Parallel probing of multiple samples in self-assembled structures

Abstract

Disclosed herein are methods for parallel probing of multiple samples, sensor chips for parallel probing of multiple samples, sensing devices for parallel probing of multiple samples, and measurement systems for parallel probing of multiple samples. The methods include providing a sensor chip, the sensor chip comprising a sensing layer disposed in or on a substrate, and a measurement volume adjacent to the sensing layer. The sensing layer comprises a plurality of sensing elements, each configured to generate a sensor signal characterizing a physical observable in the vicinity of the respective sensing element. A carrier fluid including a plurality of sample objects is provided to the measurement volume, each of the sample objects comprising or forming a respective sample. The number of sample objects in the measurement volume is controlled such that the sample objects form a self-assembled structure in the measurement volume. A self-assembled structure is a structure in which the arrangement of the sample objects is at least partially defined by interactions between the sample objects themselves. Measurements are performed on one or more of the samples while the sample objects are disposed in the self-assembled structure, the measurements on the samples being performed using one or more sensing elements disposed adjacent to the respective sample objects in the self-assembled structure.

Description

[Technical Field]

[0001] This invention belongs to the fields of chemical analysis and medical diagnosis. In particular, the invention relates to a method for parallel probing of multiple samples, a corresponding sensor chip, a corresponding sensing device, and a corresponding measurement system. [Background technology]

[0002] High-throughput parallel analysis of samples is essential for many applications in chemistry, life sciences, and medicine. Such experiments can be performed, for example, on standardized microplates, which typically have a rectangular array of wells for receiving samples. These standardized well layouts allow for the efficient processing of large numbers of samples using liquid handling robots.

[0003] To further increase throughput, microfluidic chips have been developed that incorporate multiple sample areas, such as microfluidic sample wells, allowing for simultaneous sample provision and processing. Sample wells typically have a size on the order of 10 μm to 100 μm, which not only enables the placement of numerous sample wells on a single chip but also facilitates the placement of sensors in close proximity to the sample. Sensors can be integrated into the chip and configured, for example, to measure the temperature or electrical or magnetic properties of the sample (see, for example, C. Yang et al., IEEE Transactions on Biomedical Circuits and Systems, vol.3, no.3, pp.160-168 (2009), H. Zhang et al., Anal. Chem. 2017, 89, 11, 5832-5839, and H. Zhang et al., npj Quantum Inf.3:31 (2017). In other examples, samples can be probed by optical means such as fluorescence spectroscopy.

[0004] However, while such microfluidic tips allow for rapid probing of multiple samples in parallel, the small size of the sample wells presents several challenges in manufacturing, particularly in handling the tips. Microfluidic tips are susceptible to mechanical damage and contamination from previous samples because it is nearly impossible to completely remove the sample from the sample well after measurement. As a result, microfluidic tips are typically disposable products, and the need to attach new tips and, in some cases, realign them for each experiment makes experiments costly and time-consuming. Furthermore, preparing samples within the sample wells is difficult due to the small length scale involved. The small volume of the sample wells can also cause the sample to evaporate during preparation and measurement, which can reduce the reliability of the measurement results. U.S. Patent Application Publication No. 2019 / 0285579 discloses a fluorescence testing system having a dielectrophoretic device. The dielectrophoretic device comprises microwells on which a test object, such as a cell, can be placed above a corresponding photodiode. Using a pair of electrodes, the test object can be captured into one of the microwells by dielectrophoresis. A similar device is also known in U.S. Patent Application Publication No. 2019 / 0250102. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] U.S. Patent Application Publication No. 2019 / 0285579 [Patent Document 2] U.S. Patent Application Publication No. 2019 / 0250102 [Non-patent literature]

[0006] [Non-Patent Document 1] C. Yang et al., IEEE Transactions on Biomedical Circuits and Systems, vol.3, no.3, pp.160-168(2009) [Non-Patent Document 2] H.Zhang et al.,Anal.Chem.2017,89,11,5832-5839 [Non-Patent Document 3] H. Zhang et al.,npj Quantum Inf.3:31(2017) [Overview of the project]

[0007] Therefore, an object of the present invention is to simplify sample preparation and sample handling for high-throughput parallel probing of multiple samples on a microfluidic sensor chip.

[0008] This objective is achieved by the method for parallel probing of multiple samples described in claim 1, the sensor chip for parallel probing of multiple samples described in claim 14, the sensing device for parallel probing of multiple samples described in claim 26, and the measurement system for parallel probing of multiple samples described in claim 35. Embodiments of the present invention are described in detail in the dependent claims.

[0009] A method for parallel probing of multiple samples according to the present invention comprises providing a sensor chip comprising a sensing layer disposed in or on a substrate, and a measurement volume adjacent to the sensing layer. The sensing layer comprises a plurality of sensing elements, each configured to generate a sensor signal characterizing a physically observable quantity in the vicinity of the respective sensing element. A carrier fluid containing a plurality of sample objects is provided to the measurement volume, each of the sample objects comprising or forming the respective sample. The number of sample objects in the measurement volume is controlled so that the sample objects form a self-organizing structure within the measurement volume. While the sample objects are arranged within the self-organizing structure, measurements are performed on one or more of the samples, and the measurements on the samples are performed using one or more sensing elements positioned adjacent to each sample object within the self-organizing structure.

[0010] The sensor chip may comprise a single-layer or multilayer substrate, and the measuring volume may be, for example, a recess on the upper surface of the substrate or a hollow volume surrounded by the substrate. In addition, the sensor chip may comprise microfluidic structures such as inlet and / or outlet channels that are in fluid communication with the measuring volume and provide a carrier fluid thereto. In some examples, the sensor chip may be a sensor chip according to any one of the embodiments of the present invention described herein, or a sensor chip of a sensing device according to any one of the embodiments of the present invention described herein.

[0011] Each sensing element is configured to generate a sensor signal, such as an optical signal, a magnetic signal, and / or an electrical signal, characterizing a physically observable quantity in its vicinity, for example, at the location of the sensing element, or within a sensing volume surrounding the sensing element. In the context of this disclosure, a sensing element can refer to any element or unit that can be used to read out a sensor signal that enables the measurement or quantification of each physical observable quantity. A sensing element may comprise one or more of capacitive, inductive, and / or resistive sensing elements, such as microelectrodes, thermistors, or microelectromechanical systems (MEMS), piezoelectric sensing elements, Hall effect sensing elements, and photosensitive sensing elements, such as photodiodes, and the sensor signal may be, for example, a current or a voltage. In some embodiments, some or all of the sensing elements may be atomic-scale or molecular-scale sensing elements, for example, atomic-scale or molecular-scale structures having light absorption and / or emission spectra dependent on a physically observable quantity, and the sensor signal may be, for example, transmitted light intensity or radiated light intensity. The sensing element may, in particular, be a solid spin system, such as those detailed below.

[0012] The physically observable quantity may be any measurable physical quantity, such as temperature, pH value, electrical conductivity, dielectric constant, electric field, magnetic field, and / or light intensity. Each of the sensing elements may be configured to measure the same physically observable quantity, or at least some of the sensing elements may be configured to measure different physically observable quantities. In some examples, the sensing elements may be configured to measure a first physically observable quantity at, for example, the location of each sensing element, which may depend on a second physically observable quantity, such as a different location around the sensing element or within the sensing volume, particularly within the measuring volume or the same or different physical observable quantity within the sensing volume. Thus, the sensor signal of the sensing element can characterize a second physically observable quantity in addition to the first physical observable quantity.

[0013] The sensing elements may be distributed homogeneously throughout the sensing layer, for example, with a uniform density and / or a uniform spacing between adjacent sensing elements, or they may be confined to spatially separated regions within the sensing layer, for example, as detailed below. An aggregate of adjacent sensing elements within a region or portion of the sensing layer may sometimes be referred to hereinafter as a sensing region. The sensing elements within a given sensing region may be spatially separated from other sensing elements within the sensing layer, or they may be a subset of the sensing elements selected from the sensing elements within a selected region or portion of the sensing layer that distributes sensing elements throughout the sensing layer, for example, sensing elements that may not be spatially separated from other sensing elements within the sensing layer.

[0014] In some embodiments, the sensing elements can form a plurality of sensors. Each of the sensors can comprise one or more sensing elements, for example, an aggregate of sensing elements configured to generate a common sensor signal, and the common sensor signal can be, for example, the sum or average of the sensor signals of the sensing elements within the aggregate. The sensors may be spatially separated and / or configured to be read independently of other sensors. In some embodiments, each of the sensors may comprise sensing elements within respective sensing regions, and the sensing regions may be spatially separated from each other, that is, each sensor may correspond to one of a plurality of spatially separated sensing regions within the sensing layer. In some examples, some or all of the sensors may comprise only a single sensing element.

[0015] In some embodiments, performing measurements on one or more samples may include, for each of the one or more samples, selecting a subset of sensing elements and selectively determining sensor signals from the sensing elements within each subset. For example, the sensor signals may be determined only for the sensing elements within the subset associated with the one or more samples on which the measurements are performed. The sensing elements within the subset for a given sample may be arranged, for example, within the sensing region, particularly within the sensing region adjacent to each sample object within the self-assembled structure. The subset may, for example, comprise all the sensing elements within each sensing region. Sensor signals may not be determined for sensing elements outside the sensing region associated with the one or more samples on which the measurements are performed, i.e., for sensing elements in other portions of the sensing layer.

[0016] Selecting a subset of sensing elements and selectively determining sensor signals from the sensing elements within the subset, for example within each sensing region, may include selectively activating the sensing elements within the subset and / or selectively reading out the sensing elements within the subset. For example, only the sensing elements within the sensing region associated with the one or more samples on which the measurements are performed may be activated and / or read out. Activating a sensing element may, for example, include changing the state of the sensing element, for example, from an off state in which the sensing element does not generate a sensor signal to an on state in which the sensing element generates a sensor signal. The sensing element may be activated, for example, electrically, for example using an electrical switch, and / or optically, for example by optically exciting the sensing element. Selectively reading out the sensing elements within the subset may include, for example, measuring sensor signals only for the sensing elements within each subset, or, for example, discarding sensor signals for sensing elements not included in each subset when processing or analyzing the measured sensor signals.

[0017] In some embodiments, the sensing elements within the sensing layer form an array of spatially separated sensors, each of which comprises one or more sensing elements. In the self-assembled structure, each sample object may be positioned adjacent to each of the sensors in the array, and measurements on the sample may be performed using each sensor. In some examples, the sensors in the array may be spatially separated sensing regions, each of which comprises multiple sensing elements.

[0018] The sensors can be arranged in a one-dimensional array where the sensors are arranged, for example, along a first direction with spacing between adjacent sensors, or in a two-dimensional array where the sensors are arranged, for example, in a plane with spacing between adjacent sensors. In some embodiments, the sensor array may be a periodic array. The sensors may be arranged, for example, in a one-dimensional periodic array, and the sensors may be positioned, for example, at equidistant intervals along a first direction. Preferably, the sensors are arranged in a two-dimensional periodic array, and the sensors may be positioned, for example, at first equidistant intervals in a first direction and at second equidistant intervals in a second direction. The second interval may be the same as or different from the first interval. Preferably, all sensors in the array are arranged in a common plane which may be parallel to the walls of the measurement volume. The sensing elements may be embedded, for example, in the bottom or top wall of the measurement volume, and the surface of each sensing element may be exposed to the measurement volume. In other examples, the sensing elements may be completely embedded in the bottom or top wall so that the sensing elements are not exposed to the measurement volume. Each sensor may be associated with a unit cell of the array, where a unit cell is the basic unit of the array formed by a continuous tiling or translation of identical unit cells. A unit cell of the array may be, for example, a region closer to a given sensor than any other sensor in the array.

[0019] In a preferred embodiment, the physical dimensions of each sample object correspond to the spacing of the sensor array, i.e., the pitch or center-to-center distance between adjacent sensors in the sensor array along the first and / or second directions. The sample object may be, for example, a monodisperse object having a diameter or width corresponding to the first and / or second spacing of the sensor array. For this purpose, the spacing of the sensor array may be selected so that the spacing of the sensor array corresponds to the physical dimensions of the sample object when probing a sample object of a predetermined size, such as a cell or a bead. In other words, the provided sensor chip can be adapted to the physical dimensions of the sample object. Alternatively, the physical dimensions of the sample object may be selected so that the physical dimensions of the sample object correspond to the spacing of the sensor array when probing a sample object having an adjustable size, such as a microdroplet. For example, to adapt the physical dimensions of a microdroplet to the spacing of the sensor array, the flow velocity of the carrier fluid and / or sample fluid in the droplet generator, the viscosity of the carrier fluid and / or sample fluid, and / or the surface tension at the carrier fluid-sample fluid interface can be adjusted. In some embodiments, the physical dimensions of the sample object may be larger than the physical dimensions of the sensor or sensing area. The diameter or width of the sample object may be, for example, at least 50%, and in some examples at least 100%, larger than the diameter or width of the sensor or sensing area.

[0020] The sample object may be, for example, microdroplets dispersed in a carrier fluid. The microdroplets may contain or consist of the sample fluid, which may be a biological sample fluid containing, for example, a biological sample fluid containing a protein, DNA, bacteria, cells or a part thereof, or a chemical sample fluid containing, for example, one or more reagents and / or products of a chemical reaction. The microdroplets may have a clearly defined shape (e.g., spherical) in the carrier fluid due to, for example, surface tension at the interface between the microdroplets and the carrier fluid, which can also prevent the microdroplets from fusing together when they come into contact with each other. In some examples, the microdroplets may be monodisperse microdroplets, i.e., they may have the same diameter or width. In other embodiments, the sample object may also be other objects, in particular cells or components thereof, solid particles, or microbubbles. The sample object may be, for example, microbeads, e.g., agarose beads, or magnetic particles.

[0021] In some examples, the sample fluid and the carrier fluid may be immiscible, the sample fluid may be, for example, an aqueous solution, and the carrier fluid may contain a hydrophobic fluid such as oil. Preferably, the carrier fluid contains one or more of toluene, chloroform, methanol, dimethyl sulfoxide (DMSO), and tetrahydrofuran (THF). The carrier fluid and microdroplets can form an emulsion in which the carrier fluid is the continuous phase and the sample fluid is the dispersed phase. Additionally or alternatively, the carrier fluid and / or sample object may contain a surfactant, such as an amphiphilic molecule, to stabilize the microdroplets in the carrier fluid. The microdroplets may include, for example, a shell layer formed by the surfactant, which may surround, for example, a core containing the sample fluid. In some examples, the microdroplets are vesicles or liposomes having a lipid bilayer surrounding a core formed by the sample fluid.

[0022] A carrier fluid containing multiple sample objects is supplied to the measurement volume, for example, by pipetting it into the measurement volume or through an inlet channel of a sensor tip. The number of sample objects in the measurement volume is controlled so that the sample objects form a self-organizing structure within the measurement volume. To this end, the number of sample objects in the measurement may be adjusted, for example, by supplying additional sample objects to the measurement volume or by removing sample objects from the measurement volume. This may include, for example, continuously supplying a carrier fluid containing sample objects to increase the number of sample objects in the measurement volume until a self-organizing structure is formed. In some embodiments, this may also include releasing the carrier fluid from the measurement volume without removing the sample objects therefrom, for example, by pipetting or through an outlet channel having a cross-sectional area smaller than the cross-sectional area of ​​the sample objects.

[0023] In the context of this disclosure, a self-organizing structure of a sample object means a structure in which the arrangement of the sample objects is at least partially defined by interactions between the sample objects themselves, for example, by repulsive and / or attractive surface-to-surface interactions between sample objects that are in contact with or in close proximity to each other. In some embodiments, the interactions between sample objects may be at least partially mediated by a carrier fluid. Interactions with adjacent sample objects can prevent the movement of a given sample object within the self-organizing structure. In other words, the position of a given sample object in the self-organizing structure may not be determined by, or at least not solely by, the structural features of the sensor chip. In some embodiments, the self-organizing structure may be periodic, for example, so that adjacent sample objects are positioned at equidistant intervals in one or two directions.

[0024] In a self-organizing structure formed within a measurement volume, sample objects may be arranged such that, for example, each sample object is adjacent to each of the sensors in the sensor array. For example, the sample objects may be aligned with the unit cells associated with each sensor. In some examples, the centers of the sample objects may be aligned with the centers of each sensor, for example, such that the distance between the center of the sample object and the center of each sensor is minimized. In some examples, the sample objects may be in contact with the surface of each sensor or with the surface of the wall portion of the measurement volume closest to each sensor. Preferably, each sample object is arranged adjacent to its respective sensor. The self-organizing structure may have the same structure as the sensor array, for example, i.e., the sample objects may be arranged in the same pattern as the sensors. In some embodiments, the self-organizing structure may be periodic and have the same grid structure as the sensor array, i.e., the sample objects may be arranged in the same periodic pattern as the sensors, i.e., i.e., each sample object is aligned with one of the unit cells of the array.

[0025] In other embodiments, the sample object within the self-assembled structure may be arranged such that some or all of the sample object is adjacent to each sensing region in the sensing layer, and each sensing region may comprise, for example, a subset of sensing elements selected for each sample. In other words, the arrangement of the sample object in the self-assembled structure may conform to the arrangement of selected subsets or sensing regions in the sensing layer, or vice versa. In some examples, the sensing regions may be defined by structural features of the sensor chip, such as the distribution of sensing elements in the sensing layer, or they may be predetermined sensing regions that can be selected before the formation of the self-assembled structure, and the sample object within the self-assembled structure may be arranged such that some or all of the sample object is adjacent to each predetermined sensing region.

[0026] After the self-assembled structure is formed, a measurement is performed using some or all of the sensing elements in the sensing layer while the sample object is positioned within the self-assembled structure. The measurement on the sample may be performed, for example, using the sensing region or sensing elements of the sensor associated with each sample. Preferably, the sample object does not move while the measurement is being performed; i.e., the self-assembled structure may remain stationary during the measurement. In some examples, this may involve interrupting the flow of the carrier fluid through the measurement volume.

[0027] By preparing a self-assembling structure within the measurement volume, sample objects can be positioned adjacent to the corresponding sensing region or sensor without requiring individual structural features such as hydrophilic or hydrophobic surface coatings for each sample well or sensing region or sensor. Instead, the position of the self-assembling structure relative to the sensing region or sensor array can be defined holistically using a few boundaries or guiding structures, such as the side walls of the measurement volume. This allows for the use of measurement volumes with flat walls, for example, greatly simplifying the manufacturing and handling of sensor tips. In particular, the measurement volume can be cleaned more easily than individual sample wells, potentially allowing for the reuse of sensor tips multiple times without the risk of contamination. This not only reduces costs but also improves throughput because sensor tips do not need to be replaced between measurements. Furthermore, the preparation of samples on sensor tips becomes easier, as positioning of individual sample objects by targeted pipetting, for example, is not required. Thus, the proposed method can be easily automated, enabling fast, cost-effective parallel probing of a large number of samples.

