Method and system for automatically loading a microvolume liquid sample

Abstract

Methods and systems for automatically loading samples to an analytical instrument are disclosed. The method includes positioning a first pedestal and a second pedestal of the analytical instrument at a loading position, extending a first nozzle towards a sample space between the two pedestals, releasing a first sample from the first nozzle to the sample space so that the first sample is in direct contact with both the first surface and the second surface, and retracting the first nozzle away from the first sample held between the first surface and the second surface.

Description

PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1METHOD AND SYSTEM FOR AUTOMATICALLY LOADING A MICRO VOLUME LIQUID SAMPLEFIELD OF THE INVENTION

[0001] The present description relates generally to methods and systems for autoloading microvolume samples, and more particularly, to automatically loading and removing microvolume samples with respective to an analytical instrument.SUMMARY

[0001] In one aspect, a method for automatically loading samples for an analytical instrument includes positioning a first pedestal and a second pedestal of the analytical instrument at a pedestal loading position, where a sample space between a first surface of the first pedestal and a second surface of the second pedestal is provided for receiving a sample, extending, by operating a first actuator mechanically coupled to a first nozzle, the first nozzle towards the sample space, releasing, by operating a first pump fluidically connected to the first nozzle, a first sample from the first nozzle to the sample space so that the first sample is in direct contact with both the first surface and the second surface, and retracting, by operating the first actuator, the first nozzle away from the first sample held between the first surface and the second surface.

[0002] In one aspect, a sample autoloading system for an analytical instrument includes a first actuator mechanically coupled to a first nozzle. The sample autoloading system also includes a first pump fluidically coupled to the first nozzle. The sample autoloading system also includes a controller includes a processor and a memory storing instructions that, when executed by the processor, configure the sample autoloading system to position a first pedestal and a second pedestal of the analytical instrument at a pedestal loading position, where a sample space between a first surface of the first pedestal and a second surface of the second pedestal is provided for receiving a first sample, extend, by operating the first actuator, the first nozzle towards the sample space, release, by operating the first pump, a first sample from the first nozzle to the sample space so that the first sample is in direct contact with both the first surface and the second surface, and retract, by operating the first actuator, the first nozzle away from the first sample held between the first surface and the second surface.PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1

[0003] It should be understood that the summary above is provided to introduce in simplified form a selection of concepts that are further described in the detailed description. It is not meant to identify key or essential features of the claimed subject matter, the scope of which is defined uniquely by the claims that follow the detailed description.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0004] FIG. 1 illustrates an example of an analytical instrument.

[0005] FIG. 2 illustrates an example of a sample autoloading system.

[0006] FIG. 3A shows one embodiment of a part of the sample autoloading system of FIG. 2.

[0007] FIG. 3B shows the sample autoloading system of FIG. 3A integrated with an analytical instrument.

[0008] FIG. 4A is a side view of another embodiment of the sample autoloading system coupled to an analytical instrument.

[0009] FIG. 4B is another side view of the system of FIG. 4A.

[0010] FIG. 4C is a top view of the system of FIG. 4A.

[0011] FIG. 5A illustrates a sample space between pedestals of an analytical instrument.

[0012] FIG. 5B illustrates a first distal end of the first nozzle releasing a sample.

[0013] FIG. 5C illustrates a second distal end of the second nozzle removing a sample.

[0014] FIG. 6A illustrates one example of the distal end of the nozzle.

[0015] FIG. 6B illustrates another example of the distal end of the nozzle.

[0016] FIG. 6C illustrates another example of the distal end of the nozzle.

[0017] FIG. 6D illustrates another example of the distal end of the nozzle.

[0018] FIG. 6E illustrates another example of the distal end of the nozzle.

[0019] FIG. 6F illustrates another example of the distal end of the nozzle.

[0020] FIG. 7 illustrates operation of various components of the sample autoloading system over time for measuring multiple samples.

[0021] FIGS. 8 A, 8B, 8C, 8D, 8E and 8F illustrate the status of various components of the sample autoloading system at various time points of FIG. 7.

[0022] FIG. 9 is a flowchart for using an sample autoloading system and an analytical instrument for measuring properties of multiple samples.PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1

[0023] FIG. 10 are photos showing sample loading under various configurations.

[0024] FIG. 11A and 1 IB are photos showing sample unloading using an example second nozzle.

[0025] FIGS. 12A and 12B are photos showing sample unloading using another example second nozzle.

[0026] Like reference numerals refer to corresponding parts throughout the several views of the drawings.DETAILED DESCRIPTION

[0027] Spectrophotometers designed to be used with fiber optics has made it possible to measure optical property of samples of microvolume or microliter volume, such as samples in the volume range of 0.25 microliters to 10 microliters. Such spectrophotometers use the surface tension of the liquid sample to confine the sample between two surfaces of the pedestals for measuring the sample's physical, optical, and electrochemical properties. Examples of the spectrophotometers for optical property measurement are disclosed in U.S. Patents US6809826B2 and US6628382B2, the entire contents of both patents are hereby incorporated by reference in their entirety. These spectrometers can measure optical properties of a small volume sample with large dynamic range and high accuracy. In recent years, the spectrophotometers are further improved to measure more sample properties. For example, electrochemical property measurement may further facilitate understanding the sample composition. Patent application WO2024173752A1, which is incorporated herein by reference in its entirety, discloses spectrophotometers for measuring the electrochemical properties, such as the electrical conductivity and pH value, of the sample, wherein the electrodes are integrated within the pedestals. Provisional application US63 / 690,457, filed on September 4th, 2024, which is incorporated herein by reference in its entirety, discloses replaceable caps for the pedestals of the spectrophotometers to perform the pH measurement. Provisional application US63 / 764,088, filed on February 2nd, 2025, which is incorporated herein by reference in its entirety, further discloses estimating the sample temperature based on the electrical conductivity measurement.

[0028] Applicant recognizes that the above spectrophotometers require users to manually load / unload samples onto / from the pedestals. The manual sample loading process includes manually lifting the upper pedestal, pipetting a microvolume sample onto the bottom pedestal, and lowering the lifted pedestal. The manual sample unloading process includes manually liftingPCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1one pedestal, and pipetting or wiping the measured sample away from the pedestals. The manual sample loading and unloading processes are time consuming and labor-intensive. As laboratories across the world become more and more automated, there is a need for automatically load and unload multiple samples for the spectrophotometers.

[0029] In order to address the above issues, methods and systems for automatically loading and unloading one or more samples for an analytical instrument (such as the spectrophotometers) are disclosed herein. In one aspect, a method for automatically loading microvolume (or microliter) samples to the analytical instrument, includes positioning a first pedestal and a second pedestal of the analytical instrument at a pedestal loading position, extending a first nozzle towards a sample space between the first and second pedestals, releasing a first sample from the first nozzle to the sample space, and retracting the first nozzle away from the sample space.

