Sensor system for fluorescence detection

Abstract

A sensor system is described. The sensor system is suitable for fluorescence detection of fluorescently labeled particles of a liquid in a capillary. The sensor system comprises a capillary mounting module, an optical head, a slide plate, a light source arrangement for delivering excitation light to the optical head, and a detector arrangement for receiving emission signal light from the optical head. The optical head is mountable to the slide plate. The capillary is mountable in a housing of the capillary mounting module. The slide plate is mountable to a slide plate receiving arrangement of the capillary mounting module such that the slide plate is slidable from an offline position to an online position.

Description

Technical Field

[0001] The present invention relates to a sensor system for fluorescence detection of fluorescently labeled particles in a liquid (e.g., a flowing liquid in a capillary). Background Technology

[0002] Fluorescence detection methods and systems are crucial for a wide range of chemical analyses, particularly in areas such as molecular interactions, protein folding, drug design, materials science, sensors, nanotechnology, separation, and the origin of life. In medicine and medicinal chemistry, there is a significant need for rapid and reliable characterization of biomolecules and determination of molecular interactions.

[0003] In many testing methods, a liquid sample containing a target for analysis is fed into a capillary for analysis.

[0004] One example is capillary electrophoresis, an analytical technique that uses an applied voltage to separate fluorescently labeled ions based on their electrophoretic mobility within a capillary. Electrophoretic mobility depends on the molecule's charge, viscosity, and atomic radius. The rate of particle movement is directly proportional to the strength of the applied electric field—the stronger the field, the faster the migration. Neutral substances are unaffected; only the ions move with the electric field. If two ions are the same size, the one with the larger charge moves the fastest. For ions with the same charge, the smaller particle experiences less friction and generally migrates faster. Capillary electrophoresis is the most widely used because it provides faster results and high-resolution separations. The desired determination can be performed by exciting fluorescently labeled ions within a specific volume of liquid in a capillary.

[0005] Another preferred example is flow-induced dispersion analysis (FIDA), a non-immobilization technique that can be used for characterizing and quantifying molecular size, biomolecular interactions, and protein concentration.

[0006] To obtain reliable results from fluorescence emission readouts, the sensor system used to excite the endogenous or exogenous fluorophores of labeled particles (e.g., molecules, ions, aggregates, complexes, or binding partners) is crucial, and it is especially important that the sensor system used is highly reliable and has low signal loss. Many existing sensor systems are quite difficult to align with the desired precision, and even small deviations from precise alignment can have a significant impact on the quality or reliability of the detection.

[0007] US5037199 describes a cell assembly for spectrophotometric analysis or detection of substances within a small sample volume, such as a capillary sample cell. The assembly includes a spherical lens that is in direct contact with or adjacent to the outer wall of the capillary cell. The lens and cell are mounted together to form a detachable cell assembly.

[0008] Because the lens and the cell are mounted together, aligning these components with other optical elements of the sensor can be relatively difficult. Furthermore, switching between different capillaries is also challenging.

[0009] US5926271 describes a laser-induced fluorescence detector comprising: a laser beam emitting device; a dichroic mirror for orthogonally deflecting the laser beam; a lens having a small numerical aperture; a spherical lens; a specially designed cell within a capillary containing a solute containing at least one fluorescent substance of unknown fluorescence at the laser wavelength; the same device collecting the fluorescence emitted by the fluorescent substance using optical filters; a photomultiplier tube; and a computer for displaying the analytical results. The spherical lens converts the laser beam into a very small diverging beam, thereby achieving a high irradiated volume within the capillary cell. The cell employs a controlled geometry to prevent laminar mixing and turbulence during liquid flow, and the collecting device is a high numerical aperture device, such as a spherical lens. US5926271 does not describe how the optical elements are aligned.

[0010] A new sensor system is needed for the fluorescence detection of fluorescently labeled particles in a liquid in a capillary, wherein one or more of the above-mentioned drawbacks are mitigated. Summary of the Invention

[0011] The purpose of this invention is to provide a sensor system for fluorescence detection of fluorescently labeled particles in a liquid in a capillary, which is very easy to align with high alignment accuracy, and preferably, the sensor system is virtually alignment-free.

[0012] In one embodiment, the aim is to provide a sensor system for fluorescence detection of fluorescently labeled particles in a capillary, which is very compact and very easy to install and apply.

[0013] In one embodiment, the aim is to provide a sensor system for fluorescent detection of fluorescently labeled particles in a liquid in a capillary, wherein the capillary is very easy to replace.

[0014] In one embodiment, the aim is to provide a sensor system for fluorescence detection of fluorescently labeled particles in a liquid in a capillary, the sensor system being highly reliable and having very high sensing accuracy.

[0015] In one embodiment, the aim is to provide a sensor system for fluorescence detection of fluorescently labeled particles in a liquid in a capillary, the sensor system having very low loss.

[0016] In one embodiment, the aim is to provide a sensor system for fluorescence detection of fluorescently labeled particles in a liquid in a capillary, enabling highly advanced measurements.

[0017] These and other objectives have been achieved by the invention or embodiments thereof as defined in the claims and described below.

[0018] It has been discovered that the present invention or its embodiments have many additional advantages, which will become apparent to those skilled in the art from the following description.

[0019] The phrase “molecular interaction” refers to any non-covalent interaction between a first particle and a second particle, wherein each particle can be a molecule, a cluster of molecules, or a complex of molecules, independent of each other.

[0020] The term "particle" is used herein to refer to any part of matter comprising at least one molecule, such as an organic or inorganic molecule. A particle may include, for example, a molecule, an aggregate, a cluster, a complex, or any combination thereof.

[0021] The term "chemical substance" is used herein to refer to any chemical substance that is at least partially soluble in or soluble in a biological liquid sample. In practice, a chemical substance can be any chemical substance suspected of being capable of triggering an immunogenic reaction. A chemical substance is conveniently a molecule or complex, such as an antigen.