[0028] Microdroplets arranged in a periodic structure have been previously used, for example, to increase the density of microdroplets used as microreactors in the imaging plane of a microscope; see U.S. Patent Application Publication 2012 / 0184464 and ACHatch et al, Lab Chip, 2011, 11, 2509. Similar methods for forming microdroplet arrays within microfluidic structures are known, for example, in CEStanley et al., Chem. Commun., 2010, 46, 1620-1622 and P. Parthiban et al., Soft Matter, 2019, 15, 4244-4254.

[0029] The sensor chip may include boundary or guiding structures configured to restrict or guide the movement of a sample object within the measurement volume. The boundary or guiding structures, collectively referred to below as boundary structures, may include, for example, one or more of the following, as detailed below: guiding walls protruding from the side walls of the measurement volume, the bottom wall and / or top wall of the measurement volume, and / or hydrophilic and / or hydrophobic coatings on the bottom wall and / or top wall of the measurement volume. The self-assembling structure may be formed by interactions between the sample object and the boundary structure, and by surface-to-surface interactions between the sample objects. The interaction between the sample object and the boundary structure may be, for example, a direct interaction between the boundary structure and the sample object itself, or it may be mediated by a carrier fluid. The boundary structure may be positioned or molded so that the self-assembling structure is aligned with a sensing region or sensor array, as will be described later, for example, with respect to the sensor chip and sensing device according to the present invention. For this purpose, the boundary structure may be positioned, for example, at a distance corresponding to half the spacing between the sensor arrays from the outermost sensor in the array. The boundary structures may be aligned, for example, with the edges of the unit cells of the sensor array, such that each edge of the outermost unit cell of the sensor array aligns with one of the boundary structures.

[0030] In a self-assembling structure, interactions between the sample object and the boundary structure, as well as surface-to-surface interactions between the sample objects, can prevent the sample objects from moving, and thus, for example, can fix the sample objects in a predetermined position adjacent to each sensor or sensing area. In other words, for example, because each sample object is in contact, it may not be possible to move a given sample object without moving at least one other sample object. Preferably, the self-assembling structure is formed such that at least 90%, and in some examples at least 95%, of the sample objects are prevented from moving along two or more orthogonal directions in a plane parallel to, for example, the bottom or top wall of the measurement volume. This may be sufficient to prevent the entire self-assembling structure from moving or collapsing during measurement. In some examples, a sample object in a self-assembling structure positioned adjacent to the inlet or outlet of the measurement volume may still be able to move in one or more directions without moving other sample objects.

[0031] In some embodiments, the sample object may have a circular cross-section. The sample object may have, for example, a spherical, ellipsoidal, elliptical, or cylindrical shape. The self-organized structure may be, for example, a close-packed circle when projected or observed along a direction perpendicular to the sensing layer and / or the wall of the measurement chamber adjacent to the sensing layer. In a close-packed circle, the sample objects may be arranged within a single layer such that their circumferences are in contact with or close to each other, and thus prevent the sample objects from moving. A close-packed circle can correspond to the densest possible arrangement of the sample objects under boundary conditions imposed by the boundary structure within the measurement volume.

[0032] In some embodiments, the sample objects within the self-assembled structure do not have to have a circular cross-section, but the self-assembled structure may nevertheless resemble a close-packed circle in the sense that, for example, the centers of the sample objects and / or contact points between sample objects are aligned with corresponding points in an ideal close-packed circle. The circumference of the sample objects within the self-assembled structure may be tangent to (or inversely to) the circles in the close-packed circle at points where the sample object is in contact with or near an adjacent sample object. The physical dimensions of the sample objects may be equal to, for example, the diameter of the close-packed circle. The sample objects may have an essentially non-circular cross-section when provided, for example, in a carrier fluid, and / or may deform when forming a self-assembled structure, for example, when in contact with the boundary structure of adjacent sample objects and / or sensor chips.

[0033] The self-assembled structure may, in particular, be a close-packed arrangement of equal circles, i.e., a close-packed arrangement of circles having the same diameter. All of the sample objects may, for example, have a circular cross-section having the same diameter. Thus, some or all of the sample objects may be arranged, for example, in a two-dimensional hexagonal lattice within the self-assembled structure, i.e., each sample object is surrounded by six equidistant adjacent sample objects, thereby forming a self-assembled periodic structure. The two-dimensional hexagonal lattice corresponds to a close-packed arrangement of equal circles in a uniform space and may hereafter be referred to as a uniform close-packed arrangement of equal circles. In other examples, some or all of the sample objects may be arranged in a linear chain within the self-assembled structure, with each sample object in contact with two adjacent sample objects.

[0034] In some examples, the sample object may have a spherical shape, and the self-assembled structure may be a close-packed arrangement of spheres, particularly a close-packed arrangement of equal spheres, i.e., it may correspond to the densest possible arrangement of spheres under the boundary conditions imposed by the boundary structure within the measurement volume. The sample object within the self-assembled structure may be arranged within a single layer, for example, within a single plane, and the close-packed arrangement of spheres within a single layer corresponds to a close-packed arrangement of circles when projected in a direction perpendicular to the layer.

[0035] In some embodiments, the carrier fluid containing the sample object can be supplied through a microfluidic inlet channel that is in fluid communication with the measurement volume. Controlling the number of sample objects in the measurement volume may involve maintaining the flow of the carrier fluid containing the sample object through the inlet channel until a self-organizing structure is formed. In this way, sample objects can be continuously added to the measurement volume until a self-organizing structure is formed. In some examples, this may involve releasing the carrier fluid from the measurement volume, for example, through a microfluidic outlet channel, while preventing the sample object from leaving the measurement volume, for example, by using an outlet channel having a width or cross-sectional area smaller than the width and cross-sectional area of ​​the sample object, respectively, or by appropriately adjusting the width or cross-sectional area of ​​the outlet channel using, for example, a valve.

[0036] In a preferred embodiment, the method further includes, for example, tracking the movement of one or more sample objects on the sensor chip before and / or after performing measurements on each sample. Tracking the movement of sample objects may include, for example, determining the point in time when the sample object reaches one or more predetermined points on the sensor chip, such as the inlet of the measurement volume, the outlet of the measurement volume, and / or the output port of the sensor chip. Tracking the movement of sample objects may further include, for example, associating the sample object with each sensor or sensing element in order to associate the sample object with the measurement results obtained from each sensor or sensing element. Additionally or alternatively, tracking the movement of sample objects may also include associating the sample object and / or the measurement results with information about the composition and / or formation process of the sample object. The sample object may be formed, for example, using a droplet generator, with a composition and / or other properties that change over time. Tracking the movement of sample objects may allow for relating the sample objects and / or measurement results to the time when each sample object was formed, a specific composition, e.g., the concentration of the sample substance, and / or specific parameters used to form the sample object, e.g., the flow velocity in the droplet generator, the fluid composition, and / or the temperature. The movement of sample objects may be tracked based, for example, the flow velocity of the carrier fluid, the duration of the carrier fluid flow, and / or the position of each sensor or sensing element. In a preferred embodiment, the movement of one or more sample objects on a sensor chip is tracked continuously, for example, by determining the position of the sample objects on the sensor chip at multiple points in time. One or more sample objects may be tracked using, for example, a camera configured to record images of the sample objects on the sensor chip. Tracking sample objects on a sensor chip may allow for, for example, the selection of sample objects based on their respective measurement results. In some examples, sample objects may include markers that allow them to be distinguished from each other, for example, by spectroscopic means, as described, for example, Y. Feng et al., Microsystems & Nanoengineering Vol. 6, 109 (2020).

[0037] In a preferred embodiment, the sensing element is a magnetic quantity sensing element, for example, an atomic or molecular-scale structure exhibiting magnetic field-dependent behavior between different states of the magnetic quantity sensing element, e.g., a magnetic field-dependent energy spectrum and / or magnetic field-dependent transition rate. The sensing element may, in particular, be an optically addressable solid spin system. An optically addressable solid spin system is a quantum system with spin degrees of freedom located or embedded in a solid host material, where the spin degrees of freedom can be read out and / or manipulated via optical transitions and / or microwave fields. The spin system may, in particular, be an object that behaves like an artificial atom or molecule, i.e., a system exhibiting an energy spectrum like an atom or molecule and having at least two different spin states. The spin system may, for example, be an optically active defect in a crystal structure. The energy levels of different spin states may shift in the presence of a magnetic field. Furthermore, the spin system may have, for example, spin state-dependent transition rates between different states of the spin system (e.g., electronic states of the spin system). Thus, a solid spin system may be used as a probe for a magnetic field, for example, by determining the energy difference and / or transition rates between states of the spin system. In a preferred embodiment, the substrate contains or is made of diamond, and the solid spin system is diamond color centers, i.e., optically active site defects in the diamond crystal structure. Preferably, the spin system is nitrogen vacancy (NV) centers in diamond, particularly negatively charged nitrogen vacancy centers.

[0038] Performing measurements on a sample may include illuminating solid spin systems located within sensing regions adjacent to each sample object within the self-assembled structure with light to optically excite the solid spin systems within the sensing regions, and detecting the optical signals emitted by the solid spin systems within the sensing regions.

[0039] Preferably, a solid spin system in part or all of the sensing region is simultaneously excited by illuminating the sensing region with light propagating along an optical illumination path through a sensor chip connecting part or all of the sensing region, i.e., so that light pulses propagating along the illumination path sequentially pass through each sensing region. The wavelength of the light can be adjusted, for example, to the absorption wavelength of the spin system. Illumination of the sensing region along the illumination path can be used in particular to optically polarize the spin system in the sensing region and / or to excite the spin system in the sensing region and induce a light signal to be detected, i.e., for optical readout. The intensity and / or pulse duration of the light pulses may be selected, for example, so that the spin system is prepared in a predetermined quantum state. In some examples, the intensity and / or pulse duration may be selected so that the spin system in the sensor undergoes multiple transitions, for example, to increase fluorescence intensity and / or for optical polarization of the spin system, i.e., to optically pump the spin system to a predetermined state. In a preferred embodiment, the sensing region is illuminated multiple times, for example, a first time for optical polarization and a second time for inducing a light signal to be detected. At least one, preferably both, of the illuminations are produced by light propagating along the illumination path.

[0040] The optical signals can be detected simultaneously, for example, using a multi-channel photodetector. The optical signals may be, for example, the intensity of light emitted by the spin system at one or more emission wavelengths (e.g., fluorescence emitted by an excited spin system), or, for example, the intensity of light transmitted through the sensing region to determine the absorption rate of light by the spin system at one or more absorption wavelengths. The detected signals can, for example, enable the extraction of information about the state of the spin system, such as the occupation probabilities of one or more spin states, which can be used, for example, to extract information about the magnetic field strength and / or orientation at each sensor, which may at least partially arise from the corresponding sample.

[0041] The present invention further provides a sensor chip for parallel probing of multiple samples using a method according to any one of the embodiments described herein. The sensor chip comprises a measuring volume configured to receive a carrier fluid containing multiple sample objects. The sensor chip further comprises an array of sensors disposed within or adjacent to a first wall of the measuring volume, the sensor array having a first spacing a1. Each sensor comprises one or more sensing elements, each configured to generate a sensor signal characterizing a physically observable quantity in the vicinity of the respective sensing element. The sensor chip comprises two or more boundaries or guiding structures configured to restrict or guide the movement of sample objects within the measuring volume. The two or more boundaries or guiding structures are arranged to confine the solid objects such that each solid object aligns with each of the sensors when a close-packed solid object having a circular cross-section with a diameter equal to the first spacing a1 is placed within the measuring volume and the close-packed solid object covers the entire first wall of the measuring volume.

[0042] The sensor chip may comprise a single-layer or multilayer substrate, preferably the substrate or at least a portion thereof being optically transparent in the ultraviolet, visible, and / or near-infrared spectra. The measuring volume may be, for example, a recess on the upper surface of the substrate, or a hollow volume surrounded by the substrate. In some embodiments, the sensor chip may comprise a removable cover for opening and closing the measuring volume. In addition, the sensor chip may comprise microfluidic structures, such as inlet and / or outlet channels, that are in fluid communication with the measuring volume to supply or discharge a carrier fluid to or from the measuring volume. The sensor chip may also comprise a droplet generator, for example, as detailed below. The first wall may be, for example, the bottom or top wall of the measuring volume, which may be formed, for example, by the substrate and / or a removable cover. Preferably, the first wall has a flat surface and is free from any protrusions and / or recesses. In some examples, the surface of the sensor and / or the surface of the sensing element may be exposed to the measuring volume and may be coplanar with the surface of the first wall, for example. In other examples, the sensor and / or sensing element may be completely embedded within the first wall or in another layer below the first wall, and may not be exposed to the measurement volume. In some embodiments, each sensor may comprise a sensing element within its respective sensing region, for example, as detailed above. The sensing elements may be confined to a plurality of spatially separated sensing regions, for example, within the first wall or in an adjacent sensing layer, and the sensing regions may be arranged in an array, thereby forming an array of sensors.

[0043] The sensors can be arranged in a one-dimensional array or a two-dimensional array. The sensors may also be arranged in a one-dimensional periodic array, and the sensors may be positioned, for example, at equidistant intervals a1 along a first direction. Alternatively, the sensors may be arranged in a two-dimensional periodic array, and the sensors may be positioned, for example, at first equidistant intervals a1 in the first direction and at second equidistant intervals a2 in the second direction. Hereafter, the first interval or the second interval may also be referred to as the interval a0 of the sensor array. Therefore, any reference to the interval a0 should be understood as referring to the first interval for a one-dimensional array and to either the first interval a1 or the second interval a2 for a two-dimensional array.

[0044] Preferably, all sensors are arranged in the same plane, which may be parallel to, for example, a first wall. The sensors may be arranged, for example, in the substrate of a sensor chip adjacent to the measurement volume or in a sensing layer on the substrate. Each sensor may be associated with a unit cell of an array, where the unit cell is the basic unit that forms the array by a continuous tiling or translation of identical unit cells. In one example, the sensors are arranged in a two-dimensional hexagonal grid, i.e., each sensor is surrounded by six equidistant adjacent sensors. Thus, the unit cells of the array may be, for example, hexagonal, and the edges of the unit cells associated with a given sensor are defined by the perpendicular bisectors of the vectors connecting the sensor to its adjacent sensors. In another example, the sensors are arranged in a two-dimensional rectangular grid, and the unit cells of the array have a rectangular shape. In yet another example, the sensors are arranged in a one-dimensional equidistant chain, and the unit cells may be defined, for example, as squares around a given sensor having a square size corresponding to the spacing a0 between adjacent sensors.

[0045] The boundary or guide structure, collectively referred to below as the boundary structure, may comprise, for example, one or more side walls of the measuring volume, each of which extends at an angle, preferably greater than 60°, with respect to the first wall. The side walls may, in particular, be perpendicular to the first wall. Preferably, some or all of the side walls of the measuring volume have a flat surface, i.e., without any inclined portions, protrusions, and / or recesses. Additionally or alternatively, the boundary structure may comprise one or more guide walls projecting from the first wall of the measuring volume and / or from a second wall of the measuring volume opposite the first wall. The boundary structure may further comprise one or more hydrophilic and / or hydrophobic coatings on the first and / or second walls of the measuring volume, the coatings may define, for example, areas on the first wall that can be wetted by a carrier fluid, or areas of the first wall that cannot be wetted by a carrier fluid.

[0046] The boundary structure is immovable, and when a sufficiently large number of solid objects having a circular cross-section with a diameter equal to the spacing a0 of the sensor array are placed on the first wall, the solid objects are arranged in a close-packed plane in which each solid object is aligned with each of the sensors. The solid objects may have, for example, a spherical, ellipsoidal, elliptical, or cylindrical shape. When projected along a direction perpendicular to the first wall, the close-packed solid objects can correspond to a close-packed circle of equals. Each solid object can be positioned above each of the sensors, for example, so that the center of the solid object in a plane parallel to the first wall is aligned with the center of the sensor, and / or so that the solid object is placed within a unit cell associated with the sensor, for example, so that the edge of the unit cell is tangent to the circumference of the solid object when viewed along a direction perpendicular to the first wall. As detailed above, the close-packed solid objects having a circular cross-section can correspond to the densest possible arrangement of solid objects under the boundary conditions imposed by the boundary structure in the measurement volume. In the resulting structure, each solid object may be in contact with at least one other solid object. Furthermore, at least a portion of the solid objects may be in contact with one or more of the boundary structures. Contact between the solid objects and the boundary structures can disrupt the inherent translational invariance of uniform close-packing of equal circles, thereby fixing the solid objects in a desired arrangement. In some embodiments, one or more of the boundary structures can confine the solid objects by interactions mediated by the carrier fluid, instead of, or in addition to, direct interaction with the solid objects. For example, hydrophilic or hydrophobic coatings can promote or prevent wetting of their respective surfaces by the carrier fluid, thereby confine the objects provided in the carrier fluid. In other words, in some examples, the close-packing of solid objects in the measurement volume is formed and / or aligned with the sensor array only if the solid objects are provided in the carrier fluid.

[0047] Therefore, two or more boundary structures may be configured to confine multiple sample objects having a circular cross-section, which are not truly non-deformable solid objects as described above, to a self-organized close-packed arrangement of equal circles within the measurement volume, such that each sample object is positioned adjacent to each sensor. In other words, when a sufficiently large number of sample objects are placed within the measurement volume, the sample objects form a self-organized structure within the measurement volume in which each sample object is aligned with each sensor in the sensor array. As detailed above with respect to the method according to the present invention, the same applies to sample objects that do not have a circular cross-section but are nevertheless configured to form a self-organized structure similar to a close-packed arrangement of equal circles. The physical dimensions of the sample objects may be selected, for example, so that the physical dimensions of the sample objects correspond to the spacing of the sensor array.

[0048] As detailed above, the sensor array can correspond to a tiling of identical unit cells, with each sensor associated with its respective unit cell. The boundary structure can be arranged, for example, so that segments of the boundary structure are aligned with the edges of the unit cells of the sensor array along the circumference of the sensor array, allowing the sample object to be confined to each unit cell within the self-organizing structure, for example, by interactions between the sample object and the boundary structure, and by interactions between the sample objects themselves. Preferably, each edge of the outermost unit cell of the sensor array is aligned with one of the boundary structures.

[0049] In some embodiments, each of the outermost sensors in the sensor array may be positioned at a distance from at least one of the boundary structures corresponding to half of the first interval a1, i.e., a1 / 2, where the distance between the sensor and the boundary structure may be, for example, the distance between the center of the sensor and each boundary structure. In this way, a sample object having physical dimensions corresponding to the first interval, for example, a diameter corresponding to the first interval, aligned with one of the outermost sensors, can come into contact with each boundary structure. The outermost sensors in the sensor array may be, for example, sensors that allow each solid object in the close-packed area aligned with the sensor to move without moving another solid object in the close-packed area, i.e., without moving another solid object if it were not a boundary structure.