[0030] At the pedestal loading position, the first surface of the first pedestal and the second surface of the second pedestal are positioned at a loading distance from each other. The sample space is a three-dimensional space defined and bounded by the first and second surfaces. The first and second surfaces are facing each other. The first nozzle is mechanically coupled with a first actuator configured to translate a first distal end of the first nozzle relative to the sample space. The first nozzle is also fluidically connected with a first pump configured to flow one or more liquid samples from one or more reservoirs to the first nozzle to release the sample to the sample space from the first distal end. The fluidic connection may be achieved by microfluidic tubing connected between the first pump and the first nozzle.

[0031] While releasing the first sample from the first nozzle to the sample space, the first sample flows out of the first distal end of the first nozzle. The first sample flowed out of the first distal end of the first nozzle is in direct contact with the first and second surfaces of the pedestals. That is, during sample releasing, there is at least a time point wherein the first sample is in direct contact with the first distal end, the first surface, and the second surface. After the entirety of the first sample is released from the first distal end, the first nozzle is retracted away from the sample space, so that the first sample is held between the first surface and the second surface by surface tension.

[0032] In some examples, the volume of the sample is between 0.25 microliters to 10 microliters, including 0.25 microliters and 10 microliters.PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1

[0033] In this way, the microvolume sample is automatically loaded to the pedestals of the analytical device without human intervention. The nozzle for delivering the sample can be easily replaced for maintenance or avoiding sample contamination.

[0034] In some aspects, the pedestals remain at the pedestal loading position throughout the sample loading process (i.e., from extending the nozzle to the sample space until the first nozzle is retracted from the sample space). In other aspects, the pedestal separation may be reduced from the loading distance during or after the first nozzle extended towards the sample space, to ensure that the first sample is in direct contact with both the first and second surfaces. By ensuring that the first sample is in direct contact with both surfaces, the entire volume of the microvolume first sample in the first nozzle can be completely released from the first nozzle to the sample space.

[0035] The first and second surfaces of the pedestals may be of the same or different shapes or sizes. The central axes of the first and second surfaces are aligned. In other words, the central axis of the pedestals passing the geometric center of both the first surface and the second surface. In one example, both the first surface and the second surface are round. In one example, at least one of the two surfaces are flat. In other examples, one or both of the two surfaces may be curved. The distance between the two surfaces of the pedestals (i.e., pedestal separation or a distance between the pedestals) is defined as the distance between the two surfaces along the central axes of the two surfaces. The first and second surfaces may be hydrophobic to avoid residual sample left on the pedestal surface. Optical fibers and / or electrodes may be integrated to one or both of the pedestals. The end of the optical fiber may be included in the first and / or second surface. The first / second surface may be electrically coupled to the electrode.

[0036] In one aspect, after retracting the first nozzle, at least one sample property of the first sample is measured using the analytical instrument. The sample property may include one or more optical, physical, and electrochemical properties. For example, the sample property includes one or more absorbance, transmission, fluorescence, temperature, pH, and electrical conductivity. During the measurement, the pedestal separation may be adjusted, for example to adjust the optical pathlength or shape of the sample, while measuring the sample property. As such, multiple samples may be automatically loaded into and measured by the analytical instrument without human intervention.

[0037] After measuring the sample property, the first pedestal and the second pedestal are positioned at a pedestal unloading position, wherein the pedestal separation is set at a predetermined unloading distance. A second nozzle, mechanically coupled to a second actuator,PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1extends towards the sample space, and removing, by operating a second pump fluidically connected to the second nozzle, the first sample held between the two surfaces into the second nozzle. In one example, the second nozzle is the same as the first nozzle, and the second actuator is the same as the first actuator. As such, one set of nozzle, pump, and actuator is required to achieve automatic sample loading and unloading. In another, preferred, example, the second nozzle is different from the first nozzle, and the second actuator is different from the first actuator. By separating the components for sample loading and unloading, multiple samples can be measured more efficiently. For example, while the first sample is measured by the analytical instrument and / or removed by the second nozzle, a second sample flows to the first nozzle. As such, the idle time (not measuring any sample) of the analytical instrument can be reduced.

[0038] In one example, the first and second samples have the same composition. They may be drawn from the same reservoir to the first nozzle. In another example, the first and second samples have different composition. They may be drawn from different reservoirs to the first nozzle.

[0039] The loading distance and the unloading distance may be determined based on the sample's volume. If multiple samples are going to be measured, the loading distances and the unloading distances may be adjusted for the sample volume of each of the multiple samples. The volume of the sample loaded to the analytical instrument can be controlled / adjusted by operating the first pump and / or valve(s) coupled to the first pump.

[0040] In one aspect, during sample unloading (or removal), extending the second nozzle towards the sample space includes positioning the second distal end of the second nozzle in direct contact with the first sample held between the first surface and the second surface. That is, during sample unloading, there is at least one time point wherein the first sample is in direct contact with both pedestal surfaces and the second distal end of the second nozzle. As such, minimal pedestal separation adjustment is needed for sample removal, therefore reduces the time lag between measurement and sample removal. Further, the entire volume of the first sample can be removed.

[0041] At the pedestal loading position, the loading distance is greater than the inner diameter of the first distal end of the first nozzle. At the pedestal unloading position, the unloading distance is greater than the inner diameter of the second distal end of the second nozzle. In one example, the first distal end of the first nozzle is blunt. In another example, the second distal end of the second nozzle is beveled. The beveled tip can facilitate complete sample removal from thePCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1pedestals after the measurement. This is because the beveled shape introduces both vertical and axial suction forces on the sample held between the two pedestal surfaces.

[0042] In another example, the first and second surfaces are positioned horizontally, and the second surface is below the first surface, wherein a surface of the beveled second distal end of the second nozzle is facing the second surface. As such, the gravitational force and further facilitate complete sample removal from the pedestals.

[0043] Each nozzle (e.g., first or second nozzle) includes one distal end open to ambient air for flowing the samples out of or into the nozzle and another distal end connected to pumps or valves via tubing. For example, the first distal end of the first nozzle and the second distal end of the second nozzle are not connected with other components and open to ambient air. The nozzle may have a rigid, elongated, body made of materials including plastic or metal. The nozzle is mechanically coupled to an actuator to extend or retract one distal end of the nozzle relative to the sample space. The external profile of the nozzle may have varied outer diameters along its length. For example, as shown in FIGS. 6B and 6F, the nozzle may have an external profile including a tapered portion.