[0022] The term "drug" is used in this document to refer to an active agent, such as an active agent of a drug or an active agent suitable for use in a drug.

[0023] The term “target” is used in this document to refer to a target of a chemical substance, unless otherwise stated.

[0024] The term “binding partner” is used in this document to refer to any molecule or group of molecules capable of non-covalent interaction with a chemical substance.

[0025] A binding partner is preferably (other than a marker) identical to: a target of a chemical substance, a target analog and / or a molecule or complex having a binding site of the same or corresponding chemical substance as the target. A binding partner may, for example, be a fragment of the target molecule.

[0026] The term "fluorescent marker" is used herein to refer to any endogenous or exogenous marker that can be detected by an optical reader device. In one embodiment, the marker includes elements, groups of elements, portions, and / or any combination of one or more of these, wherein the marker can be detected directly by the reader device and / or after being affected by external and / or internal sources.

[0027] The terms “mark” and “signature” are used interchangeably.

[0028] The phrases “emit signal” and “fluorescent signal” are used interchangeably.

[0029] The phrase “light that emits signals” in this text means “light that emits signals”.

[0030] The term "capillary" in this document refers to a narrow tube or channel through which fluid flows at a microscale. Capillaries can be made of any material that is light-transparent to wavelengths within the range of the excitation (exiting) light wavelength and the emission signal wavelength. Suitable materials include glass, silicon, or polymers such as polydimethylsiloxane (PDMS).

[0031] The capillary is advantageously narrow enough to ensure laminar flow of the aqueous solution. Advantageously, the capillary has an inner diameter of less than 1 mm, for example less than 0.5 mm, preferably 10 µm to 200 µm.

[0032] The term "buffer solution" refers to an aqueous solution that is resistant to pH changes in the context in which it is used. Buffer solutions advantageously include...

[0033] The terms “test” and “analysis” are used interchangeably.

[0034] It should be emphasized that the term “comprising / including” as used herein should be interpreted as an open-ended term, meaning that it should be understood as indicating the presence of a specifically stated feature (such as an element, unit, integer, step, component, or combination thereof), but does not exclude the presence or addition of one or more other unstated features.

[0035] The reference to "some embodiments" or "one embodiment" means that a particular feature, structure, or characteristic described in connection with such embodiments is included in at least one embodiment of the disclosed subject matter. Therefore, the appearance of the phrase "in some embodiments" or "in one embodiment" in different places throughout the specification does not necessarily refer to the same embodiment. Furthermore, those skilled in the art will understand that particular features, structures, or characteristics can be combined in any suitable manner within the scope of the invention as defined by the claims.

[0036] The term “basically” should be understood in this document to encompass routine product deviations and tolerances.

[0037] Throughout the specification or claims, unless otherwise stated or required by context, the singular form encompasses the plural form.

[0038] All features of the present invention and its embodiments described herein, including the scope and preferred scope, may be combined in various ways within the scope of the present invention unless there is a specific reason not to combine such features.

[0039] After numerous attempts and experiments, the inventors of this invention provide a sensor system with an improved architecture, as described below and as defined in the claims, wherein the sensor system is relatively easy to use, and the alignment of the optical elements is very easy and the user does not need any specific optical expertise.

[0040] It has been found that the sensor system of the present invention provides very accurate measurements, believed to be at least in part due to very accurate alignment, which can be established virtually automatically due to the architecture of the sensor system.

[0041] This sensor system is suitable for detecting fluorescently labeled particles in a liquid within a capillary, wherein the liquid may flow in the capillary before and / or during detection. It should be understood that in some embodiments, the liquid may be in a non-flowing state during detection, for example, because the liquid has temporarily stopped flowing.

[0042] The sensor system includes a capillary mounting module, an optical head, a light source device suitable for delivering excitation light to the optical head, and a detector device suitable for receiving emitted signal light from the optical head.

[0043] The sensor system includes a sliding plate.

[0044] In one embodiment, the optical head is included in or pre-installed in a mounting bracket to secure it to the sliding plate, thereby requiring fewer components for the user to install during use.

[0045] In one embodiment, the optical head is mounted on or can be mounted on a sliding plate, which provides greater freedom during installation and makes it easier to replace the sliding plate in case of damage.

[0046] The capillary mounting module includes a housing with a recess for mounting a capillary, wherein the housing may have a reading window leading to the capillary. In one embodiment, the housing may include a support housing for supporting the capillary. The reading window may advantageously be an opening in the housing, such as an opening in the housing support housing, forming a direct and preferably uncovered opening to the capillary.

[0047] The capillary mounting module includes a sliding plate receiving device adapted to receive a sliding plate so that the sliding plate can slide from an offline position to an online position, wherein in the offline position the sensor system is not ready to detect, and in the online position the sensor system is ready to detect.

[0048] The optical head includes an optical port for directing light through a reading window toward and from the capillary.

[0049] The optical head includes a flange adjacent to the optical port, wherein when the flange of the sliding plate mounted with the optical head is a certain distance away from the housing, the sliding plate is in an offline position, and when the flange contacts the housing, the sliding plate is in an online position.

[0050] The particles of the liquid are advantageously dissolved and / or dispersed in the liquid.

[0051] Fluorescently labeled particles can include any kind of artificial or natural fluorophore, which can be exogenous or endogenous, such as one or more endogenous portions of liquid particles in a capillary. Particles can include any kind of particles that can be dispersed in a liquid, such as molecules, complexes, aggregates, binding pairs, etc. Examples of endogenous fluorophores include tryptophan, tyrosine, phenylalanine, aromatic amino acids, NADH, flavins, pyridoxal derivatives, and chlorophyll, and combinations thereof. The corresponding fluorophores have corresponding excitation and emission signal wavelengths. The endogenous fluorescence spectral characteristics of tryptophan, tyrosine, and phenylalanine are described, for example, in Yang et al., “Intrinsic Fluorescence Spectra of Tryptophan, Tyrosine and Phenyloalanine,” 5th International Conference on Advanced Design and Manufacturing Engineering (ICADME 2015), Atlantic Press.