[0050] In some embodiments, two or more boundary structures are arranged such that, in close packing of solid objects where each solid object is aligned with each of the sensors, for example with each unit cell, the contact between solid objects and the contact between solid objects and boundary structures prevents at least 90%, preferably at least 95%, of the solid objects from moving in a plane parallel to the first wall.

[0051] In some embodiments, the two or more boundary structures comprise two opposing boundary structures separated by a distance D equal to an integer multiple of the sensor array spacing a0, i.e., D = M·a0, where M is a positive integer, particularly an integer greater than 1. The integer M may be, for example, 5 to 1000, and in one example, 10 to 100. This may allow, for example, M solid objects or sample objects having physical dimensions corresponding to a0, e.g., a diameter corresponding to a0, to be placed between opposing boundary structures such that the M solid objects or sample objects are in contact with each other and with the opposing boundary structures, thereby forming a substantially incompressible chain (e.g., a chain that can only be deformed by deforming the solid objects or sample objects).

[0052] Additionally or alternatively, two or more boundary structures may be used to separate the sensor arrays a0.

number

number

[0053] As described above, the sensor array may be a two-dimensional periodic array having a first spacing a1 in a first direction and a second spacing a2 in a second direction. The second spacing a2 may be equal to the first spacing a1 or different from the first spacing a1. In some examples, the sensors in the array may be arranged, for example, in a rectangular grid, with the second direction being perpendicular to the first direction and the second spacing being different from the first spacing.

[0054] In a preferred embodiment, the sensors in the array are spaced apart a h It is arranged in a hexagonal lattice where =a1=a2. The hexagonal lattice is formed by two basis vectors or transformation vectors corresponding to two sides of an equilateral triangle.

number

number

number

number

[0055] In some embodiments, the sensor chip may further include a droplet generator configured to produce microdroplets of the sample fluid in a carrier fluid, particularly monodisperse microdroplets, i.e., microdroplets having a uniform size. The droplet generator may be configured to produce microdroplets, for example, by cross-flow droplet generation, and may include a T-junction where, for example, a first channel through which the carrier fluid is supplied intersects a second channel through which the sample fluid is supplied at a certain angle. In other examples, the droplet generator may be configured to produce microdroplets by parallel-flow droplet generation, by hydrodynamic flow focusing, and / or by step emulsification. The size of the microdroplets may be controlled, for example, by adjusting the flow velocity and / or composition of the carrier fluid and / or sample fluid.

[0056] In some embodiments, the sensor chip may include a microfluidic inlet channel and a microfluidic outlet channel, the inlet and outlet channels being in fluid communication with the measurement volume. The sensor chip may further include means for selectively preventing the sample object from leaving the measurement volume through the outlet channel. The sensor chip may include, for example, a valve configured to adjust the width or cross-sectional area of ​​a portion of the outlet channel, so that, for example, the carrier fluid can be discharged from the measurement volume through the outlet channel, but the sample object cannot pass through the valve.

[0057] Each sensing element is configured to generate a sensor signal, in particular an optical sensor signal, a magnetic sensor signal, and / or an electrical sensor signal, which characterizes a physically observable quantity in the vicinity of each sensing element, for example, at the location of each sensing element or in the sensing volume surrounding each sensing element, as detailed above with respect to the method according to the present invention. The sensor signal can characterize, for example, temperature, pH value, electrical conductivity, dielectric constant, electric field, magnetic field, and / or light intensity. Each sensing element may comprise, for example, one or more of electrodes, in particular electrodes exposed to the measuring volume, capacitive sensing elements, inductive sensing elements, resistive sensing elements, piezoelectric sensing elements, Hall effect sensing elements, and photodiodes.

[0058] In a preferred embodiment, the sensor is a magnetic quantity sensor, the sensing element is a magnetic quantity sensing element, and each sensor comprises a plurality of magnetic quantity sensing elements. The sensing element may be, for example, an optically addressable solid spin system, as detailed above. The optically addressable solid spin system may, in particular, be nitrogen vacancy (NV) centers in diamond. NV centers can be used, for example, to locally measure electric and magnetic fields (see, e.g., R. Schirhagl et al., Annu. Rev. Phys. Chem. 65, 83-105 (2014)), and to perform nuclear magnetic resonance (NMR) spectroscopy on small samples, as reported, e.g., DRGlenn et al., Nature 555, 351-354 (2018) and WO2018 / 052497A2.

[0059] The solid spin system may be located in a sensing region situated in a sensing layer, which may be, for example, a surface layer beneath the surface of a first wall exposed to the measurement volume. The sensing layer may contain or consist of diamond, and may have a surface-perpendicular thickness of 1 μm to 1000 μm, in some examples 2 μm to 100 μm, and in one example 5 μm to 10 μm. In some examples, the sensing layer may form at least partially the upper surface of the first wall. In other examples, one or more additional layers, such as an optical coating, may be placed between the sensing layer and the surface of the first wall. In some examples, the spin system may be confined to the sensing region, while in other examples, the spin system may be distributed across the entire surface layer. In some embodiments, the density of the spin system in the sensing layer outside the sensing region may be at least 1 / 100, preferably at least 1 / 1000, of the density of the spin system within the sensing region.

[0060] In some embodiments, the sensor chip may include a light guide system configured to provide an optical path through the sensor chip, connecting some or all of the sensing regions, for example, so that light propagating along the optical path passes through each sensing region sequentially at least once. In other words, some or all of the sensing regions may be arranged along the optical path provided by the light guide system. Preferably, the light propagating along the optical path passes through each sensing region the same number of times, for example, once.

[0061] The light guide system may include one or more optical elements that modify the propagation of light along the optical path, in particular, such as reflective structures, optical coatings, and / or waveguides. The light guide system may include, for example, one or more reflective coatings, in particular broadband or dichroic reflective coatings. The reflective coatings may be located, for example, on the surface of a first wall exposed to the measuring volume, on the bottom surface of a substrate facing the surface of the first wall, and / or on one or more sides of the substrate extending between the top and bottom surfaces. In some examples, the propagation of light along the optical path may also include one or more internal total internal reflections on the surface of the sensor chip, i.e., the light guide system may be configured such that the angle of incidence of the optical path on each surface is greater than the critical angle of internal total internal reflection.

[0062] In some embodiments, at least two segments of the optical path are not parallel to each other, for example, due to reflection from a reflective element of the light guide system, or due to curvature or bending of a waveguide element of the light guide system. Each of the non-parallel segments may be located between or extend between two or more sensing regions. In some examples, the optical path may additionally comprise one or more sets of parallel segments. The optical path may form a periodic pattern, such as a zigzag pattern and / or a meandering pattern, for example, in one or more planes, such as a plane perpendicular or parallel to the surface of a first wall. In some examples, the optical path may form a non-intersecting pattern, in particular a non-intersecting periodic pattern.

[0063] The sensors and / or sensing elements may be exposed to the measurement volume or separated from the measurement volume by a portion of the first wall. The sensors and / or sensing elements may, for example, be completely embedded in the first wall or located in a layer below the first wall. The distance between each sensor and the surface of the first wall exposed to the measurement volume may be, for example, less than 5 times, preferably less than 2 times, the spacing a0 of the sensor array. In some examples, the distance between the sensor and the surface of the first wall may be less than or equal to the spacing a0, and in one example, less than 50% of the spacing a0. This facilitates interaction between each sensing element and the sample object in the measurement volume and reduces crosstalk between sensors. The distance between the sensor and the surface of the first wall may be, for example, the distance between the center of the sensor and the surface of the first wall.

[0064] The present invention further provides a sensing device for parallel probing of multiple samples using a method according to any one of the embodiments described herein. The sensing device comprises a sensor chip, which comprises a substrate and a measuring volume configured to receive a carrier fluid containing multiple sample objects. The substrate comprises a plurality of optically addressable sensing elements arranged in or below a sensing layer within a first wall of the measuring volume, each of which sensing elements is configured to generate a sensor signal characterizing a physically observable quantity in the vicinity of the respective sensing element. The sensing device further comprises an illumination system for illuminating the sensing elements. The sensor chip comprises two or more boundary or guiding structures configured to restrict or guide the movement of sample objects within the measuring volume. The two or more boundary or guiding structures are arranged such that when a solid object having a circular cross-section of diameter d is placed within the measuring volume and the solid object covers the entire first wall of the measuring volume, the solid object is arranged in a self-organizing structure in which a plurality of subsets of the solid object are each arranged along one of a plurality of straight lines. The illumination system is configured to provide multiple illumination light beams, each propagating through the substrate along an aligned optical path with one of several straight lines to illuminate sensing elements adjacent to each subset of solid objects within the self-organizing structure.

[0065] The sensing device according to the present invention provides an alternative method for implementing the method according to the present invention compared to the sensor chip according to the present invention. While the sensor chip according to the present invention provides a boundary structure that enables the placement of multiple sample objects within a self-organizing structure adapted to an array of individually spatially separated sensors on the sensor chip, as detailed above, the sensing device according to the present invention provides means for selectively illuminating sensing elements that can be uniformly distributed, for example, across the entire sensing layer, using a pattern of light adapted to the self-organizing structure of the sample objects in the measurement volume, as imposed by the boundary structure. In this way, sensing regions adjacent to the sample objects in the self-organizing structure can be selectively activated and / or read out, for example, to form an "illumination-induced" array of sensors adapted to the self-organizing structure.

[0066] The sensor chip of the sensing device may be at least partially similar to any one of the embodiments of the sensor chip according to the present invention described herein. For example, the substrate, measuring volume, and / or boundary structure of the sensor chip of the sensing device may be similar to the respective elements described above, which are omitted here for brevity. The sensor chip may also include additional components as described above for the sensor chip according to the present invention, such as droplet generators, microfluidic inlet and / or outlet channels, and / or valves. In some embodiments, the sensor chip of the sensing device may be a sensor chip according to one of the embodiments of the present invention described herein. The sensing elements within the sensing layer may, for example, form spatially separated sensing regions or arrays of sensors.

[0067] The sensing layer on which the optically addressable sensing element is located may form at least a portion of the first wall, i.e., it may have a surface exposed to the measurement volume. The sensing layer may be, for example, a surface layer of the substrate, or may be arranged or deposited on the surface layer of the substrate. In other embodiments, one or more layers, such as an optical coating and / or a hydrophilic or hydrophobic coating, may be placed between the sensing layer and the measurement volume so that the sensing layer is not exposed to the first volume.

[0068] In the context of this disclosure, an optically addressable sensing element refers to a sensing element whose state can be changed using light. The sensing elements may be configured, for example, to be optically activated. Each of the sensing elements may be configured, for example, to be switched using light from an off state in which the sensing element does not generate a sensor signal to an on state in which the sensing element generates a sensor signal. Additionally or alternatively, the sensing elements may be configured, for example, to be optically read out. Each of the sensing elements may be configured, for example, to be optically excited from a first state to a second state and to generate a sensor signal in response to the excitation. The sensor signal may be, for example, a photosensor signal. The sensor signal may be, for example, the intensity of light emitted by each sensing element following photoexcitation, e.g., fluorescence intensity, or the intensity of light absorbed by each sensing element due to photoexcitation. In a preferred embodiment, the sensing element is an optically addressable solid spin system, e.g., a nitrogen vacancy center.

[0069] The boundary structure is arranged such that solid objects within the self-organizing structure form multiple subsets, and the solid objects of a given subset are arranged along their respective lines. As detailed above, this can also allow for the arrangement of sample objects, particularly sample objects having circular cross-sections with the same diameter d, in the corresponding self-organizing pattern. The solid objects of a given subset can form a linear chain, for example, with each solid object in contact with or in close proximity to two adjacent solid objects. Each subset may comprise, for example, 5 to 1000 solid objects, or 10 to 100 solid objects in some examples. The self-organizing structure may include, for example, 2 to 100 such subsets, or 5 to 20 in some examples. Some or preferably all of the lines may be parallel to each other, i.e., each subset may be arranged in parallel. In some embodiments, the self-organizing structure may be a uniform close-packing of equal circles or spheres, and the multiple lines may be parallel to the basis vectors of the corresponding hexagonal lattice. Each of the solid objects in the self-organizing structure may, in some examples, be part of a subset, while in other examples, one or more solid objects in the self-organizing structure may not be part of a subset.

[0070] The illumination system may comprise one or more optical elements, such as beam splitters, diffractive optical elements, reflective coatings, mirrors, waveguides, and / or lenses, to provide multiple illumination light beams. The illumination system is configured to provide illumination light beams such that each illumination light beam propagates through the substrate along an optical path aligned with each straight line and, therefore, with each subset of solid objects in the self-organizing structure. The optical path may extend, for example, so that the optical path can be projected onto each straight line along a direction perpendicular to the straight line, i.e., so that it coincides with the straight line when viewed along a direction perpendicular to the straight line. In other words, the optical path may extend in a plane containing the straight line, and in particular may be parallel to the straight line. At least a portion of the optical path extends through a sensing layer so that the sensing element can be illuminated by the illumination light beam. The light for generating the illumination light beams may be provided by one or more external light sources, such as lasers. In some embodiments, the illumination system may not include a light source. In other embodiments, the illumination system may also comprise one or more light sources for generating the illumination light beams.

[0071] The illumination system can be configured to split an incident light beam into multiple illumination light beams. The incident light beam may be supplied, for example, by an external light source or a light source that forms part of the illumination system. The illumination system may include, for example, one or more beam splitters, each of which may be configured, for example, to split an illumination light beam from an incident light beam and couple the illumination light beams into their respective optical paths. The beam splitters may be, for example, non-polarizing beam splitters that can be configured to split the incident light beam by a partially reflective surface or interface, and / or polarizing beam splitters that can be configured to split the incident light beam by a surface of an interface having polarization-dependent reflectivity. Additionally or alternatively, the illumination system may also include one or more diffractive optical elements, each of which is configured to split a light beam, such as an incident light beam, into two or more beams by diffraction.

[0072] Some or all of the optical paths of the illumination light beams may be parallel to each other, and the optical paths may be arranged, for example, with a uniform spacing A1 between adjacent optical paths. In particular, the spacing A1 = d or

number

number

[0073] One or more of the optical paths of the illumination light beam, or in some examples all of the optical paths of the illumination light beam, can extend through the sensing layer at an angle of less than 10°, preferably less than 5°, with respect to the first wall of the measurement volume. In some embodiments, each of the optical paths may include reflections on the upper or lower surface of the sensing layer, e.g., total internal reflections at the first wall of the measurement volume, or reflections in a reflective coating on the first wall. In other embodiments, each optical path may be parallel to the first wall of the measurement volume.

[0074] Additionally or alternatively, for one or more of the optical paths of the illumination beam, and in some examples for all of the optical paths of the illumination beam, the light propagating along each optical path may be sequentially reflected from a first surface above the sensing layer and a second surface below the sensing layer, such that the optical path intersects the sensing layer within the sensing region. The sensing region may correspond to the portion of the sensing layer where the sensing element is illuminated by the illumination beam, and thus can be optically addressed using the illumination system, for example, to activate and / or read out each sensing element. The optical path of the illumination beam sequentially passes through each of the corresponding sensing regions, and as a result, the sensing elements within these sensing regions can be addressed using a single light beam. Preferably, each sensing region is adjacent to one of the solid objects in the self-assembled structure, for example, such that the center of the sensing region aligns with the center of each solid object in the self-assembled structure. This may, for example, enable targeted addressing of the sensing element in the vicinity of a sample object in the corresponding self-assembled structure.

[0075] Reflections on the first surface and / or the second surface may occur, for example, by total internal reflection at each surface or interface. In some embodiments, the illumination system may also include a reflective coating on the first surface and / or the second surface, the reflective coating configured to reflect the illumination light beam. The first surface may be close to the sensing layer, for example, less than 2 μm from the top surface of the sensing layer, and in some examples less than 1 μm. The distance between the top surface of the sensing layer and the first surface may be selected such that the distance between each portion is smaller than the diameter of the illumination light beam, for example, so that the portions of the optical path in the sensing layer before and after reflection at the first surface are close enough to each other to form a single sensing region. The first surface may be, for example, the first wall of the measuring volume and / or the top surface of the sensing layer. The second surface may be located at a greater distance from the sensing layer, for example, 10 μm to 1000 μm from the bottom surface of the sensing layer, so that portions of the optical path before and after reflection at the second surface are located outside the sensing layer, thereby forming spatially separated sensing regions. The second surface may be, for example, the bottom surface of the substrate. Preferably, the first and second surfaces are parallel to each other.

[0076] In some embodiments, the sensing elements may be uniformly distributed throughout the sensing layer, for example, such as having a uniform density of sensing elements or an average spacing between adjacent sensing elements within the sensing layer. Therefore, the sensing elements may be located not only in the vicinity of the optical path of the illumination light beam, but also in other parts of the sensing layer. The illumination light beam propagating through the substrate can define sensing regions, i.e., portions of the sensing layer where sensing elements are illuminated and thus addressable by the illumination light beam for, for example, selective activation and / or readout of each sensing element. As a result of the alignment between the optical path of the illumination light beam and the solid objects in the self-organizing structure, these "illumination-induced" sensing regions also form a pattern adapted to the self-organizing structure. The sensing regions may be, for example, strip portions or regions of the sensing layer extending parallel to a subset of solid objects in the self-organizing structure, or they may form an array of spatially separated sensing regions that can correspond to the arrangement of solid objects in the self-organizing structure.

[0077] In other embodiments, the sensing elements do not have to be distributed throughout the entire sensing layer, but may be confined to a portion of the sensing layer. The sensing elements may be confined to an array of spatially separated sensing regions, for example, as described above for the sensor chip according to the present invention.

[0078] In some embodiments, each of the sensing elements may be configured to generate an optical sensor signal, which may be, for example, light emitted or transmitted by each sensing element. The sensing device may further include a photosensitive detector configured to record the sensor signals of the sensing elements by, for example, determining the intensity of light emitted or transmitted by one or more of the sensing elements. The photosensitive detector may be configured to record a spatially resolved image of the sensor signals of the sensing elements, i.e., to record the sensor signals of the sensing elements as a function of position in the sensing layer. The photosensitive detector may be configured to determine the intensity of light as a function of position in the sensing layer in a plane parallel to the first wall of the measurement volume, for example. The photosensitive detector may include, for example, a camera chip having multiple photosensitive pixels, such as a CCD or CMOS chip, on which the sensing layer or a portion thereof is imaged, for example, using a microscope imaging system.