[0044] In one example, the unloading distance is less than 1.15 mm. In another example, the unloading distance is less than 1 mm. In yet another example, the unloading distance is between 0.5 mm and 0.95 mm, including the 0.5 mm and the 0.95 mm. In some examples, the inner diameter of the second distal end of the second nozzle is similar but smaller than the unloading distance, so that the sample may be quickly and completely removed. In one example, the difference between unloading distance and inner diameter of the second distal end of the second nozzle is less than or equal to 0.5 mm.

[0045] In one aspect, a predetermined volume of the first sample is delivered to the first nozzle by operating the first pump and / or a valve fluidically coupled the first nozzle. In one example, after flowing the predetermined volume of the first sample towards the first nozzle, ambient air is flowed into the first nozzle. As such, an accurate sample volume can be delivered. Further, by flowing the ambient air, the pressure difference across the first sample facilitates pushing the first sample out of the first distal end, therefore avoiding residual sample within the first nozzle.

[0046] In one aspect, for releasing the sample, the first distal end of the first nozzle is extended into the sample space and positioned at a nozzle loading position for releasing the first sample. The first distal end is then retracted to a nozzle measurement position that is at least 1.5 mm away from a center of first sample (or the sample center of the sample space). In one example,PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1measurement of the first sample is initiated responsive to the first nozzle retracted to the nozzle measurement position. By positioning the first distal end of the nozzle at the nozzle measurement position, the sample held between the pedestals is not disturbed by the air flow from the first distal end, therefore ensures noise-free measurements.

[0047] In one example, a multi-position valve is coupled upstream of the first pump for fluidically connecting different fluids and / or gases in one or more reservoirs with the first pump. The predetermined volume of the first sample is delivered by controlling the speed of the pump and the opening / closing of the multi-position valve. The ambient air may be provided, for example, by continuously operating the first pump after switching the valve from a first position to deliver the first sample to a second position with fluidic communication to the ambient air. In other examples, the multi-position valve may be replaced by other valve system that configured to selectively route liquids and gases to the first pump. The multi-position valve may be replaced by multiple valves.

[0048] In one aspect, a second sample may be flowed towards the first nozzle when the first nozzle is at the nozzle measurement position. The method may further includes extending the first nozzle from the nozzle measurement position towards the sample space, to a nozzle pre-loading position, while measuring the at least one sample property of the first sample using the analytical instrument. As such, the first nozzle is at a closer location to the sample space to quickly load the second sample to the pedestals. This parallel sample loading and unloading sequence using two separate nozzles can maximize the sample measurement efficiency.

[0049] FIG. 1 illustrates an analytical instrument 100 for measuring a micro volume liquid sample. The analytical instrument 100 may measure both electrochemical and optical properties of the same sample. In some examples, the measurements of the electrochemical and optical properties can be conducted simultaneously. In particular, the analytical instrument 100 includes a first pedestal 101 and a second pedestal 102. The sample 105 can be held between a first surface 103 of the first pedestal and a second surface 104 of the second pedestal only by surface tension during the measurement.

[0050] The analytical instrument 100 includes a first optical fiber 114 connected to a light source 116, and a second optical fiber 115 connected to a detector 117. The optical fiber may have endings being a part of the first surface 103 or the second surface 104. One of the first / second fibers is for delivering a light, and the other fiber is for receiving the light from the sample. The optical fibers may be mounted coaxially with and perpendicular to the first andPCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1second surfaces. The first and second surfaces may each extend in the X-Y plane, parallel to each other. Z axis indicates vertical direction. The first surface is positioned above the second surface. The first pedestal and the first surface are respectively the upper / top pedestal and the upper / top surface. The second pedestal and the second surface are respectively the bottom pedestal and the bottom surface. The actuator 112 (e.g., one or more stepper motors) may be coupled to either of the pedestals to adjust the separation distance between the first and second surfaces (or pedestal separation). The detector may include a spectrograph for splitting the collected light based on its wavelengths. Such an instrument is configured to quantitatively measure the reflection, optical transmission, or fluorescent property of a sample, which may be used to determine the amount of a particular compound in a sample.

[0051] For some applications, the optical fibers can be replaced by miniature sources like light emitting diodes (LEDs). Small solid-state detectors with associated filters like those used in color charge coupled devices (CCDs) for imaging may replace the receiving fiber and detector.

[0052] The analytical instrument 100 may further include one or more electrical connections (e.g., wires) 107 and 109 that respectively electrically connect the first electrode 110 of the first surface 103 and the second electrode 111 of the second surface second surface 104 to the electronic processing unit 113. The electronic processing unit 113 can generate and receive electrical signals for measuring the electrochemical property of the sample.

[0053] The analytical instrument 100 includes camera 108 positioned axially relative to the sample to monitor the position, shape, and / or size of the sample 105. Additionally, camera 108 can be used for monitoring the positions of the nozzles for sample loading and unloading, and / or the positions of the pedestals.

[0054] The analytical instrument 100 includes controller 106 electronically coupled to one or more of the light source 116, actuator 112, detector 117, and electronic processing unit 113. In some examples, the electronic processing unit 113 may be integrated with controller 106. The controller includes a processor and a non-transitory memory for storing computer readable instructions. By executing the computer readable instructions in the processor, the analytical instrument 100 can automatically perform the measurement of one or more sample properties. Additionally, the controller may be also electronically coupled to components of a sample autoloading system shown in FIG. 2. As such, the controller 106 can be configured to implement the methods disclosed herein. The controller 106 may further electronically connected with user interface 118 for receiving user inputs and display images and measurements to the user.PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1

[0055] In some embodiments, the analytical instrument 100 may have different surface orientations for holding the sample 105, including, for example, a vertical orientation.

[0056] FIG. 2 shows a sample autoloading system 200 including a first nozzle 212 for delivering a sample from the first reservoir 220 or the second reservoir 222 to a sample space (shown in FIG. 5A) between the first pedestal 101 and the second pedestal 102 of the analytical instrument 100, and a second nozzle 214 for unloading or removing the sample held between the first pedestal 101 and the second pedestal 102. The first nozzle 212 and the second nozzle 214 are not in direct contact with the pedestals of the analytical instrument 100. The first nozzle 212 and the second nozzle 214 are respectively mechanically coupled to the first actuator 204 and the second actuator 206. The actuators are configured to independently extend or retract the corresponding nozzle towards or away from the sample space. The actuators 204 and 206 may be linear actuators including a stepper motor. The first nozzle 212 is fluidically coupled to multi-position valve 216 via first pump 208. The multi-position valve 216 may be fluidically coupled to one or more reservoirs that contains different samples. The fluidical coupling may be achieved by any tubing system. Herein, two reservoirs (first reservoir 220 and second reservoir 222) are shown. In some examples, the reservoirs may be cuvettes or multiwell plates. At a particular valve position, one of the samples in the corresponding reservoir is fluidically connected to first pump 208, so that the sample may be flowed to towards the first nozzle 212 by operating the first pump 208. In other examples, valve systems other than the multi-position valve can be used for selectively fluidically connecting the first pump 208 with one or more of the samples. At one position of the multiple valve positions, the pump is fluidically connected with the ambient air.