[0052] In one embodiment, the sliding plate forms part of the optical head, for example, as an integrated part of the optical head.

[0053] In one embodiment, the slide plate is a separate component that is mounted to or can be mounted to an optical head. When the slide plate is a separate component, it may be easier to manufacture or less costly to replace if it wears out or is damaged.

[0054] The housing of the capillary mounting module preferably includes an alignment recess adjacent to the reading window, wherein the alignment recess has a shape that matches the flange. Advantageously, a portion of the flange is shaped to fit into the alignment recess. This provides efficient and simple alignment without requiring additional alignment by the user of the sensor system. The alignment recess may, for example, have a depth of 0.1 mm or greater, such as 1 mm or greater.

[0055] The alignment recess can advantageously extend along the periphery of the reading window, for example, along the smooth (e.g., circular) periphery of the reading window.

[0056] In one embodiment, the flange has a height of at least 0.1 mm, for example, 1 mm. If required, the flange may be even higher, for example, up to 1 cm or more.

[0057] In one embodiment, the sliding plate receiving device and the sliding plate are engaged or engageable via one or more sliders and rails, the sliders and rails forming part of the sliding plate receiving device of the sliding plate and the capillary mounting module, respectively.

[0058] The slider may include, for example, a protrusion capable of moving or sliding along the track. The slider may be advantageously designed to fit securely into the track. One or more sliders may independently have one or more grooves or slots for receiving the track, thereby ensuring smooth movement along the desired path.

[0059] One or more tracks are advantageously part of or constitute a guide element that provides a path for the slider to move along the tracks. The tracks are advantageously substantially straight.

[0060] In one embodiment, the slider includes one or more wheels or rollers.

[0061] Advantageously, the optical head includes a spherical lens. The spherical lens is preferably at least partially located within the optical aperture. Preferably, the spherical lens contacts the outer surface of the capillary when the sliding plate of the optical head, or a sliding plate mounted with the optical head, is mounted to a sliding plate receiving device and is in the online position. In one embodiment, the spherical lens is in physical contact with the capillary when the sliding plate mounted with the optical head is in the online position.

[0062] As explained further below, this position of the spherical lens helps ensure that fluorescently labeled particles in the liquid within the capillary are effectively excited, and that the emitted signals are effectively collected and detected.

[0063] When the sliding plate is mounted to the sliding plate receiving device, the flange conveniently protrudes toward the housing, preferably toward the reading window of the housing. The sliding plate forms part of the optical head, or the sliding plate is mounted to the optical head.

[0064] The flange can be advantageously located near the aperture.

[0065] In one embodiment, the flange completely or partially surrounds the optical port. In one embodiment, the flange may be formed by two or more flange peaks located around (e.g., surrounding) the optical port.

[0066] The sensor system advantageously includes safety measures to prevent excitation light from being emitted through the optical port.

[0067] Safety measures ensure that no one is accidentally harmed by the excitation light from the light source. This excitation light is known to cause harm to the eyes of humans and animals. By providing safety measures, it is not necessary for users to wear protective eyewear, because without the sliding plate of the optical head, or the sliding plate mounted with the optical head, which is installed to the sliding plate receiving device and in the online position, the light source cannot function. In the online position, the excitation light is contained within the detection system and cannot reach the eyes of the user or bystander.

[0068] Safety measures preferably include a pin device located at the capillary mounting module housing and an engagement opening in the optical head. Advantageously, the pin device engages with the optical head via the engagement opening when the sliding plate of the optical head, or a sliding plate mounted together with the optical head, is mounted to the sliding plate receiving device and is in the online position. A sensor, such as a mechanical or electrical sensor, is present in the wall portion of the engagement opening, which detects whether the pin device is correctly inserted into the engagement opening; if so, power is supplied to one or more light sources. When the pin device is not correctly inserted into the engagement opening, no power is supplied to drive one or more light sources.

[0069] Thus, the sensor system can be configured to prevent excitation light from being emitted through the optical port unless the pin device engages with the optical head.

[0070] In one embodiment, the light source device includes at least one light source and an input end of a supply optical waveguide device, the input end being arranged to receive a beam of light including excitation light from the at least one light source and propagate it to a second end of the supply optical waveguide device. Thus, the excitation light from the light source can be transmitted from the light source to the optical head. In one embodiment, the light source can be positioned remotely from the optical head, for example, at a distance of up to 10 m or more. Conveniently, the distance between the light source and the optical head is from 0.5 m to 20 m.

[0071] In one embodiment, the second end of the supply optical waveguide is mounted to feed light to the optical head.

[0072] The optical head advantageously includes optical components forming an excitation optical path for excitation light, wherein the excitation optical path includes, along the path, a second end of a supply waveguide device, a first collimator device, a dichroic mirror, a converging lens device, and a spherical lens. As described above, the spherical lens is advantageously located at least partially within the optical aperture.

[0073] The detector device advantageously includes a receiving section, at least one detector, and an output of a receiving optical waveguide arranged to propagate and deliver emission signal light emitted by excited fluorescently labeled particles in a liquid in a capillary to the receiving section of the detector device.

[0074] Advantageously, the optical head includes optical components that form an emission signal optical path for emission signal light emitted by the excited fluorescently labeled particles. The emission signal optical path includes, along its path, a spherical lens, a converging lens assembly, a dichroic mirror, a second collimator assembly, and an input end of a receiving optical waveguide assembly.

[0075] In one embodiment, the input end of the receiving optical waveguide is mounted to receive light from an optical head. A first collimator is conveniently adapted to collimate the light received from the second end of the supply optical waveguide. In one embodiment, the light received from the second end of the supply optical waveguide is divergent, for example, due to propagation into the free space of the first collimator.

[0076] The optional free space propagation from the second end of the supply optical waveguide device to the first collimator device should advantageously not exceed a few centimeters, for example up to 5 cm, or even up to 1 cm. Preferably, the optional free space propagation from the second end of the supply optical waveguide device to the first collimator device can be 0.25 cm to 0.5 cm.