[0079] The sensing device may include a controller configured to acquire a spatially resolved image of a sensor signal from a photosensitive detector. The controller may be implemented in hardware, software, or a combination thereof. The controller may include, for example, a processor and a memory that stores instructions executed by the processor to provide the functions described herein. The controller may also be configured to select a region of interest in the spatially resolved image for each of at least a portion of the solid objects in the self-assembling structure, the region of interest including sensor signals arising from sensing regions adjacent to each solid object in the self-assembling structure. Thereafter, the controller may also be configured to selectively determine sensor signals associated with a particular sample object in the corresponding self-assembling structure, for example, as detailed above in the method according to the present invention. The region of interest may, for example, correspond to a portion of the photosensitive detector onto which each sensing region is imaged. In other examples, the region of interest may be smaller than the sensing region and may include, for example, only sensor signals arising from the central portion of each sensing region. The region of interest may, for example, be an area of ​​a predetermined size around a point in the spatially resolved image associated with the center of each solid object or sample object. The controller may store a list of locations associated with solid objects in the self-assembling structure in order to select a region of interest. In another example, the controller may be configured to determine the position of each solid object or sample object within the measurement volume from, for example, an image of each object within the measurement volume, and to select a region of interest accordingly.

[0080] In a preferred embodiment, the sensing element is an optically addressable solid spin system, particularly a diamond color center, such as a nitrogen vacancy center in diamond. As detailed above, the solid spin system may be uniformly distributed throughout the sensing layer or confined to spatially separated sensing regions within the sensing layer. In some examples, the density of the solid spin system in the substrate outside the sensing region may be, for example, at least 1 / 100, preferably at least 1 / 1000, of the density of the solid spin system within the sensing region.

[0081] The sensing device may further include a mount configured to receive a sensor chip, for example, by holding the sensor chip in a fixed position relative to an illumination system. In some embodiments, the illumination system or a part thereof is positioned on the mount, for example, on the frame of the mount on which the sensor chip is placed. The mount may be adjustable and may be configured, for example, to move and / or tilt the sensor chip and / or illumination system to align it with each other and / or with respect to an incident light beam supplied by a light source.

[0082] The present invention further provides a measurement system for parallel probing of multiple samples using a method according to any one of the embodiments described herein. The measurement system comprises a mount configured to receive a sensor chip, the sensor chip comprising a sensing layer disposed in or on a substrate, and a measurement volume adjacent to the sensing layer. The sensing layer comprises a plurality of sensing elements, each configured to generate a sensor signal characterizing a physically observable quantity in the vicinity of the respective sensing element. The measurement system further comprises a microfluidic unit configured to supply a carrier fluid containing a plurality of sample objects to the measurement volume when the sensor chip is placed in the mount. The measurement system also comprises a measurement device configured to read sensor signals from the sensing elements when the sensor chip is placed in the mount. The measurement system further comprises a controller, the controller configured to control the microfluidic unit and the measurement device. The controller is configured to control the microfluidic unit to control a plurality of sample objects in the measurement volume so that the sample objects form a self-organizing structure within the measurement volume. The controller is further configured to control the measuring device to perform measurements on one or more of the samples while the sample objects are positioned within the self-assembling structure, and the measurements on the samples are performed using one or more sensing elements positioned adjacent to each sample object within the self-assembling structure.

[0083] The measurement system may be configured, in particular, for use with a sensor chip and / or sensing device according to one of the embodiments described herein. In some examples, the measurement system may also include one or more sensor chips according to one of the embodiments described herein, an illumination system for providing multiple illumination light beams as described above, and / or a sensing device according to one of the embodiments described herein.

[0084] The microfluidic unit may comprise, for example, one or more reservoirs for the carrier fluid and / or sample fluid, and one or more connectors configured to connect to input or output ports of a sensor chip for supplying or removing the carrier fluid and / or sample fluid. The microfluidic unit may further comprise one or more pumps for generating flow of the carrier fluid and / or sample fluid. In some embodiments, the microfluidic unit may also comprise a droplet generator for preparing a sample object in the carrier fluid, for example, as described above. In other examples, the microfluidic unit may be configured to supply the carrier fluid and sample fluid separately to the sensor chip, for example to a droplet generator on the sensor chip, or the sample object may be prepared in the carrier fluid before supplying the carrier fluid to the microfluidic unit.

[0085] The measuring device may, for example, comprise a plurality of measuring channels, each of which may be associated with, for example, a sensor or sensing area on a sensor chip and configured to read a sensor signal from the respective sensor or sensing area. As detailed above, the sensor signal may be, for example, an electrical signal or an optical signal. Therefore, each measuring channel may comprise, for example, a voltmeter, an ammeter, and / or a photodetector, such as a photodiode or a photomultiplier tube. In particular, the measuring device may comprise a photodetector configured to record a spatially resolved image of the optical sensor signal of a sensing element, as described above for the sensing device according to the present invention.

[0086] The controller may be implemented in hardware, software, or a combination thereof. For example, the controller may comprise a processor and a memory for storing instructions executed by the processor to provide the functions described herein. The controller may be configured to control the number of sample objects in the measurement volume, for example, by generating control signals for a pump or valve of a microfluidic unit. The controller may further be configured to determine the number of sample objects in the measurement volume using an optical or electromagnetic droplet detector and / or a camera, for example, by monitoring the flow rates of a carrier fluid and / or sample fluid. The controller may, in particular, be configured to track sample objects on a sensor chip. The controller may further be configured to generate a control or trigger signal for the measuring device to initiate measurement of one or more samples once a self-assembling structure is formed. The controller may also be configured to read measurement results from the measuring device, which may be analog or digital signals quantifying sensor signals, for example. In some embodiments, the controller may further be configured to perform some or all of the steps of a method for parallel probing of multiple samples according to any one of the embodiments disclosed herein. The controller may also be configured to provide some or all of the functions of the controller for the sensing device according to the present invention, as described above; that is, the controller for the sensing device may be at least partially integrated into the controller of the measurement system.

[0087] The present invention further provides a set comprising a measurement system according to any one of the embodiments described herein and a sensor chip according to any one of the embodiments described herein, wherein the measurement system is adapted for use with the respective sensor chip. In particular, the mount of the measurement system can be configured to receive the respective sensor chip. Furthermore, a microfluidic unit can be configured to provide a carrier fluid containing multiple sample objects to the measurement volume of the sensor chip, and the measurement device can be configured to read sensor signals from each of the sensors in the sensor array of the sensor chip.

[0088] The present invention also provides a set comprising a measurement system according to any one of the embodiments described herein and a sensing device according to any one of the embodiments described herein, wherein the measurement system is adapted for use with the respective sensor chip. In particular, the mount of the measurement system may be configured to receive the sensor chip of the sensing device. The illumination system and the measurement system or a part thereof of the sensing device may be provided as a single integrated system. For example, the illumination system or a part thereof may be located on the mount of the measurement system. The microfluidic unit may be configured to provide a carrier fluid containing multiple sample objects to the measurement volume of the sensor chip, and the measurement device may be configured to read sensor signals from the sensing element on the sensor chip, for example, as described above.

[0089] A detailed description of the present invention and exemplary embodiments thereof is given below with reference to the drawings. The drawings show the following schematic diagrams. [Brief explanation of the drawing]

[0090] [Figure 1a] This is a top view of a sensor chip according to an exemplary embodiment of the present invention. [Figure 1b] Figure 1a is a side view of the sensor chip. [Figure 2]This is a top view of a sensor chip having a hexagonal sensor array according to an exemplary embodiment of the present invention. [Figure 3a] This is a top view of a sensor chip equipped with a guide wall according to an exemplary embodiment of the present invention. [Figure 3b] This is a top view of a sensor chip including a hydrophilic or hydrophobic coating according to an exemplary embodiment of the present invention. [Figure 4] A side view of a measurement system according to an exemplary embodiment of the present invention. [Figure 5] This is a flowchart of a method for parallel probing of multiple samples according to an exemplary embodiment of the present invention. [Figure 6] These are microscopic images of multiple microdroplets arranged in a self-organized periodic structure on a sensor chip according to an exemplary embodiment of the present invention. [Figure 7a] This is a top view of a sensing device according to an exemplary embodiment of the present invention. [Figure 7b] Figure 7a is a side view of the sensor chip of the sensing device. [Figure 8] This is a flowchart of a method for parallel probing of multiple samples, including the selection of a subset of sensing elements, according to an exemplary embodiment of the present invention. [Figure 9] Figure 7a shows a sensor chip of a sensing device according to another exemplary embodiment of the present invention. [Modes for carrying out the invention]

[0091] Figures 1a and 1b show schematic diagrams (not to exact scale) of a sensor chip 100 for parallel probing of multiple samples 112A according to an exemplary embodiment of the present invention. The sensor chip 100 is shown in a top view in Figure 1a and in a side view in Figure 1b.

[0092] The sensor chip 100 comprises a substrate 102 which may be a single-layer or multilayer substrate, and may comprise or consist of an optically transparent material such as glass and / or a transparent thermoplastic material such as poly(methyl methacrylate) (PMMA). Preferably, the substrate 102 contains or consists of diamond. The substrate 102 may comprise one or more layers or portions consisting of diamond, for example, at least a sensing layer 102C. In the example of Figures 1a and 1b, the substrate 102 comprises a lower substrate 102A and an upper substrate or cover 102B, the upper substrate or cover 102B which may be detachably disposed on the lower substrate 102A, for example, to open and close the measuring volume 104 of the sensor chip 100. In other examples, the lower and upper substrates 102 may be permanently attached to each other or may be formed as a single piece. In yet another example, the sensor chip 100 may not have a cover 102B. The thickness of the lower substrate 102A perpendicular to the upper surface of the lower substrate 102A, i.e., parallel to the Z-axis in Figure 1b, may be, for example, 10 μm to 5 mm. The cross-sectional area of ​​the sensor chip 100 in the XY plane of Figure 1a, which may hereafter be referred to as the horizontal plane, is, for example, 0.01 mm². 2 ~100cm 2 In some cases, 0.1 cm 2 ~10cm 2 That's fine.

[0093] The sensor chip 100 includes a measuring volume 104 formed by a recess on the upper surface of a lower substrate 102A, as shown in the examples in Figures 1a and 1b, and the lower substrate 102A may be covered by a cover 102B to seal the measuring volume 104. Thus, the bottom surface of the recess forms a first wall or bottom wall 104-A of the measuring volume 104, and the bottom surface of the cover 102B forms a second wall or top wall 104-B of the measuring volume 104 opposite the bottom wall 104-A. The measuring volume 104 can have a height of, for example, 10 μm to 1 mm, and the height of the measuring volume 104 is the distance between the bottom wall 104-A and the top wall 104-B. In the examples of Figures 1a and 1b, the measurement volume 104 is a microfluidic channel extending along the X direction. The width D of the measurement volume 104 perpendicular to the direction of flow in the microfluidic channel may be, for example, 10 μm to 100 μm, and the length of the measurement volume 104 parallel to the direction of flow may be, for example, 100 μm to 10 mm.

[0094] The sensor chip 100 further comprises two inlet or input ports 106A, 106B and an outlet or output port 108, which are in fluid communication with the measuring volume 104 and may be used, for example, to supply or remove fluid to or from the measuring volume 104. The sensor chip 100 also comprises a droplet generator 110 positioned between the input ports 106A, 106B and the measuring volume 104. The droplet generator 110 is configured to generate microdroplets of the first fluid (e.g., sample fluid) in a second fluid (e.g., carrier fluid), in particular monodisperse microdroplets having a uniform size. For this purpose, the droplet generator 110 may, for example, include a T-junction where a first flow path from the first input port 106A intersects a second flow path from the second input port 106B at a certain angle, and the outlet of the T-junction is in fluid communication with the measuring volume 104. This may enable the generation of microdroplets of the sample fluid provided at the first input port 106A into the carrier fluid provided at the second input port 106B. In other examples, the droplet generator 110 may have a different design and may be configured to generate microdroplets, for example, by parallel flow droplet generation, by hydrodynamic flow focusing, and / or by step emulsification. In other embodiments, the sensor chip 100 may not have a droplet generator 110, but a carrier fluid already containing the sample object may be provided to the sensor chip 100 via the input port.

[0095] The measurement volume 104 is configured to receive a carrier fluid containing multiple sample objects 112. In the examples of Figures 1a and 1b, the sample objects 112 are microdroplets of the sample fluid in the carrier fluid generated by the droplet generator 110, for example, to study the properties of the sample fluid or objects or substances contained therein. In other embodiments, the sample objects 112 may be microbubbles or fine particles, such as microbeads, e.g., agarose beads. To generate the microdroplets 112, the carrier fluid and microdroplets can be obtained from an emulsion using a carrier fluid that is immiscible with the sample fluid, for example, as detailed below for Method 500. Additionally or alternatively, surfactants, such as amphiphilic molecules, may be mixed with the sample fluid and / or carrier fluid, for example, as shown in Figure 1b, such that a shell layer 112B, e.g., a lipid bilayer, is formed around the core 112A of the microdroplet 112, where the core 112A contains each sample, e.g., a fixed amount of sample fluid. The microdroplets 112 may have the same composition, or they may have different compositions, for example, by varying the composition of the sample fluid, such as the concentration of one or more objects or substances in the sample fluid over time. The physical dimensions of the sample object or microdroplets 112, such as width or diameter d, may be, for example, 10 μm to 100 μm.

[0096] The sensor chip 100 is located in or on the lower substrate 102C and further comprises a sensing layer 102C adjacent to the measurement volume 104. Multiple sensing elements 115A, 115B are arranged in the sensing layer 102C, each of which is configured to generate a sensor signal, such as an optical sensor signal or an electrical sensor signal, that characterizes a physically observable quantity in the vicinity of each sensing element 115A, 115B, for example, at the location of each sensing element 115A, 115B. Each of the sensing elements 115A, 115B may be, for example, an optically addressable solid spin system 115A (e.g., a nitrogen vacancy center) or a microelectrode 115B, as shown in the inset below Figure 1b.

[0097] The sensing elements are grouped into multiple spatially separated sensors 114A / 114B for probing the sample 112A, which are shown by dotted rectangles in Figures 1a and 1b. Each of the sensors 114A / 114B may be, for example, a sensing region 114A within the sensing layer 102C, and the sensing region 114A comprises multiple solid spin systems 115A and is separated from adjacent sensing regions 114A by portions of the sensing layer 102C that do not have solid spin systems or have solid spin systems of a lower density. In another example, each of the sensors 114A / 114B may be a sensor 114B comprising a single sensing element, for example, a single microelectrode 115B. In some examples, the sensor chip 100 may also include different types of sensors and / or sensing elements, such as combinations of microelectrodes and solid spin systems. In the following, the sensors 114A / 114B within the sensing layer 102C will be referred to as sensor 114, and each sensor 114 may be, for example, the sensing region 114A or sensor 114B as described above. Therefore, the sensing elements 115A / 115B may also be referred to as sensing element 115.

[0098] The sensors 114 are arranged in a periodic array on the bottom wall 104-A of the measuring volume 104. In the example of Figures 1a and 1b, the sensors 114 are arranged in a one-dimensional array or linear chain with a spacing a1 between adjacent sensors 114, where the spacing a1 is measured between the centers of each sensor 114. The unit cell 116 of the sensor array, i.e., the basic unit from which the array can be formed by continuous tiling, can be defined, for example, as a square of length a1 centered on each sensor, as shown by the thick dashed line in Figure 1a.

[0099] Each of the sensors 114 is configured to generate a common sensor signal that characterizes a physically observable quantity in its vicinity, for example, at the location of each sensor 114. The common sensor signal of the sensors 114 may correspond, for example, to the sum or average of the sensor signals of the sensing elements 115 of each sensor 114, or, if each sensor 114 has only a single sensing element, to the sensor signal of the sensing element 115. The value of the physically observable quantity characterized by the common sensor signal of the sensors 114 may be sensitive to changes in the sensing volume surrounding the sensor 114, at least a portion of the sensing volume may overlap with a portion of the measurement volume 104, thus enabling probing of the characteristics of the sample 112A. In the example of Figure 1b, the sensor 114 is completely embedded in the lower substrate 102A so that the sensor 114 and its sensing element 115 are not exposed to the measurement volume. In other examples, the sensor 114 may also be exposed to the measuring volume 104, for example, so that some or all of the sensing elements 115 are exposed to the measuring volume 104. The surface of the sensor 114 or sensing element 115 may be, for example, coplanar with the upper surface of the lower substrate 102A, or it may protrude from the upper surface of the lower substrate 102A. In some examples, the sensor 114 may also be located on the cover 102B instead of the lower substrate 102A.

[0100] In a preferred embodiment, each of the sensors 114 is a magnetic quantum sensor comprising a plurality of optically addressable solid-state quantum systems 115A arranged in a sensing region 114A, as shown in the lower left inset of Figure 1b. In particular, the surface layer of the lower substrate 102A adjacent to the measurement volume 104, such as the sensing layer 102C, or the entire lower substrate 102A, is a diamond slab. In the sensing layer 102C, a plurality of nitrogen vacancy centers are embedded in the diamond crystal structure as sensing elements 115A, thereby forming the sensing region 114A. The NV centers may, in particular, be in a negatively charged state exhibiting a triplet electronic ground state with spin S=1. The spin state of the NV centers can be manipulated using microwaves and can be read out and / or initialized via an optical transition to an excited triplet state, for example, through spin-dependent fluorescence in the excited state. This makes it possible to use the NV centers as nanoscale magnetometers for measuring magnetic fields, for example, through optically detected magnetic resonance (ODMR).

[0101] In other embodiments, different types of sensing elements may be used, such as temperature sensing elements, current sensing elements, voltage sensing elements, inductive sensing elements, and / or capacitive sensing elements. In some examples, each of the sensors 114 may comprise one or more electrodes 115B, as shown, for example, in the inset on the lower right of Figure 1b, and the electrodes 115B may be exposed to the measuring volume 104.

[0102] The sensor chip 100 includes two or more boundary or guiding structures configured to restrict or guide the movement of the sample object 112 within the measuring volume 104 in order to align the sample object 112 with the sensor array. In the example of Figures 1a and 1b, two opposing side walls 104-1 and 104-2 extend between the bottom wall 104-A and the top wall 104-B of the measuring volume 104 and can correspond to, for example, the side walls of a recess in the lower substrate 102A, forming the boundary or guiding structure. The side walls 104-1 and 104-2 extend parallel to each other along the X-axis and are separated by a distance D. The distance D is selected to match the spacing a1 of the sensor array. Furthermore, the side walls 104-1 and 104-2 are positioned such that the sensor 114 is centered between the side walls 104-1 and 104-2, and thus the side walls 104-1 and 104-2 are aligned with the two opposing edges of each unit cell 116 of the sensor array.