[0057] The second nozzle 214 is fluidically coupled to the second pump 210, and the second pump 210 is further fluidically coupled to the third reservoir 218 for collecting sample removed from the pedestals of the analytical instrument. In some examples, the third reservoir 218 may be replaced with a multi-position valve connected with multiple reservoirs, similar to the multiposition valve 216 coupled with the first reservoir 220 and the second reservoir 222. As such, different samples may be recollected and stored in different reservoirs. The first and second pumps may be selected from a peristaltic or a suction pump.

[0058] The sample autoloading system 200 may include a controller 202 that is electronically connected to the one or more actuators, pumps, and valves. The controller 202 may include a processor and a non-transitory memory for storing computer readable instructions. ByPCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1executing the computer readable instructions in the processor, the sample autoloading system 200 can automatically and sequentially loading and removing multiple microvolume samples for the analytical instrument.

[0059] The sample autoloading system 200 may be integrated with the analytical instrument 100 (FIGS. 3A-3B), or as an add-on to the analytical instrument 100 (FIGS. 4A-4C). The controller 202 may be integrated with controller 106 of FIG. 1 for implementing the entire sample loading, measurement, and removal workflow.

[0060] FIG. 3A shows a part of an example sample autoloading system integrated with the analytical instrument (such as the analytical instrument 100 shown in FIG. 1). The nozzle 304 can be either the first nozzle for loading the sample or the second nozzle for unloading the sample. An actuator, motor 302, is mechanically coupled with the nozzle 304 via one or more gear 306. By rotating the motor 302, the distal end 314 of nozzle 304 can be extend or retract along the x-axis. The nozzle 304 is also attached to linear guide 316, which can manually adjust the height of nozzle 304 relative to base 308 in the y-axis. The motor is coupled to the base 308 via linear guide 318 so that position of the nozzle 304 in the x-axis can be manually adjusted.

[0061] FIG. 3B shows the example sample autoloading system of FIG. 3A and a part of the analytical instrument. The analytical instrument may be a NanoDrop system. The distal end (such as distal end 314) of the nozzle 304 is extended towards the pedestals 310 of the analytical instrument along the x-axis. The base 308 is the base that the pedestals 310 are attached to. The port 312 located at the other distal end of nozzle 304 can be coupled with a pump or a valve via tubing, for delivering or removing the sample to or from the pedestals 310.

[0062] FIG. 3A and FIG. 3B show motor and nozzle on one side of the pedestals 310. The same components can be also positioned on the opposing side, for example along the x-axis, of the pedestals 310.

[0063] FIG. 4A, FIG. 4B, and FIG. 4C show a portion of an example sample autoloading system, separated from the analytical instrument, as a standalone module. In this example, the first actuator 404 and second actuator 406 are fixed to a frame 414, which can be removably attached to the analytical instrument. Once attached to the analytical instrument, as shown in FIG. 4A, the first actuator 404 and the second actuator 406 are positioned on opposite sides of the pedestals 402.PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1

[0064] FIG. 4B is a side view showing the analytical instrument when the first pedestal 408 is separated or lifted away from the second pedestal 416. FIG. 4C is a top view of FIG. 4B, showing the first nozzle 412 driven by the first actuator 404, as well as the second nozzle 410 driven by the second actuator 406. The distal ends of the second nozzle 410 and the first nozzle 412 locates on opposite sides of the second pedestal 416.

[0065] FIG. 5A illustrates the sample space 502 defined by the first surface 103 of the first pedestal 101 and the second surface 104 of the second pedestal 102. The top (along Z direction) of the three-dimensional sample space 502 is bounded by the first surface 103, the bottom of the sample space 502 is bounded by the second surface 104. In the axial (X-Y) plane, the sample space 502 is bounded by the boundary of the first surface 103 and the second surface 104. If the area of the first surface 103 is not the same as the second surface 104, as shown herein FIG. 5A, the sample space 502 is bounded by the surface with larger area, that is, the second surface 104 in this example. As such, the sample space 502 in this example has a cylindrical shape. The sample center 508 is the geometric center of the sample space 502, which locates at the intersection of the central axis 504 of the pedestals and the sample plane 506. The central axis of the first surface 103 and the central axis of the second surface 104 are aligned with the central axis 504. The central axis 504 goes through the geometric centers of first surface 103 and second surface 104. The sample plane 506 is an axial (X-Y) plane in the middle and with the same distance from the first pedestal 101 and the second pedestal 102. When moving the nozzles towards or away from the sample space 502, the nozzles are moved towards or away from the sample center 508 of the sample space 502.

[0066] FIG. 5B illustrates the first nozzle 212 releasing the sample 105 into the sample space 502 between the first surface 103 and the second surface 104. The pedestal separation 510 is the distance between the first surface 103 and the second surface 104 along the central axis 504 of the pedestals. During sample loading, the pedestal separation 510 may be set at the loading distance. When flowing the sample to the sample space 502 from the first distal end 514 of the first nozzle 212, the sample 105 is in direct contact with the first distal end 514, the first surface 103, and the second surface 104. The central axis of the first nozzle 212 may be substantially within the sample plane 506, or within a small angle (e.g., ±0.6 degrees) relative to the sample plane 506.

[0067] FIG. 5C illustrates the second nozzle 214 unloading the sample 105 from the sample space 502 between the first surface 103 and the second surface 104. The pedestal separation isPCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1set to the unloading distance. The second distal end 516 of the second nozzle 214 is in direct contact with the sample 105 in order to remove the sample. The second distal end 516 is beveled, with the beveled surface facing downwards (opposite to the Z direction). The central axis 512 of the second nozzle 214 may be positioned higher than the sample plane 506, with the top surface close to but not touching the first surface 103. In other words, the central axis 512 is closer to the first surface 103 comparing to the second surface 104 when removing the sample 105 into the second nozzle 214. The central axis 512 of the second nozzle 214 may be parallel to the sample plane 506, or within a small angle (e.g., ±0.6 degrees) relative to the sample plane 506.