[0077] In one embodiment, a first collimator device is coupled to a second end of a supply optical waveguide device. Advantageously, the first collimator device is adapted to diverge the light before collimating it.

[0078] The first collimator device may include one or more lenses, preferably including plano-convex lenses, and preferably the first collimator device is in the form of a collimation package.

[0079] In one embodiment, the plano-convex lens is or includes an aspherized plano-convex lens.

[0080] In one embodiment, the second collimator device is adapted to focus the transmitted signal light to feed the transmitted signal light to the input of the receiving optical waveguide device, and the second collimator device is advantageously adapted to collimate the transmitted signal before diverging the light, and then focus the transmitted signal light to the input of the receiving optical waveguide device.

[0081] The second collimator device may include one or more lenses, preferably including plano-convex lenses, and preferably the second collimator device is in the form of a collimation package.

[0082] The supplying optical waveguide device and / or receiving optical waveguide device may independently include at least one of optical fiber, planar waveguide, silicon-on-insulator (SOI) waveguide and / or liquid waveguide.

[0083] The supply optical waveguide can be any type of waveguide suitable for transmitting wavelengths including excitation light from one or more light sources. Advantageously, the supply optical waveguide is relatively compact, which ensures that the optical head can be connected to the output of the supply optical waveguide in a relatively simple manner.

[0084] To ensure the desired flexibility, in one embodiment it is desirable to supply the optical waveguide device comprising one or more optical fibers, such as a single optical fiber or a bundle of optical fibers.

[0085] The receiving optical waveguide can be any type of waveguide suitable for transmitting wavelengths including the transmitted signal. Advantageously, the receiving optical waveguide is relatively compact, which ensures that the optical head can be connected to the output of the receiving optical waveguide in a relatively simple manner.

[0086] To ensure the desired flexibility, in one embodiment it is desirable for the receiving optical waveguide device to include one or more optical fibers, such as a single optical fiber or a bundle of optical fibers.

[0087] In one embodiment, the supply optical waveguide device and / or the receiving optical waveguide device independently comprise optical fibers, such as two or more optical fibers, such as an optical fiber bundle, such as a fan-shaped optical fiber bundle sold by Thorlabs.

[0088] In one embodiment, the supply optical waveguide is in the form of a single optical fiber. When the sensor system comprises a single light source, a single optical fiber may suffice for the supply optical waveguide.

[0089] In one embodiment, the sensor system includes two or more light sources, and the supply optical waveguide is in the form of a single optical fiber, wherein the single optical fiber is selected as an optical fiber whose transmission bandgap includes the wavelengths of two or more light sources.

[0090] In one embodiment, the sensor system includes two or more light sources, and the supply optical waveguide is in the form of two or more optical fibers, wherein each optical fiber is selected as a transmission fiber whose bandgap contains the wavelength of the corresponding light source among the two or more light sources.

[0091] In one embodiment, the receiving optical waveguide device is in the form of a single optical fiber with a transmission bandgap that includes the wavelength of the transmitted signal.

[0092] In one embodiment, the receiving optical waveguide device includes two or more optical fibers, wherein the two or more optical fibers have different transmission band gaps, wherein each of the plurality of optical fibers has a transmission band gap that includes at least a portion of the wavelength of the emitted signal, such as a portion of the emitted signal emitted from different markers of fluorescently labeled particles and / or a portion of the emitted signal emitted from the same marker of fluorescently labeled particles, wherein the emitted signal spans a wavelength range, and wherein a portion of the emitted signal includes a portion of the emitted wavelength range.

[0093] In one embodiment, the first collimator device is in the form of a collimation package, and the second end of the optical waveguide device can be optically coupled and / or physically coupled to the first collimation package.

[0094] The first collimator device is conveniently adapted to receive and collimate the excitation light, and to transmit the collimated excitation light to the dichroic mirror, wherein the dichroic mirror is adapted to reflect the collimated excitation light toward the spherical lens via the converging lens device.

[0095] The converging lens device is preferably adapted to converge the excitation light and transmit the converged excitation light to the spherical lens.

[0096] When the sliding plate, which is mounted with the optical head, is in the online position, the converging lens assembly and the spherical lens converge the light beam to have a focal point in the wall portion including the contact point on the outer surface of the capillary, thereby ensuring that the light beam diverges in the liquid volume in the capillary to excite fluorescently labeled particles in the liquid volume.

[0097] It has been found that by placing a converging lens before the spherical lens along the excitation light path, the excitation light entering the spherical lens is ensured to be converged. Compared to the case without a converging lens, this ensures that the excitation light is more sharply converted as it passes through the spherical lens, thereby ensuring that the excitation light diverges more sharply in the liquid within the capillary. Therefore, compared to the case without a converging lens, a larger portion of the liquid containing fluorescently labeled particles will be affected by the excitation light, and a greater number of fluorescently labeled particles will be excited.

[0098] When fluorescently labeled particles in a given volume of liquid are excited, the fluorescent label emits an emission signal almost immediately. The time from the excitation of the fluorescently labeled particles to the emission of the fluorescence signal is typically in the range of nanoseconds to microseconds.

[0099] A spherical lens is suitable for receiving emission signal light emitted from excited fluorescently labeled particles in a liquid.

[0100] The emitted signal propagates in all directions, thereby forming a diverging emitted signal light that propagates to the spherical lens. The spherical lens causes the emitted signal light to be transmitted toward the dichroic mirror via the converging lens assembly. The spherical lens and the converging lens assembly are adapted to diverge the emitted signal light to have a beam diameter that does not exceed the diameter of the converging lens assembly.

[0101] Advantageously, the spherical lens and converging lens device are adapted to diverge the emitted signal light to have a beam diameter larger than that of the spherical lens. The beam diameter of the emitted signal light advantageously reaches, but does not exceed, the diameter of the converging lens device when the emitted signal light leaves it. This ensures that the loss of the emitted signal light is minimized, and preferably lossless, while ensuring a desired large beam diameter so that the beam of the emitted signal light is suitable for convergence during subsequent propagation from the converging lens device.