[0103] In this way, when the measurement volume 104 is completely filled with an object such as a sample object 112 having a circular cross-section with a diameter d corresponding to the spacing a1, the side walls 104-1 and 104-2 arrange the sample objects 112 in a self-organizing structure in which each sample object 112 is aligned with one of the sensors 114, for example, as shown in Figure 1a, so that the entire bottom wall 104-A is covered by the sample objects 112, and so that the sample objects 112 are centered within each unit cell 116. In the self-organizing structure, the sample objects 112 form a close-packed area of ​​equal circles, and each sample object 112 is in contact with the side walls 104-1 and 104-2 and the other sample objects 112. In some examples, the sample objects 112 can be spherical, as shown in Figures 1a and 1b, and the self-organizing structure can correspond to a close-packed area of ​​equal spheres. In the self-assembling structure, the interactions between the sample object 112 and the side walls 104-1, 104-2, and the interactions between the sample objects 112 themselves, prevent all sample objects 112 except those positioned at the edges of the self-assembling structure from moving within the measurement volume 104, thereby ensuring stable positioning for each sensor 114. In some embodiments, the sensor chip 100 may further include a boundary or guide structure (not shown) that prevents the self-assembling structure or the sample objects positioned at its edges from moving along the direction of flow within the measurement volume 104.

[0104] In the example of Figure 1b, the height of the measuring volume 104 also corresponds to the gap a1, ensuring that the spherical sample object 112 is in contact with both the bottom wall 104-A and the top wall 104-B, thereby ensuring that the sample object 112 is adjacent to the sensor 114 along the Z direction in Figure 1b, which may also be called the vertical direction. In other examples, the height of the measuring volume 104 may be greater than the gap a1, or the measuring volume 104 may be open from above, for example, when the cover 102B is not present. In such cases, the position of the sample object 112 along the vertical direction can be controlled, for example, by controlling the level of filling of the carrier fluid in the measuring volume 104 and / or by using a carrier fluid having a lower density than the sample object 112. In some examples, the sample object 112 may not be spherical, but may still have a circular cross-section with a diameter d in the XY plane of Figure 1a, and may have, for example, an ellipsoid, ellipse, or cylindrical shape. The height of the measuring volume 104 may be less than, for example, the gap a1. In yet another example, the sample object 112 within the self-assembled structure does not have to have a circular cross-section, but the self-assembled structure may nevertheless resemble a close-packed area of ​​equal circles in the sense that, for example, the centers of the sample objects and / or the contact points between the sample objects are aligned with corresponding points in an ideal close-packed area of ​​equal circles.

[0105] Figure 2 is a top view schematic (not to exact scale) of a sensor chip 200 for parallel probing of multiple samples according to another exemplary embodiment of the present invention.

[0106] The sensor chip 200 is similar to the sensor chip 100 in Figures 1a and 1b, and also comprises a substrate 102, in which a measurement volume or measurement chamber 104 is arranged to receive a carrier fluid containing multiple sample objects 112 such as microdroplets or cells. In the example in Figure 2, the measurement volume has a rectangular shape with a first pair of opposing side walls 104-1, 104-2 separated by a first distance D1, and a second pair of opposing side walls 104-3, 104-3 separated by a second distance D2. The first and second distances may be, for example, 100 μm to 2 mm, respectively. The bottom wall of the measurement volume 104 extends between the side walls 104-1 to 104-4, and the upper surface of the bottom wall exposed to the measurement volume 104 is a flat surface without any protrusions or depressions. In some embodiments, one or more of the bottom walls and / or side walls 104-1 to 104-4 may be coated with a hydrophilic or hydrophobic coating, for example, to promote or prevent wetting of each surface by the carrier fluid. Each coating may be a uniform coating applied to the entire surface and not patterned or structured in any way.

[0107] Similar to sensor chip 100, sensor chip 200 comprises two input ports 106A and 106B, an output port 108, and a droplet generator 110 positioned between the input ports 106A and 106B and the measurement volume 104. Sensor chip 200 further comprises a microfluidic inlet channel 202 positioned between the droplet generator 110 and the measurement volume 104 to provide the measurement volume 104 with a carrier fluid containing microdroplets 112 generated by the droplet generator 110. Sensor chip 100 also comprises a microfluidic outlet channel 204 connecting the measurement volume 104 to the output port 108. A microfluidic valve 206 is positioned along the outlet channel 204, and the valve 206 is configured to selectively prevent the sample object 112 from leaving the measurement volume 104 through the outlet channel 204, for example, by adjusting the cross-sectional area of ​​the outlet channel 204, while allowing the flow of carrier fluid through the outlet channel 204.

[0108] Multiple sensors 114 are arranged in a two-dimensional periodic array on the bottom wall of the measuring volume 104, and each sensor 114 comprises one or more sensing elements (not shown), as described above with reference to, for example, Figures 1a and 1b. In the example of Figure 2, the two-dimensional periodic array has a gap of a between adjacent sensors 114. h It is a hexagonal lattice having a basis vector connecting the centers of adjacent sensors 114, as indicated by the respective arrows in Figure 2.

number

number

[0109] The side walls 104-1 to 104-4 of the measurement volume 104 constitute a boundary or guiding structure configured to restrict or guide the movement of the sample object 112 within the measurement volume 104. Distances D1 and D2 are the spacing a of the sensor array. hEqual circles or spheres having diameters corresponding thereto (e.g., cylindrical or spherical sample object 112) are selected such that a uniform close packing thereof can be arranged within the measurement volume 104 with the outermost circle / sphere in contact with the side walls 104-1 to 104-4. When the entire bottom wall of the measurement volume 104 is covered by the circles / spheres as shown in FIG. 2, the position of each circle / sphere is fixed by contact with other circles / spheres surrounding the respective circle / sphere or by contact with one or more of the adjacent circles / spheres and the side walls 104-1 to 104-4. Thus, except for the circles / spheres located at the orifices of the inlet and outlet flow paths 202, 204, none of the circles / spheres can move without moving at least one other circle / sphere, that is, the translational freedom of the circles / spheres parallel to the bottom wall of the measurement volume 104 is eliminated, and thus the resulting self-organized structure is stable. In some examples, the inlet and outlet flow paths 202, 204 may also be filled with spheres so as to prevent the circles / spheres at the orifices of the inlet and outlet flow paths 202, 204 from moving.

[0110] In the example of FIG. 2, the distance D1 between the number 104-1 and the side wall 104-2 extends parallel to the basic vector of the sensor array

Number

Number

number

number

number

number

[0111] The hexagonal grid on which the sensor 114 is arranged is specifically adapted to arrange objects having a circular cross-section, such as spheres, in a uniform, close-packed arrangement of equal circles or spheres in two dimensions, and this also constitutes a hexagonal grid. Furthermore, the positions of the side walls 104-1 to 104-4 are selected such that the hexagonal grid on which the sensor 114 is arranged and the hexagonal grid of close-packed equal circles or spheres are aligned with each other, for example, so that the unit cells of the two grids are aligned with each other in a field of view perpendicular to the bottom wall of the measurement volume 104. In this way, each circle / sphere or sample object 112 in the measurement volume can be positioned above each of the sensors 114 such that, for example, the edge of each unit cell 116 touches the circumference of the sphere in a field of view perpendicular to the bottom wall, and the center of the circle / sphere is aligned with the center of the corresponding sensor 114. This means, for example, that each of the outermost sensors 114 of the array is located a distance a from its respective side wall corresponding to the radius of the circle / sphere. h This can be achieved by positioning the side walls 104-1 to 104-4 so that they are separated by only / 2.

[0112] Figures 3a and 3b show schematic (not to exact scale) top views of sensor chips 300 and 310 for parallel probing of multiple samples according to other exemplary embodiments of the present invention. Sensor chips 300 and 310 are similar to sensor chip 200 and also include a substrate 102 having a measuring volume 104, a droplet generator 110 having two input ports, and an output port 108.

[0113] The sensor chip 300 in Figure 3a comprises a rectangular measuring volume 104 formed by a bottom wall having a flat top surface extending between two pairs of opposing side walls. Multiple guide walls 302 are arranged on the bottom wall, extending upward from the top surface of the bottom wall, for example, toward the top wall or opening of the measuring volume 104. In some embodiments, the upper parts of the guide walls 302 may be in contact with the top wall, i.e., the guide walls 302 may extend from the bottom wall to the top wall. The guide walls 302 are parallel to the pair of opposing side walls and are arranged in an alternating zigzag pattern. In the alternating zigzag pattern, every other guide wall 302 contacts the first side wall 104-3 of the other pair of opposing side walls of the measuring volume 104, leaving an opening or notch adjacent to the second side wall 104-4 of the measuring volume 104 that is opposite the first side wall 104-3, while the remaining guide walls 302 contact the second side wall 104-4, leaving an opening or notch adjacent to the first side wall 104-3. In this way, the guide walls 302 divide the measuring volume 104 into a meandering channel that extends from the inlet to the outlet of the measuring volume 104.

[0114] On the bottom wall of the measuring volume 104, a plurality of sensors 114 are arranged in a two-dimensional rectangular array having a first spacing a1 along the X direction and a second spacing a2 along the Y direction in Figure 3a, where the second spacing is greater than the first spacing. Each of the sensors 114 along the circumference of the sensor array, i.e., the outermost sensors of the sensor array, is positioned at a distance of a1 / 2 from the side wall of the measuring volume 104. The side walls 104-3 and 104-4 are separated by a distance D2 equal to an integer multiple of a1, where D2 = M·a1, and M may be, for example, 10 to 100. Furthermore, the guide wall 302 is positioned such that the meandering flow path has a width equal to the first spacing a1, and the centerline of the flow path is aligned with the center of the sensor 114, for example, the sensor chip 100 in Figure 1. In this way, objects having a circular cross-section, such as spherical or cylindrical sample objects 112 in the measuring volume 104, can be confined to a close-packed arrangement of equal circles or spheres within a rectangular grid, as opposed to a hexagonal grid of uniformly close-packed arrangements of equal circles or spheres as shown in Figure 2, for example, and thus coincide with the rectangular grid of the sensor array. This may be advantageous, for example, to reduce crosstalk between sensors 114 due to an increase in spacing a2, and to facilitate the formation of the corresponding self-organized structure of the sample objects 112 due to the additional confinement provided by the guide walls 302. In some embodiments, the sensor chip 300 may have a hydrophilic or hydrophobic coating instead of, or in addition to, the guide walls 302, as with the sensor chip 310, for example.

[0115] The sensor chip 310 in Figure 3b comprises a measuring volume 104 having a rectangular central portion 104b positioned between a proximal portion 104a and a distal portion 104c of the measuring volume 104. The central portion 104b is formed by two opposing parallel side walls extending parallel to the X-axis in Figure 3b, and the proximal portion 104a and distal portion 104c are tapered such that the widths of the proximal portion 104a and distal portion 104c perpendicular to the side walls of the central portion 104b, i.e., along the Y-direction in Figure 3b, increase from the inlet orifice and outlet orifice of the measuring volume 104 toward the central portion 104b, respectively.

[0116] In the central portion 104b of the measurement volume 104, a plurality of coatings 312 are arranged on the bottom wall of the measurement volume 104. The coatings 312 may be, for example, hydrophilic or hydrophobic coatings on the upper surface of the bottom wall, and may be configured to prevent wetting of each region by the carrier fluid containing the sample object 112, thereby forming a boundary or guide structure that makes a portion of the upper surface of the bottom wall inaccessible to the carrier fluid and the sample object 112. The coatings 312 extend parallel to the side walls of the central portion 104b and define a plurality of parallel channels that extend through the central portion 104b from the proximal portion 104a to the distal portion 104c. In some embodiments, the sensor chip 310 may also have guide walls instead of, or in addition to, the coatings 312, for example, similar to the sensor chip 300.

[0117] Multiple sensors 114 are arranged on the bottom wall of the measuring volume 104 in a two-dimensional rectangular array having first and second spacings a1, a2, similar to the sensor arrangement of the sensor chip 300 in Figure 3a, such that the sensor array 114 covers the entire central portion 104b. The coating 312 is arranged such that each channel has a width corresponding to the first spacing a1, and the sensors 314 along each channel are centered relative to the centerline of each channel. The angles between the sidewalls of the tapered proximal portion 104a, the angles between the sidewalls of the tapered distal portion 104c, and the length of the channels are selected so that when the measuring volume 104 is filled with objects having a circular cross-section, such as spherical or cylindrical sample objects 112, the sample objects 112 form a self-organized close-packed structure such that each sample object 112 in the central portion 104b is positioned above each of the sensors 114. The proximal portion 104a and distal portion 104c do not necessarily have sensors 114, but the sample object 114 placed within them can be positioned accurately relative to the sensor 114 by forming a close-packed circle or sphere that prevents the sample object 114 at the end of the flow path from moving, in particular from leaving the flow path.

[0118] Figure 4 is a schematic (not to exact scale) side view of a measurement system 400 for parallel probing of multiple samples according to an exemplary embodiment of the present invention. The measurement system 400 may be configured for use with one or more sensor chips according to any one of the embodiments described herein, for example, sensor chips 100, 200, 300, and 310. Additionally or alternatively, the measurement system 400 may also be configured for use with a sensing device according to any one of the embodiments described herein, for example, the sensing device 700 shown below in Figures 7a and 7b. The measurement system 400 may be used to perform a method for parallel probing of multiple samples according to any one of the embodiments described herein, for example, method 500 described below with reference to Figure 5, or method 800 described below with reference to Figure 8.

[0119] The measurement system 400 includes a mount 402 configured to receive a sensor chip 404. The sensor chip 404 includes a sensing layer 102C disposed in or on a substrate, the sensing layer 102C comprising a plurality of sensing elements (not shown). The sensing elements can form a periodic array of sensors 114, for example, as shown in Figure 4, as detailed above with reference to Figures 1a and 1b. The sensor chip 404 further comprises a measurement volume 104 adjacent to the sensing layer 102C. In some embodiments, the sensor chip 404 may correspond to one of the sensor chips 100, 200, 300, and 310 described above. In other embodiments, the sensor chip 404 may correspond to the sensor chip 704 of the sensing device 700 described below with reference to Figure 7. The mount 402 is configured to hold the sensor chip 404 and may include, for example, means for removably attaching the sensor chip 404 to the mount 404, such as one or more fastening clips or screws. In some embodiments, the mount 402 may also be configured to move the sensor chip 404 along one or more directions and / or tilt the sensor chip 404 around one or more axes, for example for alignment purposes. In some embodiments, the mount 402 may be similar to the mount 702 of the sensing device 700 in Figures 7a and 7b.

[0120] The measurement system 400 further comprises a microfluidic unit 406 configured to supply a carrier fluid containing multiple sample objects 112 to the measurement volume 104 of the sensor chip 404. In the example of Figure 4, the microfluidic unit 406 is configured to connect to an input port 106 of the sensor chip 404, which is in fluid communication with the measurement volume 104. The microfluidic unit 406 may include one or more reservoirs (not shown) for storing fluids such as the carrier fluid and the sample fluid. The microfluidic unit 406 may also include one or more pumps (not shown) for supplying each fluid to the sensor chip 404. The microfluidic unit 406 may further comprise a droplet generator (not shown) for generating microdroplets of the sample fluid within the carrier fluid, similar to the droplet generator 110 of the sensor chip 100 in Figure 1, for example. In other examples, the microfluidic unit 406 may not include a droplet generator, but may be configured to supply the carrier fluid and sample fluid to a droplet generator on the sensor chip 404, for example. The microfluidic unit 406 can be further configured to connect to the output ports 108A and 108B of the sensor chip 404, for example, to remove the carrier fluid and sample object 112 from the sensor chip 404.

[0121] The measurement system 400 includes a measurement device 408 configured to read electrical or optical sensor signals from sensing elements on a sensor chip 404. The measurement system 400 may, for example, be configured to read a common sensor signal from each of the sensors 114 in the sensor array of the sensor chip 404. The measurement device 408 may be configured to connect to an electrical connector (not shown) on the sensor chip 404 to provide an electrical connection between the sensors 114 and the measurement device 408. The measurement device 408 may comprise a plurality of detectors or measurement elements 410, each of which may be configured to read a common sensor signal from each of the sensors 114. Each of the measurement elements 410 may, for example, comprise a voltmeter and / or ammeter for measuring the voltage and current associated with each sensor 114, respectively. In other embodiments, the measurement elements 410 may be, for example, photosensitive detectors as detailed below.

[0122] The measurement system 400 also includes a controller 412, which may be implemented in hardware, software, or a combination thereof. The controller 412 may, in particular, include a processor (not shown) and memory (not shown), the memory storing instructions that may be executed by the processor to provide the functions described herein. The controller 412 may, for example, include a central processing unit (GPU), an application-specific integrated circuit (ASIC), a field-programmable gate array (FPGA), non-volatile memory, volatile memory, a microcontroller, and / or a system-on-a-chip (SoC). Additionally or alternatively, the controller 412 may also include other analog and / or digital electronic circuits. In some examples, a measurement device 408 may be integrated, at least partially, with the controller 412.

[0123] The controller 412 is configured to control a plurality of sample objects 112 within the measurement volume 104 by controlling the microfluidic unit 406, for example, by providing control signals to the pump and / or valves of the microfluidic unit 406, thereby generating a flow of carrier fluid containing the sample objects 112 into the measurement volume 104. The controller 412 is configured in particular to control the number of sample objects 112 within the measurement volume by controlling the microfluidic unit 406, so that the sample objects 112 form a self-assembling structure within the measurement volume 104, for example, a self-assembling structure in which each sample object 112 is positioned adjacent to each of the sensors 114, as detailed below for method 500. The controller 412 is further configured to control the measuring device 408 to perform measurements on one or more of the samples 112A while the sample objects 112 are positioned within the self-assembling structure, and the measurements on the samples are performed using one or more sensing elements positioned adjacent to each sample object within the self-assembling structure, as detailed below for example for methods 500 and 800. In some embodiments, the controller 412 may be configured to perform some or all of the steps of a method for parallel probing of multiple samples according to any one of the embodiments described herein, for example, method 500 and / or method 800.

[0124] In the example of Figure 4, the sensor 114 on the sensor chip 404 is a magnetic quantum sensor, in particular a magnetic quantum sensor that includes an optically addressable solid quantum system, such as nitrogen vacancy centers in diamond, as detailed above for the sensor chip 100 in Figures 1a and 1b. To operate the solid quantum system, for example to optically excite the solid quantum system, the measurement system 400 is configured to be used with one or more light sources 414, in particular lasers, configured to generate light at one or more absorption wavelengths of the solid quantum system to illuminate the sensor 114. In some embodiments, one or more light sources 414 may be provided as independent units or may be part of the measurement system 400. The measurement system 400 may further include an illumination system (not shown) configured to couple the light beams generated by one or more light sources 414 to an optical illumination path extending through the sensor chip 404 and sequentially intersecting some or all of the sensor 114, thereby exciting, for example, the solid quantum systems within each of the sensors 114 with a single light beam passing successively through the sensor 114. Along the illumination path, light may be reflected, for example, from the surface of the sensor chip 404, for example, by total internal reflection and / or by a reflective coating on each surface. In some examples, the illumination system of the measurement system 400 may be similar to the illumination system 706 of the sensing device 700. The measurement system 400 may include additional components for operating the solid quantum system, for example, a magnet (not shown) for applying a bias magnetic field to the sensor chip 404, and / or a microwave and / or radio frequency antenna (not shown) for applying a microwave or radio frequency signal to the sensor chip 404.