[0068] FIGS. 6A-6F show various designs of the nozzle for loading and / or unloading the samples. FIG. 6A and FIG. 6B are examples of the first nozzle. FIG. 6A shows a part of an example first nozzle 614 with a blunt first distal end 602. The horizontal dashed lines indicate the inner lumen allowing the sample to flow towards the distal end. The blunt surface 638 at the first distal end 602 may be substantially perpendicular to the central axis of the first nozzle 614. The external profile of the first nozzle 614 is cylindrical that extends along its central axis.

[0069] FIG. 6B shows another example first nozzle 616. The first nozzle 616 also has a blunt first distal end 604. The blunt surface 640 at the first distal end 604 may be substantially perpendicular to the central axis 634. Different from the first nozzle 614, the external profile of first nozzle 616 has a tapered portion 618 and a straight portion 620. At the tapered portion 618, the external profile of the first nozzle 616 tapers towards the central axis 634 of the first nozzle 616. At the straight portion 620, the external profile is parallel to the central axis 634.

[0070] FIGS. 6C-6F are various designs of a part of the second nozzle for unloading or removing the sample held between the pedestals. The second distal ends of second nozzle 622, 624, 626, and 628 all have a bevel. The bevel creates a suction force in a direction that is not aligned with the central axis of the nozzle, therefore facilitate quick and complete removal of the sample held between the pedestals. The bevel may of different sizes and / or lengths. The second nozzle 624 of FIG. 6D has a longer bevel comparing to the second nozzle 622 of FIG.6C. FIG. 6E shows an example of second nozzle 626 wherein a portion of the second distal end 610 is beveled. The second distal ends of FIGS. 6C-6E have cylindrical external profile. The second nozzle 628 of FIG. 6F has a tapered portion 630 and a straight portion 632. The tapered portion 630 tapers towards the central axis 636 of the second nozzle 628. The beveledPCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1surface (642, 644, 646, 648) of the beveled distal end may be positioned to face the second surface of the analytical instrument.

[0071] The different features of each of the example nozzle shown in FIGS. 6A-6F may be combined.

[0072] FIG. 7 illustrates the time sequences of operating various components of the sample autoloading system 200 for automatically loading and unloading multiple samples. The X-axes of the plots 702-716 are time. The time increases as indicated by the arrow of the X-axis. Plot 702 shows the distance between the first distal end of the first nozzle 212 from the central axis of the pedestals. The distance increases from 0 as shown in the direction of the Y-axis.Distance DI is the nozzle measurement position, distance D2 is the nozzle pre-loading position, and distance D3 is the nozzle loading position. Plot 704 shows the distance between the second distal end of the second nozzle 214 and the central axis of the pedestals. The distance increases from 0 as shown in the direction of the Y-axis. D4 is the nozzle unloading distance. Plot 706 shows the status of the first pump 208. When the status of the first pump is ON, the fluid or gas is flowed towards the first nozzle from the first pump. Plot 714 shows the status of the second pump 210. When the status of the second pump is ON, the fluid or gas is flowed away from the second nozzle to the second pump. Plots 708, 710, 712 correspond to three positions / valves of the multi-position valve 216. The first valve 822 (or first position of the multiple position valve) connects between the first reservoir 220 of the first sample and the first pump 208. The second valve 824 (or second position of the multiple position valve) connects between the second reservoir 222 of the second sample and the first pump 208. By turning the first / second pump ON, fluidic connection is established between the first pump and the first / second sample. The third valve 826 (or third position of the multiple position valve) connects between the ambident air and the first pump 208. By turning the third valve ON, the input of the first pump is fluidically connected with ambient air. Plot 716 shows the measurement status of the analytical instrument (such as the analytical instrument 100). When the measurement is ON, sample property is being measured by the analytical instrument.

[0073] From TO to Tl, as shown in FIG. 8 A, the first valve 822 is turned ON and the first pump 208 is turned ON. The second and third valves are OFF. The first sample is drawn from the first reservoir 220 to the first nozzle 212 by operating the first pump 208. The first nozzle 212 extends towards the sample space between the pedestals (first pedestal 101 and second pedestal 102), as shown by arrow 830. The second distal end of the second nozzle 214 isPCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1positioned at D4 838 from the central axis 504. The first nozzle 212 extends towards the distance D3 840 from TO to Tl. At Tl, the first distal end of first nozzle 212 reaches the distance D3 840 from the central axis 504, ready to release the first sample towards the sample space.

[0074] After a predetermined volume of the first sample is drawn from the first reservoir 220, at T2, the third valve 826 is turned ON and the first valve 822 is turned OFF. The duration between Tl is T2 depends on the volume of the first sample and the speed of the pump. In some examples, the pump may briefly stop at T2, during the operation of the valves.

[0075] Between Tl to T3, the first sample is flowed from the first nozzle to the sample space, as shown in FIG. 8B. The first pump 208 is ON, creating a pressure difference across the microvolume first sample 844, to ensure that all first sample 844 exits the first distal end of the first nozzle 212.

[0076] At T3, as shown in FIG. 8C, when all first sample exists the first distal end, the first nozzle 212 quickly retracted to the distance DI 848 (farther from distance D3 840 relative to the central axis 504). DI is at least 1.5 mm. When the first nozzle 212 is retracted to DI 848 at T4, the measurement (shown in Plot 716) starts. In this example, the first pump and the third valve are turned OFF from T3 to T4. In other examples, the first pump and the third valve may be kept ON from T3 to T4. When moving the sample through the tubing connected to the first nozzle and along the first nozzle, airflow out of the first distal end is created. By starting the measurement when the first nozzle is away from the first sample between the pedestals, the effect of the airflow coming out of the first nozzle on the sample can be minimized, therefore ensure accurate sample measurement.

[0077] At T4, the first pump and the second valve are turned ON, so that the second sample is drawn from the second reservoir towards the first nozzle. As such, the delivery of the second sample is initiated while the first sample is measured by the analytical instrument. By loading the second sample while measuring the first sample, the idle time of the analytical instrument can be reduced. After reaching a distance DI 848 at T4, the first nozzle starts extending to the distance D2846, closer to the sample space, to prepare to release the second sample to the sample space. By moving the first nozzle closer to the sample space, the time for driving the first nozzle to the sample space can be reduced, thus reducing the total sample loading time.

[0078] At T5, the entire predetermined volume of the second sample has been drawn from the second reservoir. The second valve is turned OFF and the third valve is turned ON. The firstPCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1pump may be stopped for a short period while operating the valve. The first pump continues to be ON till the second sample has been pushed by the ambient air drawn from third valve 826 to the first distal end of the first nozzle, ready to be delivered to the sample space. In the example shown in FIG. 7, the first pump and is turned OFF shortly after T6.