[0102] The spherical lens and converging lens device are adapted to transmit the emitted signal light from the converging lens device toward the dichroic mirror in the form of a converged emitted signal light.

[0103] A dichroic mirror is adapted to allow converged transmitted signal light to pass toward a second collimator device (e.g., a collimating package), wherein the second collimating package receives the converged transmitted signal light and couples the light into the input of a receiving optical waveguide device.

[0104] Optionally, the reflector is located between the dichroic mirror and the collimator device in the transmitted signal optical path. As will be described below and shown in the accompanying drawings, the reflector ensures that the optical head is relatively compact, thus simplifying its installation in the sensor device.

[0105] In one embodiment, the second collimator device is physically coupled to the input of the receiving optical waveguide device, thereby minimizing, and preferably eliminating, the loss of the transmitted signal light.

[0106] The spherical lens preferably has a diameter of at least 3 mm, for example, 3.5 mm or greater. Preferably, the diameter of the spherical lens should not exceed 8 mm. It has been found that spherical lenses with diameters in the range of 3.8 to 5 mm are very suitable, preferably about 4 mm.

[0107] The spherical lens preferably has a refractive index of 1.45 to 2 at λ=589 nm.

[0108] In one embodiment, the spherical lens comprises sapphire, ruby, and / or fused silica, or one or more of these materials.

[0109] Spherical lenses can conveniently include coatings, such as anti-reflective coatings. Examples of suitable anti-reflective coatings include magnesium fluoride (MgF2) coatings, silicon dioxide (SiO2) coatings, and broadband multilayer dielectric coatings.

[0110] In one embodiment, the spherical lens is a fused silica spherical lens, preferably having a back focal length (BFL) of 0.15-1.3 mm, for example 0.25 to 1.2 mm.

[0111] Spherical lenses advantageously exhibit good transmission in both UV and VIS, preferably in the wavelength range of 200 nm to 2200 nm, for example, 200 nm to 850 nm.

[0112] For a wavelength range that includes the wavelength of the excitation light and the wavelength of the emitted signal, the spherical lens conveniently has a transmittance of at least 50%, for example at least 60%, for example at least 70%, for example at least 80%, and preferably at least 90%. Preferably, the spherical lens has a transmittance of at least 90% in a wavelength range spanning from 200 nm to 850 nm.

[0113] The light source device can be adapted to deliver excitation light in the form of pulsed or non-pulsed light. The pulse of light can advantageously be adjustable.

[0114] When fluorescently labeled particles comprise two or more fluorescent labels that can be excited by excitation light of different wavelengths, the use of pulsed excitation light is particularly advantageous, whereby the different wavelengths of excitation light can be pulsed alternately. Thus, the emission signals generated by the pulses of excitation light of different wavelengths can be detected by a common detector, as further described below.

[0115] In one embodiment, the light source device is adapted to generate and deliver excitation light in the form of pulsed light, such as pulsed light at a selectable frequency, for example, pulsed light with a frequency of at least 1 kHz.

[0116] In one embodiment, the light source device is adapted to generate and deliver excitation light from two or more light sources of different wavelengths.

[0117] In one embodiment, the light source device is adapted to generate and deliver excitation light from interlaced pulses of excitation light comprising pulses of different wavelengths.

[0118] In one embodiment, the optical device forming the excitation optical path for the excitation light includes at least one excitation filter located between the first collimator device and the dichroic mirror. The at least one excitation filter may preferably have a selective bandpass, allowing the excitation wavelength used for fluorescently labeled particles to pass through. This reduces potential noise.

[0119] Advantageously, the dichroic mirror has at least one reflection bandwidth for selectively reflecting the wavelength of the excitation light (preferably the wavelength filtered by the excitation filter) and at least one transmission band for transmitting the wavelength of the emitted signal light.

[0120] A dichroic mirror is also commonly referred to as a dichroic beam splitter. A dichroic mirror can be a long-pass dichroic mirror, a short-pass dichroic mirror, or a multi-pass dichroic mirror.

[0121] The converging lens device can take the form of one or more lenses to ensure that the incident collimated excitation light is converged by the converging lens device. The converging lens device is preferably selected from: a biconvex lens having two convex surfaces (which may be the same or different); a plano-convex lens (PCX lens) having a flat surface facing the spherical lens; a doublet lens, such as a doublet lens including a positive lens and a negative lens, wherein the negative lens is closer to the spherical lens than the positive lens; or any combination thereof.

[0122] In one embodiment, the converging lens device includes a triplet lens.

[0123] In one embodiment, the converging lens device includes an achromatic lens and / or apochromatic lenses.

[0124] As described above, the optical head may include a mirror positioned to reflect the emitted signal light from the converging lens assembly toward the second collimator assembly. The mirror is preferably a dielectric mirror with a reflection bandwidth that at least includes the wavelength of the emitted signal light. In one embodiment, the mirror is a broadband dielectric mirror with a reflection bandwidth spanning at least 200 nm, for example, at least 300 nm, for example, spanning 400-700 nm.

[0125] The detector device preferably includes a receiving section, at least one detector, and an output terminal of a receiving optical waveguide device. This output terminal is optically connected to an optical head for receiving transmitted signal light from the optical head. Thus, the transmitted signal light from the optical head is transmitted to the receiving section of the detector device, and further transmitted from the receiving section to one or more detectors.

[0126] The receiving section may include one or more optical elements for preparing the transmitted signal light for one or more detectors.

[0127] In one embodiment, the receiving portion includes a third collimator device for receiving and collimating the transmitted signal light received from the output of the receiving optical waveguide device.

[0128] The third collimator device can be as described above for the first collimator device and the second collimator device.

[0129] In one embodiment, the receiving portion includes one or more filters, one or more splitters, and / or one or more focusing lenses.

[0130] In one embodiment, the receiving portion includes at least one emission filter for filtering potential noise in the emitted signal light.