[0125] In this example, the measuring device 408 is a multi-channel photodetector comprising multiple photosensitive elements as measuring elements 410. Each of the photosensitive elements 410 is configured to determine the intensity of light incident on its respective element and may comprise, for example, one or more photodiodes or photomultiplier tubes, or one or more pixels on a CCD or CMOS chip. Each of the photosensitive elements 410 is associated with one of each of the sensors 114, and the measuring system 400 may comprise an imaging system (not shown) configured to collect light emitted by a solid spin system in the sensor 114 and image the light onto each of the photosensitive elements 410. In some embodiments, the measuring device 408 may comprise a camera chip having multiple photosensitive pixels, and the controller 412 may be configured to select a subset or region of interest from the multiple photosensitive pixels as each of the photosensitive elements 410 for each of the sensors 114, for example, as detailed below for the sensing device 700 in Figure 7 and the method 800 in Figure 8.

[0126] The measurement system 400 further includes a camera 416 located opposite the measurement device 408 in the example of Figure 4. The camera 416 is configured to capture an image of the sample object 112 on the sensor chip 404, which may be used, for example, to track the sample object 112 on the sensor chip 404 and / or to monitor the formation of self-organizing structures of the sample object 112 in the measurement volume 104. In some examples, the controller 412 may be configured to automatically track the sample object 112 on the sensor chip 404 using the camera 416, for example, using computer vision technology. In other examples, the controller 412 may be configured to provide the user with images acquired from the camera 416 for manual tracking and / or monitoring. In some embodiments, the measurement device 408 may also be used as a camera for capturing an image of the sample object 112.

[0127] In the example shown in Figure 4, the sensor chip 404 further comprises a sorting unit 418 positioned along the exit channel of the sensor chip 404 and configured to sort sample objects 112 by selectively redirecting them to one of the two output ports 108A, 108B of the sensor chip 404, for example. The sorting unit 418 may comprise one or more microfluidic elements, such as one or more electrodes for generating an electric field, one or more inductive elements for generating a magnetic field, one or more optical elements or light sources for generating an optical potential, and / or valves and / or channels for generating a bypass flow. The controller 412 is configured to control the sorting unit 418 and, in particular, may be configured to control the sorting unit 418 to classify sample objects 112 based on measurement results obtained using the sensor 114, for example, by redirecting sample objects 112 associated with measurements above a threshold to the first output port 108A and sample objects 112 associated with measurements below a threshold to the second output port 108B.

[0128] Figure 5 shows a flowchart of Method 500 for parallel probing of multiple samples according to an exemplary embodiment of the present invention. Method 500 can be implemented, for example, using one of the sensor chips 100, 200, 300, 310, 404, and 704, using a measurement system 400, and / or a sensing device 700. Hereinafter, Method 500 will be described using sensor chip 200 and system 400 as non-limiting examples for illustrative purposes. Method 500 is not limited to the order of execution shown in the flowchart of Figure 5. As long as it is technically feasible, Method 500 may be performed in any order, and its steps may be performed at least partially concurrently (for example, steps 504, 506, and 508 described below).

[0129] Method 500 includes, in step 502, providing a sensor chip having a sensing layer disposed in or on a substrate and a measuring volume adjacent to the sensing layer, wherein the sensing layer comprises a plurality of sensing elements. For example, a sensor chip such as sensor chip 200 may be provided, comprising a periodic array of sensors 114 disposed on a substrate 102 and a measuring volume 104 adjacent to the sensor array. The sensor chip 200 may be mounted, for example, on a mount 402 of a measurement system 400. In embodiments in which the sample 112A or sample object 112 has a predetermined size, for example, when probing cells or microdroplets of a predetermined size, the spacing of the sensors 114 on the sensor chip 200 is, for example, spacing a h By providing a sensor chip 200 that corresponds to the physical dimensions of the sample object 112, it can be particularly adapted to sample 112A or sample object 112.

[0130] In step 504, a carrier fluid containing multiple sample objects 112 is supplied to the measurement volume 104 of the sensor chip 200. Each of the sample objects 112 has or forms each sample 112A, which may be a quantity of sample fluid, such as a biological sample fluid that may contain a biological sample, such as a protein, DNA, bacteria, cells, or a part thereof, or a chemical sample fluid that may contain one or more reagents and / or products of a chemical reaction. In one example, each of the sample objects 112 is a microdroplet containing cells or bacteria in the sample fluid, where the cells or bacteria are configured to produce a substance such as ethanol. Method 500 can be used, for example, to evaluate how efficient a cell or bacterium is in producing a substance in order to select the most efficient cell or bacterium from a plurality of cells or bacteria. The measurement performed in step 508 can be used to determine the concentration of a substance in the microdroplet. A solid spin system, such as a nitrogen vacancy center, may allow the concentration of ethanol in the microdroplet to be determined, for example, by nuclear magnetic resonance spectroscopy.

[0131] Providing a carrier fluid containing multiple sample objects 112 may, in particular, involve generating multiple microdroplets of the sample fluid in the carrier fluid, for example, using a droplet generator 110 of a sensor chip 200 or a droplet generator of a microfluidic unit 406. In this example, the microdroplets can constitute the sample objects 112. For this purpose, a carrier fluid that is immiscible with the sample fluid can be used. For example, as described in EP2270236B1, the sample fluid may be, for example, an aqueous solution or a suspension, and the carrier fluid may be an oil (or vice versa), such as a hydrocarbon oil (e.g., hexadecane), a fluorocarbon oil (e.g., octadecafluoroodecahydronaphthalene or 1-(1,2,2,3,3,4,4,5,5,6,6-undecafluorocyclohexyl)ethanol), a silicone oil, or a mineral oil. In another example, the sample fluid may be a first oil, and the carrier fluid may be a second oil immiscible with the first oil, such as silicone oil and mineral oil, or hydrocarbon oil and fluorocarbon oil. To stabilize the microdroplets, a surfactant such as an amphiphilic compound may be used, for example, a polyethylene glycol-perfluoropolyether (PEG-PFPE) block copolymer fluorinated surfactant, or octoxynol 9(C) as described in J.-L. Baret, Lab Chip, 2012, 12, 422-433. 14 H 22 O(C2H4O) n Triton X-100), sodium dodecyl sulfate (SDS), sorbitan monooleate (C 24 H 44 O6, Span 80), and glyceryl monooleate (C 21 H 40 One or more surfactants (O4, monoolein) can be added to the sample fluid and / or carrier fluid. The surfactant can form a shell layer 112B around the core 112A of each microdroplet, thereby preventing, for example, the microdroplets from fusing together. The physical dimensions of the microdroplets are, for example, the diameter of the microdroplets at intervals a hThe spacing of the sensor array on the sensor chip 200 may be adjusted accordingly. The size of the microdroplets can be controlled, for example, by adjusting the flow rate of the carrier fluid and / or sample fluid in the droplet generator, and / or by adjusting the composition of the carrier fluid and / or sample fluid.

[0132] In step 506, the multiple sample objects 112 in the measurement volume 104 are controlled so that the sample objects 112 form a self-organizing structure, such as a self-organizing periodic structure, within the measurement volume 104. In the self-organizing structure, each sample object 112 may be positioned adjacent to, for example, each of the sensors 114 on the sensor chip 200. For example, a flow of carrier fluid containing microdroplets 112 is generated through the inlet channel 202 to supply the microdroplets 112 to the measurement volume 104, thereby continuously filling the measurement volume 104. At the same time, the carrier fluid may be removed from the measurement volume 104 through the outlet channel 204, and the valve 206 may be configured so that the microdroplets 112 cannot pass through the valve 206. In this way, the number of microdroplets 112 in the measurement volume 104 can be increased in stages.

[0133] As the number of microdroplets 112 in the measurement volume 104 increases, the microdroplets 112 can come into contact with each other and with the boundary structures in the form of sidewalls 104-1 to 104-4. The interactions between the microdroplets 112 themselves and between the microdroplets 112 and sidewalls 104-1 to 104-4 result in the formation of a self-organized close-packed structure as shown in Figure 2, when the entire bottom wall of the measurement volume 104 is covered with microdroplets 112. As detailed above with reference to Figure 2, the sensors 114 in the array are arranged in a hexagonal grid adapted to the arrangement of circles or spheres in a uniform close-packed structure of equal circles / spheres, and the sidewalls 104-1 to 104-4 are arranged such that, for example, each microdroplet 112 in the measurement volume 104 is positioned on each of the sensors 114, so that the self-organized close-packed structure of microdroplets 112 aligns with the sensor array. In this self-assembled periodic structure, adjacent microdroplets 112 and sidewalls 104-1 to 104-4 fix each microdroplet 112 in its respective position, preventing the microdroplets 112 from moving parallel to the bottom wall of the measurement volume. In some embodiments, the microdroplets 112 may include a monolayer of amphiphilic molecules, such as a lipid monolayer, as a shell layer 112A, or a bilayer of amphiphilic molecules, such as a lipid bilayer, may be formed when adjacent microdroplets 112 come into contact with each other. This can further stabilize the self-assembled periodic structure formed within the measurement volume 104.

[0134] In step 508, while the sample object 112 is positioned within the self-assembling structure, measurements are performed on one or more of the samples 112A, and in some embodiments, on all of the samples 112A. The measurements on the samples 112A are performed using one or more sensing elements 115 positioned adjacent to each sample object 112 within the self-assembling structure. Measurements on the samples 112A may be performed, for example, using sensors 114 on a sensor chip 200, adjacent to each sample object 112 positioned within the self-assembling structure. Measurements on one or more samples 112A may be performed in parallel, for example, by simultaneously reading measurement signals from each of the sensors 114. The sample object 112 within the self-assembling structure may remain stationary during measurement, i.e., it may not move relative to the sensors 114. This may also allow for multiple repetitions of measurements and / or multiple different measurements to be performed while the sample object 112 remains adjacent to each sensor 114.

[0135] As detailed above with reference to Figures 1a and 1b, the sensor 114 may be a magnetic quantity sensor, and may include an optically addressable solid quantum system 115A, for example, a nitrogen vacancy center in diamond, as the sensing element 115. Therefore, performing a measurement may include illuminating the sensor 114 to optically polarize the solid quantum system 115A, applying one or more microwave and / or radio frequency pulses to the sensor 114 to manipulate the state of the solid quantum system 115A, illuminating the sensor 114 to optically excite the solid quantum system 115A, and / or performing an optical readout of the state of the solid quantum system 115A by detecting an optical signal, such as the fluorescence intensity emitted by the solid quantum system 115A in the sensor 114. The optically addressable solid quantum system may be used, for example, to perform nuclear magnetic resonance (NMR) spectroscopy.

[0136] Method 500 may further include rinsing the sensor chip 200, particularly the measuring volume 104, after performing the measurement in step 508, for example. For this purpose, the measuring volume 104 can be rinsed, for example, with water or a buffer solution to remove the sample object 112 from the measuring volume 104. Thereafter, Method 500 can be repeated using the same sensor chip 200 to probe, for example, another set of samples.

[0137] Figure 6 shows a microscopic image of a plurality of microdroplets 112 arranged in a self-organized periodic structure within a measurement volume 104 of a sensor chip according to an exemplary embodiment of the present invention. The measurement volume 104 comprises two opposing side walls 104-1, 104-2 separated by a distance D = 1300 μm. The measurement volume 104 is filled with monodisperse microdroplets 112 of a sample fluid containing water in a carrier fluid containing fluorocarbon oil, and the microdroplets 112 have a diameter d = 104 ± 2 μm. As a result of surface-to-surface interactions between the microdroplets 112, the microdroplets 112 are arranged in a self-organized periodic structure, i.e., a uniform close-packed arrangement of equal spheres forming a lattice with hexagonal unit cells 116. The distance D between the side walls 104-1, 104-2 is selected so that 14 linear chains of microdroplets 112 in a uniform close-packed arrangement of equal spheres can be arranged within the measurement volume 104, i.e., N = 13.

number

[0138] Figures 7a and 7b show schematic diagrams (not to exact scale) of a sensing device 700 for parallel probing of multiple samples according to an exemplary embodiment of the present invention. Figure 7a shows the sensing device 700 in a top view, and Figure 7b shows the sensor chip 704 of the sensing device 700 in a side view.

[0139] The sensing device 700 includes a mount 702 configured to receive a sensor chip 704 of the sensing device 700. The mount 702 may include, for example, a frame having a recess or notch in which the sensor chip 704 can be placed. The frame may consist of, for example, metal, glass, plastic, or a combination thereof, or include them, and is preferably configured to hold the sensor chip 704 such that its top and bottom surfaces are accessible, particularly for microscopic imaging. In some embodiments, the mount 702 may be similar to the mount 402 of the measuring system 400 in Figure 4.

[0140] The sensor chip 704 comprises a substrate 102, which may be, for example, a diamond slab. A measuring volume 104 for receiving a carrier fluid containing multiple sample objects 112 is formed in or on the substrate 102, for example, as detailed above for the sensor chip 100 in Figures 1a and 1b. The substrate 102 comprises multiple optically addressable sensing elements 115A disposed within a sensing layer 102C adjacent to the measuring volume 104. The sensing layer 102C may be a surface layer of the substrate 102C forming the first wall or bottom wall 102-A of the measuring volume 104, for example, as shown in Figure 7b. In the example of Figure 7b, the sensing elements 115A are optically addressable solid spin systems, in particular nitrogen vacancy centers embedded in the diamond crystal structure of the sensing layer 102C. The depth of the sensing layer 102C perpendicular to the bottom wall 104-A of the measuring volume 104 may be, for example, 5 μm to 10 μm.

[0141] Preferably, the NV centers are distributed throughout the entire sensing layer 102C, which facilitates the fabrication of the sensor chip 704. The density of NV centers in the sensing layer 102C may be uniform, for example, 10 15 cm -3 ~10 18 cm -3 For example, 10 16 cm -3 ~10 17 cm -3 This may also be the case. In other examples, the NV centers may be confined to a spatially separated sensing region 114A, which can form, for example, an array of sensors, as detailed above for the sensor chip 100 in Figures 1a and 1b and the sensor chip 200 in Figure 2. The density of NV centers in the sensing region 114A may be at least 100 times, and in some examples at least 1000 times, greater than, for example, the density of NV centers in the sensing layer 102C outside the sensing region 114A.

[0142] The sensor chip 704 further comprises a plurality of boundary structures configured to restrict or guide the movement of the sample object 112 within the measurement volume 104. In the example of Figure 7a, the boundary structures are the side walls 104-1, 104-2, 104-3, and 104-4 of the measurement volume 104, which form a rectangular enclosure for the carrier fluid and the sample object 112 contained therein. The distance between opposing side walls is selected so that a uniform, close-packed arrangement of equal circles or spheres having diameter d can be placed within the measurement volume 104, with the outermost circles or spheres in contact with the side walls 104-1, 104-2, 104-3, and 104-4, thus preventing any movement of circles or spheres parallel to the bottom wall 104-A. The side walls 104-1, 104-2, 104-3, and 104-4 may be arranged similarly to, for example, the side walls of the measurement volume on the sensor chip 200 in Figure 2. This allows for the formation of a corresponding self-organized structure of a sample object 112 having a circular cross-section with diameter d in the measurement volume 104, for example, a spherical sample object 112 as shown in Figures 7a and 7b.

[0143] In a self-organized structure, that is, in close packing of circles, the sample object 112 forms multiple subsets, and all the sample objects 112 within a given subset are arranged along a straight line, for example, along a horizontal line parallel to the X-axis as in the example in Figure 7a, as a linear chain. Adjacent subsets or linear chains are displaced from each other by a distance A1 along the Y-direction, where in a uniform close packing of circles

number

[0144] In other embodiments, the arrangement of the side walls 104-1, 104-2, 104-3, 104-4 may differ, and / or the boundary structure of the sensor chip 704 may include, in addition to or instead of, the side walls 104-1, 104-2, 104-3, 104-4, as described above for, for example, the sensor chips 200, 300, and 310, other elements such as guide walls and / or hydrophilic and / or hydrophobic coatings. Each boundary structure of the sensor chip 704 is arranged such that when the sample object 112 having a circular cross-section of diameter d is placed inside the measuring volume 104 such that the sample object 112 covers the entire first wall 104-A of the measuring volume 104, the sample object 112 is arranged in a self-organizing structure in which multiple subsets of the sample object 112 are arranged along each of multiple straight lines in a rectangular grid with spacings a1 and a2, as in the example of Figures 3a and 3b.

[0145] The sensing device 700 further includes an illumination system 706 for illuminating the sensing element 115A in the sensing layer 102C. The illumination system 706 is configured to split an incident light beam 708, which may be generated by an external light source such as a laser (not shown), into a plurality of illumination light beams 710, which may also be referred to below as illumination beams. For this purpose, the illumination system 706 includes a plurality of beam splitters 712 and micromirrors 714 along the optical path of the incident light beam 708. Each of the beam splitters 712 is configured to split a portion of the incident light beam 708 to produce one illumination beam 710 each. The beam splitters 712 may be, for example, polarized or unpolarized beam splitters, and are preferably configured so that the incident light beam 708 is split into equal portions, i.e., each illumination beam 710 has the same optical power. The micromirrors 714 are configured to reflect the remaining portion of the incident light beam 708 after it has passed through the beam splitters 710 to produce another illumination beam 710. The beam splitter 712 and micromirror 714 can be, for example, mounted on the frame of the mount 702 and can be adjusted to align each illumination beam 710, for example, by being tiltable around one or two axes.

[0146] The illumination system 706 is configured to provide a plurality of illumination beams 710, each of which propagates through the substrate 102 of the sensor chip 704 along an optical path aligned with each of the subsets of sample objects 112, i.e., aligned with each straight line in which the subset of sample objects 112 are positioned. Thus, the sensing elements 115 adjacent to each subset of sample objects 112 within the self-assembled structure can be illuminated by the illumination beams 710. An illumination beam or optical path is said to be aligned with a straight line if the optical path extends within a plane containing the straight line, i.e., if the optical path coincides with the straight line when viewed along a direction in a plane perpendicular to the straight line. In some embodiments, the optical path may extend parallel to a straight line or at a small angle, for example, parallel to or at a small angle to the sensing layer 102C and / or bottom wall 104-A of the measuring volume 104, while in other embodiments, the optical path may form a zigzag pattern in each plane, for example, as detailed below with reference to Figure 7b.