[0079] At T6, measurement on the sample's property by the analytical instrument is completed. The second distal end of the second nozzle starts to move towards the sample space from a distance of D4838. D4838 may be smaller than DI.

[0080] At T7, as shown in FIG. 8D, the second distal end of the second nozzle 214 is in direct contact with the first sample 844 held between the first pedestal 101 and the second pedestal 102. In this example, the distance of the second distal end of the second nozzle 214 from the central axis 504 reaches zero. In other examples, the distance between the second distal end of the second nozzle 214 and the central axis 504 may be either positive or negative. From T7 to T8, the second pump 210 is turned ON to draw the first sample 844 from the sample space into the second nozzle 214. FIG. 8D also shows the second sample 850, which is pushed close to the first distal end of the first nozzle 212. The predetermined volume of the second sample 850 is pushed close to the distal end of first nozzle 212 by air 854 drawn from the first pump 208 via the third valve 826. The pressure of air 854 is higher than the ambient air pressure.

[0081] At T8, when the first sample 844 is about to be completely removed from the pedestals, the first pump is turn ON to further push the second sample towards the distal end of the first nozzle.

[0082] At T9, as shown in FIG. 8E, when the entirety of the first sample 844 is removed from the pedestals and into the second nozzle 214, the second nozzle 214 is retracted away from the central axis 504, and the first nozzle 212 starts to move from distance D2 to D3 to load the second sample 850 to the pedestals. The second pump 210 may be turned OFF at T9. In some examples, the second pump 210 may continue to be ON to flow the first sample 844 into the third reservoir 218.

[0083] At T10, as shown in FIG. 8F, the first nozzle 212 advances to D3 840 from the central axis 504 and starts loading the second sample 850 to the sample space between the pedestals. The first pump 208 and the third valve 826 are both ON to push the second sample 850 out of the first nozzle 212 with air 854. After the second sample is loaded, the sample autoloading system may repeat the operation sequence from T3, retracting the first nozzle and preparing to measure the second sample.PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1

[0084] By repeating this sequence, the sample autoloading system can sequentially load and measure multiple samples with minimal delay due to sample loading and unloading. The operations of the pumps, actuators, and valves may be synchronized with the analytical instrument based on feedbacks of a video camera (such as the camera 108 of FIG. 1). For example, one or more of the completeness of sample removal from the first distal end of the first nozzle to the pedestals, the measurement by the analytical instrument, and sample removal from the pedestals to the second nozzle can be monitored by the video camera. In some other examples, some of these events, such as the completeness of sample removal from the first distal end of the first nozzle to the pedestals, may be monitored by a sensor positioned at the tip of the first distal end. As such, the analytical instrument can be utilized to reach its full efficiency and potential on performing various measurements on multiple samples.

[0085] FIG. 9 shows method 900 of measuring multiple samples with the analytical instrument 100 while using the sample autoloading system 200 for automatically loading and unloading the samples. The sample autoloading system 200 may be a standalone system with its own controller or a controller integrated with the analytical instrument 100.

[0086] At 902, the sample autoloading system 200 is optionally calibrated. Calibrating the sample autoloading system 200 may include determining the positions of first nozzle and the second nozzle during each step of the sample autoloading process. For example, determining the nozzle positions may include determining DI, D2, D3, and D4 of FIG. 7. The calibration may be facilitated by a camera (such as camera 108 of FIG. 1) for imaging the region around the sample space.

[0087] At 904, the analytical instrument 100 is calibrated. Calibrating the analytical instrument 100 may include determining the loading distances and the unloading distances of the pedestal separation based on the volumes of the multiple samples.

[0088] At 906, the sample autoloading system 200 is coupled to the reservoirs. The valves or positions of the multi-position valve are each fluidically coupled to the respective reservoir. For example, the valves fluidically connected to the first pump are connected to multiple samples. In some examples, the samples are held in a multi-well or multi-cuvette container. The second pump is fluidically coupled to the reservoir that holds the wastes. In some examples, the valve(s) fluidically connected to the second nozzle is coupled to multiple reservoirs for collecting the measured sample separately. In some examples, multiple valves or valve positions may be connected to one reservoir.PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1

[0089] At 908, the analytical instrument 100 and sample autoloading system 200 are synchronized to automatically load, measure, and unload each of the multiple samples. An example sequence is shown in FIG. 7.

[0090] FIG. 10 are photos taken by the camera (such as camera 108 of FIG. 1) showing that the size of the first nozzle affected the total removal of sample liquid from the first nozzle. Plot 1004, Plot 1006, and Plot 1008 show the before (left) and after (right) a liquid sample 1016 being loaded between the first pedestal 1020 and the second pedestal 1022. The outer diameter of the first distal end of the first nozzles were 0.6 mm, 0.9 mm, and 1.2 mm for Plot 1004, Plot 1006, and Plot 1008, respectively. The inner diameter of the first distal end of the first nozzle increased with the increased outer diameter. When the inner diameter of the first distal end was smaller (Plot 1004) or substantially similar (Plot 1006) comparing to the pedestal separation, the liquid samples were completely loaded from the first nozzle (1010, 1012) to the pedestals. When the inner diameter of the first nozzle 1018 was larger than the pedestal separation, as shown in Plot 1008, some residual liquid sample was left in the first distal end of the first nozzle 1018. As such, in order to accurately transfer a targeted / predetermined volume of the sample to the pedestals, the inner diameter of the first nozzle is not greater than the pedestal separation. On the other hand, smaller inner diameter of the first distal end will reduce the sample delivery efficiency. Therefore, to maximize the sample delivery speed without compromising the accuracy, the inner diameter of the first distal end is preferably comparable to but not greater than the pedestal separation.

[0091] FIG. 11A and FIG. 1 IB are photos showing the effect of the size of the second nozzle on the sample removal from the pedestals. Each FIG. 11A and FIG. 1 IB includes three photos taken sequentially over time (from left to right). The first nozzle 1108 for loading the sample between the first pedestal 1104 and the second pedestal 1106 are shown in the photos. The second nozzle 1110 had a blunt first distal end. The second nozzle 1110 extended towards the sample held between the pedestals and drew the sample into the second nozzle 1110. In FIG.11 A, the inner diameter of the second distal end of the second nozzle 1110 was smaller than the pedestal separation. The sample 1114 was completely removed from the surfaces of the pedestals. In FIG. 1 IB, the pedestal separation was greater than the one in FIG. 11 A, and greater than the inner diameter of the second distal end of the second nozzle 1110. Residual of sample 1112 was left on the surfaces of the pedestals. As such, when the second nozzle has aPCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1blunt end, the pedestal separation has to be kept relatively small, or comparable to the inner diameter of the second distal end, to successfully remove all sample from the pedestals.