[0131] The detector can be any kind of detector capable of detecting the transmitted signal. When there are two or more detectors, the two or more detectors can be the same or different.

[0132] In one embodiment, the detector includes a photodetector, such as a photodiode, avalanche photodiode, silicon photomultiplier, phototransistor, and / or photomultiplier tube.

[0133] The photodetector can be any type of photodetector. Preferably, at least one detector includes a photomultiplier tube module adapted to detect the intensity of the emitted signal light of a selected wavelength as a function of time. More preferably, at least one detector includes a focusing lens for focusing at least a portion of the emitted signal light onto the detection portion, such as a photodetector of at least one detector.

[0134] In one embodiment, the detector includes an avalanche photodiode (APD), a photomultiplier tube, and / or a silicon photomultiplier tube (SiPM), which ensures high sensitivity and the desired compactness.

[0135] The detector advantageously includes a lens for focusing the emitted signal light toward the photodetector.

[0136] In one embodiment, the receiving portion includes a beam splitter adapted to separate the wavelength of the emitted signal light into at least two emitted signal light portions. The detector arrangement conveniently includes detectors for each of the plurality of emitted signal light portions, wherein each detector is arranged to receive and detect a corresponding emitted signal light portion. The beam splitter may, for example, be configured to split the emitted signal light into a first emitted signal light portion with a wavelength below a wavelength threshold and a second emitted signal light portion with a wavelength above a wavelength threshold.

[0137] The ratio of the intensity detected by the first emitted signal portion and the second emitted signal portion, or preferably the ratio of their intensity changes over time, can provide valuable information about the properties of the fluorescent label and its interactions in biological or chemical systems.

[0138] In one embodiment, the optical head includes a beam splitter adapted to split the wavelength of the emitted signal light into at least two emitted signal light portions, wherein the beam splitter of the optical head is located in the emitted signal light path, preferably between the converging lens assembly and the second collimating package.

[0139] In one embodiment, the sensor system is adapted to perform fluorescence resonance energy transfer (FRET) measurements. FRET is a phenomenon describing the transfer of energy from an excited donor fluorescent label to an acceptor fluorescent label via nonradiative dipole-dipole interactions. FRET occurs when the emission spectrum of the fluorescent label overlaps with the absorption spectrum of the acceptor fluorescent label.

[0140] The fluorescently labeled particles preferably include a donor fluorescent label having an emission spectrum and an acceptor fluorescent label having an absorption spectrum that overlaps with the emission spectrum of the donor fluorescent label.

[0141] Preferably, the sensor system includes an optical beam splitter adapted to separate the emitted signal light wavelength into at least two emitted signal light portions, wherein the first emitted signal light portion includes the emitted signal of the emission spectrum of the donor fluorescent label, and the second emitted signal light portion includes the emitted signal of the emission spectrum of the acceptor fluorescent label. The beam splitter can be positioned as described above.

[0142] In one embodiment, the sensor system has a single excitation-single emission architecture, wherein the sensor system is adapted to be excited using a single light source (e.g., an LED) and to detect the intensity of an emitted light within a selected time period.

[0143] Single excitation, dual emission.

[0144] In one embodiment, the sensor system has a single excitation-multiple emission architecture, wherein the sensor system is adapted to be excited using a single light source (e.g., an LED) and to detect the intensity of multiple emitted light sources containing different wavelengths within one or more selected time periods.

[0145] In this document, "light source" refers to a light source having a wavelength or wavelength range; a tunable light-emitting unit (such as an RGB LED chip) should be considered as multiple light sources when it is tuned from one wavelength or wavelength range to another.

[0146] The detector device can easily communicate with a computer system to receive data representing the detected emitted signal light.

[0147] The light source device includes at least one light source.

[0148] In one embodiment, the light source device includes an input terminal of a supply optical waveguide arranged to receive excitation light from at least one light source, wherein the supply optical waveguide is in optical communication with an optical head to deliver the excitation light to an optical device forming an excitation optical path for the excitation light to excite fluorescently labeled particles in a portion of the liquid in a capillary. The light source is preferably an LED (light-emitting diode).

[0149] In one embodiment, the light source device includes at least two different light sources for generating excitation beams for corresponding fluorophores (fluorescent markers) of particles in the liquid in the capillary.

[0150] In one embodiment, the sensor system has a multi-excitation-multi-emission architecture, wherein the sensor system is adapted to be excited using two or more light sources emitting at different wavelengths and to detect the intensity of multiple emitted light sources containing different wavelengths within one or more selected time periods.

[0151] In one embodiment, two or more light sources comprise multiple LEDs, for example in the form of RGB LED chips, such as the BROADCOM HSMF-C118 RGB chip available from BROADCOM.

[0152] In one embodiment, the light source device includes two or more light sources, and the supply optical waveguide device may advantageously include a corresponding transmission waveguide for the respective excitation beam.

[0153] The optical components forming the excitation optical path for the excitation light in the optical head may advantageously include an excitation filter for each corresponding excitation beam. The excitation filter may preferably be located between the first collimating package and the dichroic mirror.

[0154] A dichroic mirror is advantageously a multi-pass dichroic mirror.

[0155] The detection system can advantageously have a dual excitation and dual emission architecture, suitable for performing dual excitation and dual emission fluorescence measurements.

[0156] In one embodiment, the optical head includes an optical transmission module, wherein the optical transmission module includes a portion of an optical device forming an excitation optical path for excitation light, the portion including a second end supplying an optical waveguide device, a first collimating package, and optionally including an optional excitation filter, and includes a portion of an optical device forming an emission signal optical path, the portion including a second collimating package and an input end receiving an optical waveguide device.

[0157] In one embodiment, the optical head includes a projection and collection module, wherein the projection and collection module includes a portion of an optical device forming an excitation optical path for excitation light, the portion including a dichroic mirror, a converging lens device, and a spherical lens, and includes a portion of an optical device forming an emission signal optical path, the portion including a spherical lens, a converging lens device, and optionally an optional reflector.

