A device for preventing liquid from spilling from a sampling probe into a sample, comprising: A substrate adapted to retain liquid droplets when they form at the open end of a sampling probe; as well as A sensor located on the surface of a substrate opposite to the sample is adapted to detect droplets of a held liquid and generate a signal to control the liquid droplets before they overflow into the sample. The substrate includes an aperture positioned to accommodate the open end of a sampling probe and allow a sample to pass through into the open end. The aperture is adapted to accumulate and retain droplets under tension as droplets grow from the sample-facing surface of the substrate toward the sample-opposite surface of the substrate, thus allowing the droplets to contact the sensor for detection.

2. The apparatus of claim 1, wherein the liquid droplets are controlled by at least one of the following: Stop the liquid supply to the sampling probe; Increase suction at the sampling probe to draw liquid droplets from the substrate; Reduce the liquid supply to the sampling probe; and A combination of increasing suction and reducing or stopping the liquid supply to the sampling probe.

3. The apparatus according to any one of claims 1 to 2, wherein, The sensor is a conductive trace located on the surface of the substrate opposite to the sample.

4. The apparatus according to any one of claims 1 to 2, wherein, The sensor is a wire located on the surface of the substrate opposite to the sample.

5. The apparatus according to any one of claims 1 to 2, wherein, The sensor is a temperature sensor located on the surface of the substrate opposite to the sample.

6. The apparatus according to claim 5, wherein, The temperature sensor is a thermocouple.

7. The apparatus according to claim 5, wherein, The temperature sensor is a resistance thermometer.

8. A method for preventing liquid from spilling from a sampling probe into a sample, comprising: When a liquid droplet forms at the open end of the sampling probe, the liquid droplet is held by the substrate. Droplets of the held liquid are detected by a sensor located on the surface of the substrate opposite to the sample. as well as Signals are generated by sensors to control the liquid droplets before they overflow into the sample. The substrate includes an aperture positioned to receive the open end of a sampling probe and allow a sample to pass through into the open end. The aperture is adapted to accumulate and retain droplets under tension as they grow from the sample-facing surface of the substrate toward the sample-opposite surface, thus allowing the droplets to contact the sensor for detection. The liquid droplets that control the liquid include at least one of the following: Stop the liquid supply to the sampling probe; Increase suction at the sampling probe to draw liquid droplets from the substrate; Reduce the liquid supply to the sampling probe; and A combination of increasing suction and reducing or stopping the liquid supply to the sampling probe.

9. The method of claim 8, further comprising generating a notification signal indicating an overflow condition.

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