[0092] FIG. 12A and FIG. 12B are photos showing the effect of the size of the second nozzle on the sample removal from the pedestals. Each FIG. 12A and FIG. 12B includes four photos taken sequentially over time (from left to right). The first nozzle 1206 for loading the sample between the first pedestal 1202 and the second pedestal 1204 are shown in the photos. The second nozzle 1212 had a beveled first distal end. The beveled surface faced towards the second pedestal 1204. The second nozzle 1212 extended towards the sample held between the pedestals and drew the sample into the second nozzle 1212. The pedestal separation in both FIG. 12A and FIG. 12B were greater than the inner diameter of the second distal end of the second nozzle 1212. Though the pedestal separation was large in FIG. 12B, the sample 1214 was completely removed from the pedestals, with similar results as removing the sample 1210 in FIG. 12A. Comparing to the blunt second nozzle 1110 in FIG. HA and FIG. 1 IB, with the beveled distal end, the second nozzle 1212 achieved more efficient sample removal and higher tolerance to the pedestal separation.

[0093] Using a motorized nozzle fluidically connected to the sample, a microvolume sample of a predetermined sample volume can be quickly and accurately loaded between two opposing surfaces of two motorized pedestals of an analytical instrument. During sample loading and unloading, the sample is in direct contact with distal end of the nozzle, as well as both surfaces of the pedestal. After sample loading, the loaded sample is held between the pedestals by surface tension for measuring various sample properties using the analytical instrument. The automatic sample loading system and the analytical instrument can be synchronized for sample loading, measurement, and unloading, for an automatic workflow of analyzing multiple samples. The sample loading system can be integrated into the analytical instruments with minimal adjustment to the analytical instrument. Components of the sample autoloading system can be easily replaced or serviced. The disclosed nozzle size and shape further ensure sample delivery accuracy and efficiency.

[0094] Example 1 : A method for automatically loading samples for an analytical instrument, comprising: positioning a first pedestal and a second pedestal of the analytical instrument at a pedestal loading position, wherein a sample space between a first surface of the first pedestal and a second surface of the second pedestal is provided for receiving a sample; extending, by operating a first actuator mechanically coupled to a first nozzle, the first nozzle towards thePCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1sample space; releasing, by operating a first pump fluidically connected to the first nozzle, a first sample from the first nozzle to the sample space so that the first sample is in direct contact with both the first surface and the second surface; and retracting, by operating the first actuator, the first nozzle away from the first sample held between the first surface and the second surface.

[0095] Example 2 : The method of example 1, further comprising: after retracting the first nozzle, measuring at least one sample property of the first sample using the analytical instrument; positioning the first pedestal and the second pedestal at a pedestal unloading position; extending, by operating a second actuator mechanically coupled to a second nozzle, the second nozzle towards the sample space; and removing, by operating a second pump fluidically connected to the second nozzle, the first sample held between the two surfaces into the second nozzle.

[0096] Example 3: The method of example 2, further comprising initiating the measurement of the first sample responsive to the first nozzle retracted to a nozzle measurement position wherein a first distal end of the first nozzle is at least 1.5 mm away from a center of the sample space.

[0097] Example 4: The method of example 3, further comprising flowing, by operating the first actuator, a second sample towards the first nozzle when the first nozzle is at the nozzle measurement position.

[0098] Example 5 : The method of example 4, further comprising extending the first nozzle from the nozzle measurement position towards the sample space after measuring the at least one sample property of the first sample using the analytical instrument.

[0099] Example 6: The method of example 4, further comprising flowing the second sample from a same reservoir holding the first sample.

[0100] Example 7 : The method of any of examples 1-6, wherein the first sample is released from a first distal end of the first nozzle, and a distance between the first surface and second surface at the pedestal loading location is greater than an inner diameter of the first distal end of the first nozzle.

[0101] Example 8 : The method of any of examples 1-7, wherein the first sample is removed into the second nozzle from a second distal end of the second nozzle, and an unloading distance between the first surface and second surfaces at a pedestal unloading position is greater than an inner diameter of the second distal end of the second nozzle.PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1

[0102] Example 9: The method of any of examples 1-8, further comprising determining the loading distance based on a volume of the first sample.

[0103] Example 10: The method of any of examples 1-9, wherein releasing the first sample from the first nozzle to the sample space includes releasing the first sample from a first distal end of the first nozzle, and wherein the first distal end is blunt.

[0104] Example 11: The method of any of examples 2-10, wherein removing the first sample held between the two surfaces into the second nozzle includes removing the first sample into a second distal end of the second nozzle, and wherein the second distal end is beveled.

[0105] Example 12: The method of any of examples 1-11, wherein both the first and second surfaces are positioned horizontally, and the second surface is below the first surface, wherein a surface of the beveled distal end of the second nozzle is facing the second surface.

[0106] Example 13: The method of example 12, wherein a central axis of the second nozzle is closer to the first surface comparing to the second surface when removing the first sample held between the two surfaces into the second nozzle.

[0107] Example 14: The method of any of examples 1-13, wherein extending the second nozzle towards the sample space includes positioning a second distal end of the second nozzle in direct contact with the first sample held between the first surface and the second surface.

[0108] Example 15: The method of any of examples 1-14, wherein measuring at least one sample property of the first sample using the analytical instrument includes adjusting a distance between the first surface and the second surface during the measurement, and the at least one sample property includes an optical or an electrochemical property of the first sample.

[0109] Example 16: A sample autoloading system for an analytical instrument, comprising: a first actuator mechanically coupled to a first nozzle; a first pump fluidically coupled to the first nozzle; and a controller includes a processor and a memory storing instructions that, when executed by the processor, configure the sample autoloading system to: position a first pedestal and a second pedestal of the analytical instrument at a pedestal loading position, wherein a sample space between a first surface of the first pedestal and a second surface of the second pedestal is provided for receiving a first sample; extend, by operating the first actuator, the first nozzle towards the sample space; release, by operating the first pump, a first sample from the first nozzle to the sample space so that the first sample is in direct contact with both the first surface and the second surface; and retract, by operating the first actuator, the first nozzle away from the first sample held between the first surface and the second surface.PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1

[0110] Example 17: The sample autoloading system of example 16, further comprising: a second actuator mechanically coupled to a second nozzle; a second pump fluidically coupled to the second nozzle; wherein the instructions further configure the sample autoloading system to: after measuring at least one sample property of the first sample using the analytical instrument, position the first pedestal and the second pedestal at a pedestal unloading position; extend, by operating the second actuator, the second nozzle towards the sample space; and remove, by operating the second pump, the first sample held between the two surfaces into the second nozzle.