[0147] In the example of Figure 7a, the illumination beams 710 are parallel to each other and propagate along the X direction. The illumination beams 710 may propagate, for example, parallel to the bottom wall 104-A of the measurement volume 104, or at a small angle with respect to the bottom wall 104-A, for example, as shown in Figure 9, at an angle of less than 10°, less than 5° in some examples, and less than 2° in one example. The spacing A1 between adjacent illumination beams 710 corresponds to the distance between adjacent linear chains of sample objects 112 in the self-assembled structure, i.e., for close packing of equal circles or spheres,

number

[0148] In some embodiments, the illumination system 706 may include one or more diffractive optical elements (not shown) instead of, or in addition to, the beam splitter 712 and the micromirror 714. Each of the diffractive optical elements may be configured to split an incident beam of light, such as an incident light beam 708, into two or more beams, such as an illumination light beam 710, by diffraction. Each of the diffractive optical elements may be configured, for example, to imprint a phase pattern and / or intensity pattern onto the incident beam, and interference between different parts of the incident beam causes the incident beam to split into two or more beams. Each of the diffractive optical elements may include, for example, a phase mask and / or a diffraction grating. The illumination system 706 may further include one or more focusing elements, such as one or more lenses, which may be configured, for example, to refract and / or deflect the two or more beams generated by the diffractive optical elements, some or all of which may propagate at an angle to the incident beam to form a pattern of parallel beams similar to, for example, the one shown in Figure 7a. For this purpose, the diffractive optical elements may be positioned, for example, at the focal plane of each focusing element.

[0149] In some embodiments, the illumination system 706 may also include one or more light sources, such as lasers (not shown), for generating one or more incident light beams and / or one or more illumination beams 710. In some examples, the illumination system 706 may include separate light sources for each of the illumination beams 710, or for each of a plurality of subsets of the illumination beams 710.

[0150] In the example of Figure 7b, the illumination system 706 further comprises optical coatings 716 and 718 located on the bottom wall 104-A of the measuring volume 104 and on the bottom surface of the substrate 102, respectively. Each of the optical coatings 716 and 718 is a reflective coating configured to reflect the illumination beam 710. Preferably, the optical coating 716 on the bottom wall 104-A adjacent to the sensing layer 102C is a broadband reflective coating configured to reflect both the absorption wavelength of the sensing element 115A, for example the wavelength of the illumination beam 710, and the emission wavelength of the sensing element 115A, which may correspond to the wavelength of the sensor signal of the sensing element 115A. The optical coating 718 on the bottom surface of the substrate 102 may be a dichroic reflective coating configured to reflect the illumination beam 710 while transmitting the sensor signal, for example, by reflecting the sensor signal, so as to reflect the absorption wavelength of the sensing element 115A and transmit the emission wavelength of the sensing element 115A. The sensor signal can be imaged, for example, through the back surface of the sensor chip 704 onto a photosensitive detector such as the measuring device 408 shown in Figure 4. In some embodiments, the illumination system 706 may not have one or both of the optical coatings 716, 718, but the illumination beam 710 may instead be reflected from each surface by total internal reflection.

[0151] The illumination system 706 is configured to couple an illumination beam 710 to the sensor chip 704 at an incident angle α with respect to the bottom wall 104-A and / or the bottom surface of the substrate 102, for example, through an inclined incident facet 720 on the side surface of the substrate 102. In the substrate 102, each of the illumination beams 710 is sequentially reflected from the optical coatings 716, 718 and can therefore propagate through the substrate 102 along a zigzag optical path in a plane parallel to the XZ plane in Figure 7b. The plane on which the zigzag optical path extends also includes the straight line in which each subset of the sample object 112 is positioned. Since the optical coatings 716, 718 are located on both sides of the sensing layer 102C, i.e., above and below the sensing layer 102C, respectively, the optical path of each illumination beam 710 sequentially intersects the sensing layer 102C in the sensing region 114A. The sensing region 114A may be, for example, the portion of the sensing layer 102C through which each illumination light beam 710 passes, that is, the portion of the sensing layer 102C through which the sensing element 115A is illuminated by each illumination beam 710. The sensing element 115A outside the sensing region 114A does not need to be illuminated by the illumination beam 710. In other words, the illumination beam 710 can generate an "illumination-induced" sensing region 114A within a homogeneous sensing layer 102C.

[0152] The illumination system 706 is configured to couple the illumination beam 710 to the sensor chip 704, so that each sensing region 114A is adjacent to each of the sample objects 112 within the self-assembling structure. In this way, the sensing elements 115A within the sensing region 114A are selectively addressed using the illumination beam 710 to activate and / or read out each sensing element 115A, thereby creating a spatially separated "illumination-induced" array of sensors adapted to the self-assembling structure of the sample object 112 within the measurement volume 102. This can be achieved, for example, by appropriately selecting the incident angle α and incident point on the incident facet 720, and by appropriately adjusting each beam splitter 712 or micromirror 714. The reflection points of the illumination beam in the optical coating 716, and therefore the sensing regions 114A, can be separated by a distance a2 equal to the diameter d of the sample object 112, for example. The reflection points, and therefore the sensing regions 114A, can be aligned with one center each of the sample object 112 within the self-assembled structure, as shown in Figure 7b.

[0153] In other embodiments, the illumination beam 710 can propagate through the sensing layer 102C parallel to the bottom wall 104-A of the measuring volume 104, or at a small angle, for example, less than 5°, in one example less than 2°. Each of the illumination beams 710 may be reflected once along the X direction, for example, at the center of the bottom wall 104-A, for example, at the coating 716, or by total internal reflection. Thus, each of the illumination beams 710 can illuminate, for example, a strip portion 710A of the sensing layer 102C beneath each subset of the sample object 112, as described above with reference to Figure 7a. In such a case, a subset of sensing elements 115A associated with a given sample object 112 may be selected as part of the data processing of the measured sensor signal, for example, as detailed below with reference to method 800 in Figure 8. This may include, for example, defining a "virtual" sensing region 114A within the strip-shaped portion 710A that can correspond to a region of interest 710B in the spatially resolved image of the sensing element 115A in the sensing layer 102C.

[0154] In some embodiments, the sensing device 700 may further comprise a measuring device (not shown) for reading sensor signals from the sensing element 115A, such as the measuring device 408 of the measuring system 400 in Figure 4. The measuring device may be a photosensitive detector configured to record a spatially resolved image of the optical sensor signal of the sensing element, for example, a camera chip having multiple photosensitive pixels, such as a CCD or CMOS chip. The sensing device 700 may further comprise a controller (not shown) for selecting a region of interest 710B in the spatially resolved image, for example, as detailed below with respect to method 800 in Figure 8. The controller may be configured to perform a method for parallel probing of multiple samples according to any one of the embodiments described herein, for example, some or all of the steps of method 500 and / or method 800. In some embodiments, the sensing device 700 or a part thereof, in particular the mount 702 and / or illumination system 706, may be provided as an integrated system together with a measuring system according to the present invention, such as the measuring system 400.

[0155] Figure 8 shows a flowchart of Method 800 for parallel probing of multiple samples according to an exemplary embodiment of the present invention. Method 800 can be implemented, for example, using one of the sensor chips 100, 200, 300, 310, 404, and 704, using a measurement system 400, and / or using a sensing device 700. Hereinafter, Method 800 will be described using the sensing device 700 and system 400 as non-limiting examples for illustrative purposes. Method 800 is not limited to the order of execution shown in the flowchart of Figure 8. As long as it is technically feasible, Method 800 may be performed in any order, and its steps may be performed simultaneously, at least in part, for example, some or all of the steps 804-810 described below.

[0156] Method 800 includes, in step 802, providing a sensor chip having a sensing layer disposed in or on a substrate and a measuring volume adjacent to the sensing layer, similar to step 502 of Method 500, for example, the sensing layer comprising a plurality of sensing elements. For example, a sensor chip such as the sensor chip 704 of a sensing device 700 may be provided, in which a plurality of optically addressable sensing elements 115A, particularly nitrogen vacancy centers, are located in the sensing layer 102C below the measuring volume 104. The sensor chip 704 may be mounted, for example, in the mount 702 of the sensing device 700 or in the mount 402 of the measuring system 400. This may include, for example, adjusting the beam splitter 712 and micromirror 714 to align the optical path of the illumination beam 710 provided by the illumination system 706 with respect to the sensor chip 704, or vice versa.

[0157] In step 804, a carrier fluid containing a plurality of sample objects 112 is supplied to the measurement volume 104 of the sensor chip 704, for example, as described above for step 504 of method 500. In step 806, the plurality of sample objects 112 in the measurement volume 104 are controlled so that they form a self-assembled structure, for example, as described above for step 506 of method 500. The self-assembled structure may be, for example, a close-packed arrangement of equal circles or spheres as shown in Figure 7a, and each of the sample objects 112 is positioned in a predetermined location within the measurement volume 104.

[0158] Method 800 further includes, in step 808, selecting a subset of sensing elements 115A on the sensor chip 704 for each sample 112A from which measurements are to be performed in step 810. The measurements on the sample 112A in step 810 may be performed using only the sensing elements 115A of each subset, for example, by selectively determining the sensor signals from these sensing elements 115A. The subset of sensing elements 115A may be selected before the formation of the self-assembled structure of the sample object 112 in step 808, for example, because the position of the sample object 112 in the self-assembled structure is known prior to, or it may be selected after the formation of the self-assembled structure, for example, based on the position of the sample object 112 in the self-assembled structure experimentally determined using a camera. In some embodiments, the subset of sensing elements 115A may also be selected after the measurements in step 810, for example, as part of the data processing of the measured sensor signals.

[0159] To select a subset of the sensing elements 115A, the region of interest 710B may be selected for each of the sample objects 112 within the self-assembled structure, for example, to perform selective readout of the sensing elements associated with the region of interest. The region of interest 710B may be defined, for example, as part of a spatially resolved image of the sensor chip 704, which may in particular be a microscopic image of the sensing layer 102C recording the intensity of light emitted by the sensing elements 115A as a function of the position of the sensing layer 102C in the XY plane of Figure 7a. The region of interest 710B in the spatially resolved image may correspond, for example, to a sensing region 114A within the sensing layer 102C adjacent to each of the sample objects 112 within the self-assembled structure, or to a portion of this sensing region 114A. The sensing region 114A may be, for example, a spatially separated sensing region or sensor defined by the non-uniform distribution of sensing elements 115A in the sensing layer 102C, as in the example of Figure 1a; an illumination-induced sensing region defined by the intersection of the illumination beam and the sensing layer 102C, as in the example of Figure 7b; or a "virtual" sensing region that can be selected from the illuminated strip portion 710A of the sensing layer 102C or from the uniformly illuminated sensing layer 102, as in the example of Figure 7a.

[0160] In addition to, or instead of, selecting the region of interest 710B, a subset of the sensing elements 115A may be selected by selective illumination of the sensing layer 102C, for example, to selectively activate and / or read out the sensing elements 115A by patterned illumination. This may include selectively illuminating the sensing layer 102C with an illumination beam 710, in particular as detailed above with reference to Figures 7a and 7b. For example, only the sensing elements 115A in the strip portion 710A of Figure 7a, or only the sensing elements 115A in the sensing region 114A of Figure 7a or Figure 7b, may be illuminated by the illumination beam 710, and thus a sensor signal for probing the sample 112A may be generated.

[0161] In step 810, while the sample object 112 is positioned within the self-assembled structure in the measurement volume 104, measurements are performed on one or more of the samples 112A, and the measurements are performed using a subset of the sensing elements 115A selected in step 808. The measurements can be performed, for example, by illuminating the sensing elements 115A in the sensing layer 102C with an illumination beam 710 and recording the intensity of the light emitted by the sensing elements 115A as a sensor signal using a photosensitive detector such as a measuring device 408. The sensor signal is selectively determined by using only the sensing elements 115A within the selected subset, for example, by selectively illuminating the sensing elements 115A with the illumination beam 710, and further by discarding sensor signals outside the region of interest 710B, i.e., sensor signals originating from sensing elements 115A outside the sensing region 114A.

[0162] Thus, Method 800 enables parallel probing of multiple samples using a sensor chip that is reusable, easily manufactured, and easy to handle. Only a few boundary structures are used to position the sample object within a clear and reproducible self-assembled structure, so as to avoid requiring microscopic structures such as microfluidic sample wells, which would complicate the manufacturing process on the sensor chip as well as sample preparation and make cleaning nearly impossible. Furthermore, selective probing of each sample can also be performed using a homogeneous sensing layer with a uniform distribution of sensing elements, which further simplifies the manufacturing of the sensor chip.

[0163] Figure 9 shows a schematic (not to exact scale) side view of the sensor chip 900 of the sensing device 700 according to another exemplary embodiment of the present invention. The sensor chip 900 is similar to the sensor chip 704 in Figure 7b, and the corresponding elements are labeled using the same reference numerals as in Figure 7, and their descriptions are omitted for brevity.

[0164] In the example shown in Figure 9, the illumination beam 710 is coupled to the sensor chip 900 via the side of the substrate 102, for example, using the illumination system 706 of the sensing device 700, so that the illumination beam 710 propagates through the sensing layer 102C at an angle β relative to the bottom wall 104-A of the measuring volume 104. The angle β can be selected, for example, so that the optical path of the illumination beam 710 remains within the sensing layer 102C across the entire substrate 102, and / or so that the illumination beam 710 can be reflected from the bottom wall 104-A by total internal reflection. Preferably, each illumination beam 710 is reflected once from the bottom wall 104-A, for example, by total internal reflection, at the center of the measuring volume 104 along the X axis, as shown in Figure 9. The angle β may be, for example, 0° to 5°, or in one example, 0.5° to 2°. Therefore, each of the illumination beams 710 can illuminate, for example, a strip-shaped portion of the sensing layer 102C beneath each subset of the sample object 112, as shown in Figure 7a.

[0165] Within the sensing layer 102C, the sensing regions 114A associated with each sample object 112 in the self-assembled structure within the measurement volume 104 can be selected or defined, for example, by selective determination of sensor signals from sensing elements 115A in the corresponding regions, or by detecting only the light emitted by NV centers in a particular portion of the sensing layer 102C.

[0166] In some embodiments, the sensor chip 900 may comprise a plurality of microlenses 902, particularly immersion lenses as shown in the example of Figure 9, which can be arranged, for example, on or adjacent to the bottom surface of the substrate 102 as shown in Figure 9. In other embodiments, the microlenses 902 may be provided, for example, as part of a sensing device 700 or a measuring system 400. Each microlens 902 may define a corresponding sensing region 114A within the sensing layer 102C, and the sensing region 114A may comprise, for example, all sensing elements 115A within the field of view of each microlens 902. Each microlens 902 may be configured to collect light emitted by the sensing elements 115A within the corresponding sensing region 114A, thereby enabling selective determination of sensor signals from the sensing elements 115A within the corresponding sensing region 114A. The microlenses 902 may be arranged in a one-dimensional or preferably two-dimensional array defining a corresponding array of sensing regions 114A within the sensing layer 102C, as shown, for example, in Figure 7a.

[0167] Additionally or alternatively, the sensing region 114A may be defined, for example, by a pinhole array 904, which may be provided, for example, as part of a sensing device 700 or a measuring system 400. The pinhole array 904 comprises a plurality of pinholes or openings, each associated with a separate sensing region 114A within the sensing layer 102C. Each pinhole is configured to transmit light originating from its respective sensing region 114A, while light originating from outside each sensing region 114A, particularly from adjacent portions of the sensing layer 102C, is blocked by the pinhole array 904. This also allows for the selective determination of sensor signals from sensing elements 115A within the corresponding sensing region 114A. The pinhole array 904 can be positioned, for example, in the image plane of a microlens 902 as shown in Figure 9, or in the image plane of an imaging system (not shown) of the measuring system 400. In other embodiments, the pinhole array 904 may be located, for example, on or adjacent to the bottom surface of the substrate 102, or on or adjacent to the measuring device 408 of a measuring system 400, which may be a camera equipped with a CCD or CMOS chip. The pinholes of the pinhole array 904 may be arranged in a one-dimensional or preferably two-dimensional array defining a corresponding array of sensing regions 114A in the sensing layer 102C, as shown, for example, in Figure 7a.

[0168] In some embodiments, the sensing region 114A may also be defined by a measuring device 408 of the measuring system 400, in addition to, or instead of, the microlens 902 and / or pinhole array 904, for example. The measuring device 408 may comprise, for example, a plurality of spatially separated measuring elements 410, each associated with one of the sensing regions 114A, as shown in Figure 9. The measuring elements 410 may be photosensitive elements such as photodiodes, CCD or CMOS chips, or spatially separated pixels of a CCD or CMOS chip. The microlens 902 or imaging system (not shown) of the measuring system 400 may be configured, for example, to image the light emanating from the sensing region 114A onto each of the photosensitive elements 410, which may be configured to determine the intensity of the light. Thus, the sensing region 114A may be defined as a region within the sensing layer 102C that is imaged onto each of the photosensitive elements 410. The spacing a2 between adjacent sensing regions 114A can correspond to the spacing between adjacent photosensitive elements 410 divided by the imaging magnification, and the size of the sensing region 114A can correspond to the size obtained by dividing the size of the photosensitive elements 410 by the imaging magnification. In other examples, the photosensitive elements 410 may be placed in close proximity to the sensor chip 900, for example, on or adjacent to the bottom surface of the substrate, which may enable the collection of light from individual sensing regions 114A without the need for an imaging system. The photosensitive elements 410 may be arranged in a one-dimensional or preferably two-dimensional array defining the corresponding array of sensing regions 114A in the sensing layer 102C, for example, as shown in Figure 7a. By using a measuring device 408 having spatially separated photosensitive elements 410 associated with each sensing region 114A, the number of photosensitive elements 410 can be reduced compared to, for example, a continuous camera chip having multiple pixels covering the same area. This can reduce the amount of data that must be processed and speed up the readout of the measuring device 408.

[0169] The sensor chip 900, the pinhole array 904, and / or the measuring device 408 may be used together with the sensing device 700 in Figure 7a to select a sensing region 114A from a strip-shaped portion 710A illuminated by, for example, the illumination beam 710. In other examples, different sensor chips and / or different types of illumination may be used, and the sensing region 114A may be similarly defined, for example, in a uniformly illuminated sensing layer, in a selectively illuminated sensing layer as in Figure 7b, and / or in a sensing layer having spatially separated sensing regions as in Figure 1b. In other words, individually addressable and distinguishable sensing regions can be obtained by one or more of the following: spatially heterogeneous or selective distribution of sensing elements in the sensing layer, spatially heterogeneous or selective illumination of the sensing layer, and spatially heterogeneous or selective detection of sensor signals from the sensing layer. Thereafter, the sample object 112 in the self-assembled structure can be individually probed using the sensing elements of each sensing region.