[0158] In some embodiments, it may be advantageous to configure the optical head as a two-part unit, comprising a light transmission module and a projection and collection module. The light transmission module and the projection and collection module can be easily detached from each other. Thus, if one of the light transmission module or the projection and collection module malfunctions, that module can be replaced without replacing other parts of the detection system.

[0159] The sensor system of the present invention is suitable for any type of detection of fluorescently labeled particles in a liquid in a capillary, wherein the liquid may flow or not flow in the capillary, preferably wherein the liquid is in laminar flow in the capillary. The sensor system of the present invention is particularly suitable for performing dispersion analysis using flow-induced dispersion analysis (FIDA) to quantify analytes such as antigens, toxins, and nucleotides (DNA, RNA). Attached Figure Description

[0160] The present invention is further described below with reference to examples and embodiments and the accompanying drawings. The drawings are schematic and may not be drawn to scale. The examples and embodiments are for illustrative purposes only and should not be construed as limiting the scope of the invention.

[0161] Figure 1 This is a schematic and perspective view of an embodiment of the sensor system of the present invention.

[0162] Figure 2 yes Figure 1 Enlarged and perspective views of a portion of the sensor system (including the optical head, the sliding plate, and the capillary mounting module with the sliding plate receiving device), with the sliding plate in an offline position.

[0163] Figure 3 yes Figure 1 A perspective view of a portion of the sensor system (including the optical head, the sliding plate, and the capillary mounting module with the sliding plate receiving device), wherein the sliding plate is in the online position.

[0164] Figure 4 This is a schematic diagram of a capillary mounting module with a sliding plate receiving device but without an optical head.

[0165] Figure 5 This is a schematic and perspective view of the optical head of another embodiment of the sensor system of the present invention.

[0166] Figure 6 yes Figure 4 Another perspective view of the capillary mounting module with a sliding plate receiving device.

[0167] Figure 7 yes Figure 4 Another front view of the capillary mounting module with a sliding plate receiving device.

[0168] Figure 8 This is a schematic diagram of the optical architecture of an embodiment of the sensor system of the present invention, applicable to single excitation and single emission.

[0169] Figure 9 This is a schematic diagram of the optical architecture of another embodiment of the sensor system of the present invention, applicable to single excitation and single emission.

[0170] Figure 10 This is a schematic diagram of the optical architecture of another embodiment of the sensor system of the present invention, applicable to single excitation and dual emission.

[0171] Figure 11 This is a schematic diagram of the optical architecture of another embodiment of the sensor system of the present invention, applicable to dual excitation and dual emission.

[0172] Figure 12 This is a schematic diagram of the optical architecture of another embodiment of the sensor system of the present invention, applicable to both dual excitation and single emission. Detailed Implementation

[0173] Figure 1 The sensor system shown includes an optical head 1, a capillary mounting module 2, a sliding plate 3, a light source device L adapted to deliver excitation light to the optical head, and a detector device D adapted to receive emitted signal light from the optical head.

[0174] The light source device L and the detector device D can be, for example, Figure 1In the common light source-detector module shown, a light-shielding barrier (not shown) prevents light from passing directly between the light source device L and the detector device D in the common light source-detector module.

[0175] The capillary mounting module 2 includes a housing 2a with a recess for mounting a capillary. Figure 1 The image shows a short section of capillary 4.

[0176] The housing 2a has a reading window 5 (which can be used for reading). Figure 6 (As seen in the image), the window leads to the capillary 4. The capillary mounting module 2 also includes a sliding plate receiving device 2b, which is adapted to receive the sliding plate 3, allowing the sliding plate 3 to slide from an offline position to an online position.

[0177] exist Figure 1 and Figure 2 In the image, sliding plate 3 is shown in the offline position.

[0178] like Figure 5 As shown, the optical head 1 includes a light port 7 for allowing light to pass through the reading window 5, exiting the capillary 4 and entering the capillary 4. The optical head 1 includes a flange adjacent to the light port 7. When the sliding plate 3 is mounted with the optical head 1, the sliding plate 3 is in an offline position when the flange 7a is a certain distance from the housing; and in an online position when the flange 7a contacts the housing 2a. Figure 3 As shown.

[0179] The optical head advantageously includes a ball lens at least partially located in the optical port 7, such that when the optical head 1 or the sliding plate mounted on the optical head 1 is in the online position, the ball lens is in contact with the outer surface of the capillary 4, preferably when the sliding plate mounted with the optical head is in the online position (e.g., Figure 3 As shown and further described below, the spherical lens is located in contact with the capillary.

[0180] Flange 7a can be as described above. For example... Figure 6 As shown, the capillary mounting module includes an alignment recess 5a adjacent to the reading window 5. The alignment recess 5a has a shape that matches the flange 7a to ensure that the flange 7a fits into the alignment recess 5a.

[0181] Similarly, Figure 6 As shown, in one embodiment, the housing 2a may include a support cover 2c for supporting the capillary.

[0182] The support housing provides a simple and safe way to install the capillary tube within the housing 2a. In this illustrated embodiment, the reading window 5 is in the form of an opening within the housing (e.g., within the housing support housing).

[0183] The recess 5a extends along the periphery of the reading window 5.

[0184] The optical head 1 is optically connected to the light source device L and the detector device D via the supply optical waveguide device 10a and the receiving optical waveguide device 10b, as described above.

[0185] Figure 1 The sensor system also includes a computer system 11, shown here as a PC with a screen 11a and a keyboard 11b.

[0186] Computer system 11 communicates with detector device D to receive and preferably process data representing the detected emitted signal light. Computer system 11 also advantageously communicates with light source device L to control and optionally adjust one or more light sources of light source device L, for example, adjusting the intensity of the excitation light and / or adjusting the optional pulse frequency of the excitation light. In the illustrated embodiment, data communication between computer system 11 and the respective light source device L and detector device D is via wire 11c, but it can also be any other data communication, such as wireless communication.