[0111] Example 18: The sample autoloading system of any of examples 16-17, wherein the first sample is released from a first distal end of the first nozzle, and a distance between the first surface and second surface at the pedestal load location is greater than an inner diameter of the first distal end of the first nozzle.

[0112] Example 19: The sample autoloading system of any of examples 17-18, wherein the instructions further configure the sample autoloading system to: flow, by operating the first actuator, a second sample towards the first nozzle while the analytical instrument is measuring the at least one sample property of the first sample.

[0113] Example 20: The sample autoloading system of any of examples 17-19, wherein extend the second nozzle towards the sample space includes position a second distal end of the second nozzle in direct contact with the first sample held between the first surface and the second surface.

[0114] Example 21: The sample autoloading system of any of examples 17-20, wherein both the first and second surfaces are positioned horizontally, and the second surface is below the first surface, and wherein remove the first sample held between the first surface and the second surface into the second nozzle includes remove the first sample into a second distal end of the second nozzle, and wherein the second distal end is beveled and with a surface of the beveled distal end facing the second surface.

Claims

PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO1CLAIMSWhat is claimed is:

1. A method for automatically loading samples for an analytical instrument, comprising:positioning a first pedestal and a second pedestal of the analytical instrument at a pedestal loading position, wherein a sample space between a first surface of the first pedestal and a second surface of the second pedestal is provided for receiving a sample;extending, by operating a first actuator mechanically coupled to a first nozzle, the first nozzle towards the sample space;releasing, by operating a first pump fluidically connected to the first nozzle, a first sample from the first nozzle to the sample space so that the first sample is in direct contact with both the first surface and the second surface; andretracting, by operating the first actuator, the first nozzle away from the first sample held between the first surface and the second surface.

2. The method of claim 1, further comprising:after retracting the first nozzle, measuring at least one sample property of the first sample using the analytical instrument;positioning the first pedestal and the second pedestal at a pedestal unloading position; extending, by operating a second actuator mechanically coupled to a second nozzle, the second nozzle towards the sample space; andremoving, by operating a second pump fluidically connected to the second nozzle, the first sample held between the two surfaces into the second nozzle.

3. The method of claim 2, further comprising initiating the measurement of the first sample responsive to the first nozzle retracted to a nozzle measurement position wherein a first distal end of the first nozzle is at least 1.5 mm away from a center of the sample space.

4. The method of claim 3, further comprising flowing, by operating the first actuator, a second sample towards the first nozzle when the first nozzle is at the nozzle measurement position.

5. The method of claim 4, further comprising extending the first nozzle from the nozzle measurement position towards the sample space after measuring the at least one sample property of the first sample using the analytical instrument.PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO16. The method of claim 4, further comprising flowing the second sample from a same reservoir holding the first sample.

7. The method of claim 1 or 2, wherein the first sample is released from a first distal end of the first nozzle, and a distance between the first surface and second surface at the pedestal loading location is greater than an inner diameter of the first distal end of the first nozzle.

8. The method of claim 2, wherein the first sample is removed into the second nozzle from a second distal end of the second nozzle, and an unloading distance between the first surface and second surfaces at the pedestal unloading position is greater than an inner diameter of the second distal end of the second nozzle.

9. The method of claim 1, further comprising determining a loading distance based on a volume of the first sample.

10. The method of claim 1, wherein releasing the first sample from the first nozzle to the sample space includes releasing the first sample from a first distal end of the first nozzle, and wherein the first distal end is blunt.

11. The method of claim 2, wherein removing the first sample held between the two surfaces into the second nozzle includes removing the first sample into a second distal end of the second nozzle, and wherein the second distal end is beveled.

12. The method of claim 11, wherein both the first and second surfaces are positioned horizontally, and the second surface is below the first surface, wherein a surface of the beveled distal end of the second nozzle is facing the second surface.

13. The method of claim 12, wherein a central axis of the second nozzle is closer to the first surface comparing to the second surface when removing the first sample held between the two surfaces into the second nozzle.

14. The method of claim 2, wherein extending the second nozzle towards the sample space includes positioning a second distal end of the second nozzle in direct contact with the first sample held between the first surface and the second surface.PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO115. The method of claim 2, wherein measuring the at least one sample property of the first sample using the analytical instrument includes adjusting a distance between the first surface and the second surface during the measurement, and the at least one sample property includes an optical or an electrochemical property of the first sample.

16. A sample autoloading system for an analytical instrument, comprising:a first actuator mechanically coupled to a first nozzle;a first pump fluidically coupled to the first nozzle; anda controller includes a processor and a memory storing instructions that, when executed by the processor, configure the sample autoloading system to:position a first pedestal and a second pedestal of the analytical instrument at a pedestal loading position, wherein a sample space between a first surface of the first pedestal and a second surface of the second pedestal is provided for receiving a first sample;extend, by operating the first actuator, the first nozzle towards the sample space; release, by operating the first pump, the first sample from the first nozzle to the sample space so that the first sample is in direct contact with both the first surface and the second surface; andretract, by operating the first actuator, the first nozzle away from the first sample held between the first surface and the second surface.

17. The sample autoloading system of claim 16, further comprising:a second actuator mechanically coupled to a second nozzle;a second pump fluidically coupled to the second nozzle;wherein the instructions further configure the sample autoloading system to:after measuring at least one sample property of the first sample using the analytical instrument, position the first pedestal and the second pedestal at a pedestal unloading position;extend, by operating the second actuator, the second nozzle towards the sample space; andremove, by operating the second pump, the first sample held between the two surfaces into the second nozzle.

18. The sample autoloading system of claim 16, wherein the first sample is released from a first distal end of the first nozzle, and a distance between the first surface and second surface at the pedestal load location is greater than an inner diameter of the first distal end of the first nozzle.PCT / US25 / 22132 28 March 2025 (28.03.2025)Docket No. TP388838WO119. The sample autoloading system of claim 17, wherein the instructions further configure the sample autoloading system to:flow, by operating the first actuator, a second sample towards the first nozzle while the analytical instrument is measuring the at least one sample property of the first sample.

20. The sample autoloading system of claim 17, wherein extend the second nozzle towards the sample space includes position a second distal end of the second nozzle in direct contact with the first sample held between the first surface and the second surface.

21. The sample autoloading system of claim 17, wherein both the first and second surfaces are positioned horizontally, and the second surface is below the first surface, and wherein remove the first sample held between the first surface and the second surface into the second nozzle includes remove the first sample into a second distal end of the second nozzle, and wherein the second distal end is beveled and with a surface of a beveled distal end facing the second surface.

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