[0170] The embodiments of the present invention disclosed herein constitute only specific examples for illustrative purposes. The present invention can be implemented with many modifications in various ways without altering its fundamental properties. Therefore, the present invention is defined solely by the claims. [Explanation of Symbols]

[0171] 100 sensor chips 102 circuit boards 102A Lower board 102B Upper circuit board / cover 104 Measurement volume 104A Bottom wall 104B Upper wall 104-1,104-2,104-3,104-4 Side wall 104a Proximal portion 104b Central part 104c distal part 106, 106A, 106B Input Ports 108, 108A, 108B output ports 110 Droplet generator 112 Sample Object 112A Sample 112B shell layer 114A, 114B Sensor / Sensing Area 115A,115B sensing element 116 unit cells 200 sensor chips 202 Inlet channel 204 Outlet channel 206 valves 300 sensor chips 302 Guidance wall 310 Sensor Chip 312 Coating 400 Measurement Systems 402 Mount 404 Sensor Chip 406 Microfluidic Unit 408 Measuring Devices 410 measurement elements 412 Controllers 414 Light source 416 Camera 418 sorting unit 500 Methods for probing multiple samples in parallel 502 Process for providing a sensor chip 504 A process for providing a carrier fluid containing multiple sample objects. 506 Process for forming a self-organized structure of a sample object 508 A process of performing measurements on one or more samples. 700 sensing devices 702 Mount 704 Sensor Chip 706 Lighting System 708 Incident light beam 710 Illumination beam 710A Strip-shaped portion 710B Area of ​​Interest 712 Beam Splitter 714 Micromirror 716 Broadband Reflective Coating 718 Dichroic Reflective Coating 720 Injection Facets 800 Methods for probing multiple samples in parallel 802 Process for providing sensor chips 804 A process for providing a carrier fluid containing multiple sample objects. 806 Process for forming a self-organized structure of a sample object 808 Step of selecting a subset of sensing elements within a sensing area. 810 A step of performing measurements on one or more samples using a selected subset. 900 sensor chips 902 Microlens 904 Pinhole Array Spacing between sensor arrays a1 and a2 D, D1, D2 side wall distance d. Diameter of the sample object A1 Path distance of illumination beam α Incidence angle of the illumination light beam

Claims

1. A method (500, 800) for parallel probing of multiple samples (112A), wherein the method (500, 800) is The present invention provides sensor chips (100, 200, 300, 310, 404, 704, 900), wherein each sensor chip (100, 200, 300, 310, 404, 704, 900) comprises a sensing layer (102C) disposed in or on a substrate (102), and a measuring volume (104) adjacent to the sensing layer (102C), wherein the sensing layer (102C) comprises a plurality of sensing elements (115A, 115B), and each of the plurality of sensing elements is configured to generate a sensor signal characterizing a physically observable quantity in the vicinity of the respective sensing element (115A, 115B). The method involves supplying a carrier fluid containing multiple sample objects (112) to the measurement volume (104), wherein each of the sample objects (112) comprises or forms a sample (112A), Controlling a plurality of sample objects (112) within the measurement volume (104) such that the sample objects (112) form a self-organizing structure within the measurement volume (104), wherein the self-organizing structure is a structure in which the arrangement of the sample objects (112) is at least partially determined by the interaction between the sample objects (112) themselves. The measurement is performed on one or more of the samples (112A) while the sample object (112) is placed within the self-assembling structure, wherein the measurement on the samples (112A) is performed using one or more sensing elements (115A, 115B) positioned adjacent to each of the sample objects (112) within the self-assembling structure. Methods including (500, 800).

2. The method according to claim 1 (500, 800), wherein performing the measurement on one or more samples (112A) includes selecting a subset of the sensing elements (115A) for each of the one or more samples (112A), wherein the sensing elements (115A) in the subset are arranged in sensing regions (114A) adjacent to each of the sample objects (112) in the self-organizing structure, and selectively determining the sensor signals from the sensing elements (115A) in the sensing regions (114A).

3. The method according to claim 2 (500, 800), wherein selecting the subset of the sensing elements (115A) and selectively determining the sensor signal from the sensing elements (115A) in the sensing region (114A) includes selectively activating the sensing elements (115A) in the sensing region (114A) and / or selectively reading the sensing elements (115A) in the sensing region (114A).

4. The sensing elements (115B) within the sensing layer (102C) form a sensor array of spatially separated sensors (114B), and each of the sensors (114B) comprises one or more sensing elements (115B). Each of the sample objects (112) is positioned adjacent to each of the sensors (114B) within the self-assembled structure. The method according to any one of claims 1 to 3 (500, 800), wherein the measurement of the sample (112A) is performed using each of the sensors (114B).

5. The spacing of the sensor array (a 1 a 2 ) is the interval (a) of the sensor array. 1 a 2 ) is selected so as to correspond to the physical dimensions (d) of the sample object (112), or The physical dimensions (d) of the sample object (112) are such that the physical dimensions (d) of the sample object (112) are such that the spacing (a) of the sensor array is equal. 1 a 2 The method according to claim 4 (500, 800), selected to correspond to ).

6. The method according to any one of claims 1 to 3 (500, 800), wherein the sample object (112) is a microdroplet dispersed in the carrier fluid.

7. The method according to claim 6 (500, 800), wherein the carrier fluid and the microdroplets (112) form an emulsion, and / or each of the carrier fluid and / or microdroplets (112) contains a surfactant that forms a shell layer (112B) around each of the samples (112A).

8. The sensor chip (100, 200, 300, 310, 404, 704, 900) comprises boundary or guidance structures (104-1, 104-2, 104-3, 104-4, 302, 312) configured to restrict or guide the movement of the sample object (112) within the measurement volume (104), The method according to any one of claims 1 to 3 (500, 800), wherein the self-organizing structure is formed by interactions between the sample object (112) and the boundary or induction structure (104-1, 104-2, 104-3, 104-4, 302, 312), and by surface-to-surface interactions between the sample objects (112).

9. The method according to claim 8 (500, 800), wherein in the self-organizing structure, the interaction between the sample object (112) and the boundary or guide structure (104-1, 104-2, 104-3, 104-4, 302, 312), and the surface-to-surface interaction between the sample objects (112) prevent at least 90%, preferably at least 95%, of the sample objects (112) from moving along two or more orthogonal directions.

10. The method according to any one of claims 1 to 3 (500, 800), wherein the sample object (112) has a circular cross-section, and the self-assembled structure is a close-packed arrangement of equal circles.

11. The method according to any one of claims 1 to 3 (500, 800), wherein the carrier fluid containing the sample object (112) is supplied through a microfluidic inlet channel (202) that is in fluid communication with the measuring volume (104), and controlling the plurality of sample objects (112) in the measuring volume (104) includes maintaining the flow of the carrier fluid containing the sample object (112) through the inlet channel (202) until the self-organizing structure is formed.

12. The method according to any one of claims 1 to 3 (500, 800), further comprising tracking the movement of the sample object (112) on the sensor chip (100, 200, 300, 310, 404) before and / or after performing measurements on each of the samples (112A).

13. The sensing element (115A) is an optically addressable solid spin system, particularly a nitrogen vacancy center in diamond, and performing the measurement on the sample (112A) is Light is shone onto a solid spin system (115A) located within a sensing region (114A) adjacent to each of the sample objects (112) within the self-assembled structure to optically excite the solid spin system (115A) within the sensing region (114A), The method according to any one of claims 1 to 3 (500, 800), comprising detecting an optical signal emitted by the solid spin system (115A) within the sensing region (114A).

14. A sensor chip (100, 200, 300, 310, 404) for parallel probing of a plurality of samples (112A) using the method (500, 800) described in claim 1, wherein the sensor chip (100, 200, 300, 310, 404) is A measurement volume (104) configured to receive a carrier fluid containing multiple sample objects (112), An array of sensors (114B) arranged within or adjacent to the first wall (104-A) of the measuring volume (104), wherein the sensor array has a first interval a 1 An array of sensors (114B) having, each of the sensors (114B) comprising one or more sensing elements (115B), each of the sensing elements configured to generate a sensor signal characterizing a physically observable quantity in the vicinity of the respective sensing element (115B), The device comprises two or more boundaries or guiding structures (104-1, 104-2, 104-3, 104-4, 302, 312) configured to restrict or guide the movement of the sample object (112) within the measuring volume (104), The two or more boundaries or guide structures (104-1, 104-2, 104-3, 104-4, 302, 312) are separated by the first interval a 1 Sensor chips (100, 200, 300, 310, 404) wherein a close-packed solid object having a circular cross-section with a diameter d equal to is arranged within the measuring volume (104), and when the close-packed solid object covers the entire first wall (104-A) of the measuring volume (104), the two or more boundaries or guide structures (104-1, 104-2, 104-3, 104-4, 302, 312) are arranged to confine the solid object so that each solid object aligns with each of the sensors (114B).

15. The aforementioned boundary or guide structure (104-1, 104-2, 104-3, 104-4, 302, 312) is The side walls (104-1, 104-2, 104-3, 104-4) of the measuring volume (104) are such that the side walls (104-1, 104-2, 104-3, 104-4) extend at a certain angle with respect to the first wall (104-A), A guide wall (302) protruding from the first wall (104-A) of the measuring volume (104) and / or from the second wall (104-B) of the measuring volume (104) facing the first wall (104-A), and / or A sensor chip (100, 200, 300, 310, 404) according to claim 14, comprising one or more hydrophilic and / or hydrophobic coatings (312) on the first and / or second walls (104-A, 104-B) of the measuring volume (104).

16. Sensor chips (100, 200, 300, 310, 404) according to claim 14 or 15, wherein the sensor array corresponds to a tiling of identical unit cells associated with each unit cell, and the segments of the boundary or guidance structure (104-1, 104-2, 104-3, 104-4, 302, 312) are aligned with the edges of the unit cells along the circumference of the sensor array.

17. Each of the outermost sensors of the sensor array is at a distance corresponding to half of the first interval a from at least one of the boundaries or guiding structures (104-1, 104-2, 104-3, 104-4, 302, 312). 1 The sensor chip (100, 200, 300, 310, 404) according to claim 14 or claim 15, which is arranged at a distance corresponding to half of 1 .

18. Sensor chip (100, 200, 300, 310, 404) according to claim 14 or 15, wherein the two or more boundary or guide structures (104-1, 104-2, 104-3, 104-4, 302, 312) are arranged in the close packing of the solid objects such that contact between the solid objects and contact between the solid objects and the boundary or guide structures (104-1, 104-2, 104-3, 104-4, 302, 312) prevents at least 90%, preferably at least 95%, of the solid objects from moving in a plane parallel to the first wall.

19. The two or more boundaries or guide structures (104-1, 104-2, 104-3, 104-4, 302, 312) are, [Math 1] A sensor chip (100, 200, 300, 310, 404) according to claim 14 or claim 15, comprising two opposing boundary or guidance structures (104-1, 104-2, 104-3, 104-4) separated by a distance D, wherein M and N are positive integers, and in particular M and / or N are positive integers greater than 1.

20. The sensor array has a first interval a in the first direction 1 It has a second spacing a in the second direction 2 A sensor chip (200, 300, 310, 404) according to any one of claim 14 or 15, which is a two-dimensional periodic array having the following characteristics.

21. The sensor (114B) in the array has a spacing a h The hexagonal grid is arranged, and the boundary or guide structure (104-1, 104-2, 104-3, 104-4, 302, 312) comprises a first pair of opposing side walls (104-1, 104-2) of the measuring volume and a second pair of opposing side walls (104-3, 104-4) of the measuring volume (104). The first pair of side walls (104-1, 104-2) are at a first distance [Math 2] Separated by, N 1 is a positive integer greater than 1, The second pair of side walls (104-3, 104-4) are D 2 = (N 2 +1)・a h or [Math 3] The second distance D is 2 Separated by, N 2 The sensor chip (200, 404) according to claim 20, wherein n is a positive integer greater than 1.

22. The sensor chip (100, 200, 300, 310) according to claim 14 or claim 15, further comprising a droplet generator (110) configured to generate monodisperse microdroplets of a sample fluid within the carrier fluid.

23. The sensor chip (200) according to claim 14 or 15, comprising a microfluidic inlet channel (202) and a microfluidic outlet channel (204), wherein the inlet channel and the outlet channel (202, 204) are in fluid communication with the measuring volume (104), and the sensor chip (200) further comprises means (206) for selectively preventing the sample object (112) from exiting the measuring volume (104) through the outlet channel (204).

24. The sensor chip (100, 200, 300, 310, 404) according to claim 14 or 15, wherein the sensing element (115B) is an optically addressable solid spin system, particularly a nitrogen vacancy center in diamond.

25. The distance between each of the sensors (114B) and the surface of the first wall (104-A) exposed to the measuring volume (104) is the first interval a 1 It is less than twice the first interval a 1 A sensor chip (100, 200, 300, 310, 404) according to claim 14 or claim 15, which is less than [value missing].

26. A sensing device (700) for parallel probing a plurality of samples (112A) using the method (500, 800) described in claim 1, wherein the sensing device (700) is A sensor chip (200, 300, 310, 404, 704, 900) comprising a substrate (102) and a measuring volume (104) configured to receive a carrier fluid containing a plurality of sample objects (112), wherein the substrate (102) comprises a plurality of optically addressable sensing elements (115A) arranged in or below a sensing layer (102C) of a first wall (104-A) of the measuring volume (104), and each of the sensing elements (115A) is configured to generate a sensor signal characterizing a physically observable quantity in the vicinity of the respective sensing element (115A), The system includes a lighting system (706) for illuminating the aforementioned sensing element (115A), The sensor chip (200, 300, 310, 404, 704, 900) further comprises two or more boundary or guiding structures (104-1, 104-2, 104-3, 104-4, 302, 312) configured to restrict or guide the movement of the sample object (112) within the measurement volume (104), wherein the two or more boundary or guiding structures (104-1, 104-2, 104-3, 104-4, 302, 312) are arranged such that when a solid object having a circular cross-section of diameter d is placed within the measurement volume (104), the solid object covers the entire first wall (104-A) of the measurement volume (104), and the solid object is arranged in a self-organizing structure in which a plurality of subsets of the solid object are each arranged along one of a plurality of straight lines. The illumination system (706) is configured to provide a plurality of illumination light beams (710), each of which propagates through the substrate (102) along an optical path aligned with one of the plurality of straight lines to illuminate sensing elements (115A) adjacent to the solid objects of each subset within the self-organizing structure of the sensing device (700).

27. The sensing device (700) according to claim 26, wherein the illumination system (706) is configured to split an incident light beam (708) into a plurality of illumination light beams (710).

28. The optical paths of the illumination light beams (710) are parallel to each other, with a spacing A 1 Separated by, [Math 4] The sensing device (700) according to claim 26 or claim 27.

29. The sensing device (700) according to claim 26 or 27, wherein one or more of the optical paths of the illumination light beam (710) extend through the sensing layer (102C) at an angle of less than 10°, preferably less than 5°, with respect to the first wall (104-A) of the measuring volume (104).

30. A sensing device (700) according to claim 26 or 27, wherein, for one or more of the optical paths of the illumination light beam (710), the light propagating along each optical path is sequentially reflected from a first surface (104-A, 716) above the sensing layer (102C) and a second surface (718) below the sensing layer (102C) such that the optical path intersects with the sensing layer (102C) in a sensing region (114A), and each of the sensing regions (114A) is adjacent to each of the solid objects in the self-organizing structure.

31. The sensing element (115A) is uniformly distributed throughout the entire sensing layer (102C) in the sensing device (700) according to claim 26 or claim 27.

32. Each of the sensing elements (115A) is configured to generate an optical sensor signal, and the sensing device (700) is configured A photosensitive detector (408) configured to record a spatially resolved image of the sensor signal of the sensing element (115A), A sensing device (700) according to claim 26 or 27, further comprising: a controller (412) configured to select a region of interest (710B) in the spatially resolved image for each of at least a portion of the solid objects in the self-organizing structure, wherein the region of interest (710B) includes a sensor signal originating from a sensing region (114A) adjacent to each of the solid objects in the self-organizing structure.

33. The sensing element (115A) is an optically addressable solid spin system, particularly a nitrogen vacancy center in diamond, according to the sensing device (700) of claim 26 or 27.

34. The sensing device (700) according to claim 26 or 27 further comprises a mount (706) configured to receive the aforementioned sensor chips (200, 300, 310, 404, 704, 900), wherein the lighting system (706) is disposed on the mount (706).

35. A measuring system (400) for parallel probing a plurality of samples (112A) using the method (500, 800) described in claim 1, wherein the measuring system (400) Mounts (402, 702) configured to receive sensor chips (100, 200, 300, 310, 404, 704, 900), wherein the sensor chips (100, 200, 300, 310, 404, 704, 900) comprise a sensing layer (102C) disposed in or on a substrate (102), and a measuring volume (104) adjacent to the sensing layer (102C), the sensing layer (102C) comprising a plurality of sensing elements (115A, 115B), each of which is configured to generate a sensor signal characterizing a physically observable quantity in the vicinity of the respective sensing element (115A, 115B), and the mounts (402, 702), A microfluidic unit (406) configured to supply a carrier fluid containing multiple sample objects (112) to the measurement volume (104) when the sensor chips (100, 200, 300, 310, 404, 704, 900) are placed within the mounts (402, 702), A measuring device (408) is configured to read sensor signals from the sensing elements (115A, 115B) when the sensor chips (100, 200, 300, 310, 404, 704, 900) are placed on the mounts (402, 702), A controller (412) is provided, The controller (412) is, Controlling the microfluidic unit (406) to control a plurality of sample objects (112) within the measurement volume (104) such that the sample objects (112) form a self-organizing structure within the measurement volume (104), wherein the self-organizing structure is a structure in which the arrangement of the sample objects (112) is at least partially determined by the interaction between the sample objects (112) themselves. A measurement system (400) is configured to perform measurements on one or more of the samples (112A) while the measuring device (408) is positioned within the self-assembling structure, wherein the measurements on the samples (112A) are performed using one or more sensing elements (115A, 115B) positioned adjacent to each of the sample objects (112) within the self-assembling structure.

36. The measurement system (400) according to claim 35, and A sensor chip (100, 200, 300, 310, 404) according to claim 14, wherein the mount (402) of the measuring system (400) is configured to receive the sensor chip (100, 200, 300, 310, 404), or A sensing device (700) according to claim 26, comprising the sensing device (700) wherein the mounts (402, 702) of the measuring system (400) are configured to receive the sensor chips (704, 900) of the sensing device (700).

Images