[0187] Figure 1 The sensor system includes safety measures, unless as follows Figure 3 The sliding plate 3 with the optical head shown is in the online position; otherwise, this safety measure prevents excitation light from being emitted through the optical port. The safety measures in this embodiment include a pin device 8a located at the capillary mounting module housing and an engagement opening 8b in the optical head. Figure 2 As shown, the pin device is not engaged with the optical head through the engagement opening, thus a safety measure prevents the excitation light from being emitted through the optical port. This can be provided, for example, by a sensor located within the engagement opening 8b in the optical head, wherein the power supply to the light source is cut off unless the sensor within the engagement opening 8b contacts the pin device 8a.

[0188] exist Figure 3 In this configuration, the sliding plate 3 with the optical head is in the online position, and the power supply to the light source is turned on, for example, via a user command (e.g., via computer system 11).

[0189] The sliding plate 3 includes flanges 12a, 12b, and 12c, used to temporarily hold the optical head 1 in a fixed position relative to the sliding plate 3. Figure 4 and Figure 7 As shown, the sliding plate 3 includes a front flange 12a, a lower flange 12b, and an upper flange 12c. Those skilled in the art will understand that any arrangement of the sliding plate for temporarily or permanently holding the optical head 1 in a fixed position relative to the sliding plate can be provided by any other holding component, such as a holding device including two or more flanges (e.g., at least one lower flange and one upper flange).

[0190] like Figure 7 As shown, the front flange 12a includes two mounting protrusions 12d, which ensures secure mounting with the optical head.

[0191] like Figure 5 As shown, the optical head 1 includes two front recesses 14a. When the optical head 1 is mounted together with the sliding plate 3, the two mounting protrusions 12d of the front flange 12a engage with the two front recesses 14a of the optical head 1.

[0192] Similarly, the optical head 1 includes a top recess 14b, and the upper flange 12c includes a protrusion 12f that engages with the top recess 14b of the optical head 1 when the optical head 1 is mounted with the sliding plate 3.

[0193] The capillary mounting module 2 also includes a mounting hole 9 for mounting the capillary mounting module 2 in a testable device housing.

[0194] The device housing may be, for example, the housing of the device described in WO21180289, wherein the sensor system of the present invention forms part of the reader device described in WO21180289.

[0195] The sliding plate receiving device 2b includes a pair of tracks 15, which are in the form of parallel channel-like grooves extending along the height direction of the sliding plate receiving device 2b. For example... Figure 6 As shown, the sliding plate 3 includes a pair of sliders 16, which are in the form of ridges that are slidably engaged in the track 15.

[0196] Figure 5 The optical head 1 shown is Figure 1 A variant of the optical head 1, the difference being that the supply optical waveguide device 10a' and the receiving optical waveguide device 10b' are shown as a bundle of optical fibers.

[0197] As mentioned above, the optical head 1 can be a single unit, or it can be in the form of two or more modules that are detachable from each other. Figure 5 The optical head 1 shown comprises two modules: a light transmission module 1a and a projection and collection module 1b. These will be described further below.

[0198] exist Figure 8 The optical architecture of one embodiment of the sensor system of the present invention is shown in the figure. Figure 8 The optical architecture of the embodiment is suitable for single excitation (i.e., a single light source 21) and single emission (i.e., a single detector 30).

[0199] Figure 8 The sensor system includes a light source device L, which includes a light source 21 and an input terminal of a supply optical waveguide device 10a, the input terminal being arranged to receive a beam of light including excitation light from the light source and propagate it to a second end of the supply optical waveguide device 10a.

[0200] The optical head includes optical devices forming an excitation optical path for excitation light, which includes, along the path, a second end of a supply optical waveguide device 10a, a first collimator device 23, an excitation filter 24, a dichroic mirror 25, a converging lens device 26, and a spherical lens 27 located in the optical aperture, which is used to converge the excitation beam to have a focal point in the wall portion including the contact point on the outer surface of the capillary 4.

[0201] The detector device D includes a receiving section 22 and at least one detector 30. The receiving section 22 includes an output terminal of a receiving optical waveguide device 10b, which is arranged to propagate and deliver emission signal light emitted by excited fluorescently labeled particles in the liquid in the capillary to the receiving section of the detector device.

[0202] In this embodiment, the receiving portion 22 of the detector device D includes a third collimator device 22a and an emission filter 22b.

[0203] The detector includes a photodetector 30b and a focusing lens 30a for focusing the emitted signal light toward the photodetector 30b.

[0204] The optical head 1 includes optical devices that form an emission signal light path for emission signal light emitted by excited fluorescent labeled particles. The emission signal light path includes a spherical lens 27, a converging lens device 26, a dichroic mirror 25, a reflector 28, a second collimator device 29, and an input end of a receiving optical waveguide device 10b.

[0205] The various optical components can be as described above.

[0206] The detector can be any kind of detector capable of detecting the transmitted signal. In the case of two or more detectors, the two or more detectors can be the same or different.

[0207] Figure 9 The optical architecture of the sensor system of the present invention shown in the embodiment is... Figure 8 The optical architecture of the embodiment differs in that the reflector (in) Figure 8 The number 28 is omitted, and the light source device L and the detector device D are set at a certain distance from each other. Figure 8 The optical architecture of the embodiment is more Figure 9 The optical architecture of the embodiment is more compact.

[0208] Figure 10 The optical architecture of the sensor system of the present invention shown in the embodiment is suitable for single excitation (i.e., one light source 21) and dual emission (i.e., two detectors 30', 30''). Figure 10 The optical architecture of the embodiment and Figure 8The optical architecture of the embodiment differs in that the detector device D includes two detectors 30', 30'', and the receiving section 22 includes a splitter 31, such as a wavelength splitter as described above, which separates the emitted signal light into two emitted signal light portions; and the two detectors are arranged to receive and detect the corresponding emitted signal light portions. Furthermore, each of the two detectors 30', 30'' of the detector device D includes a spectral filter 30c located between the focusing lens 30a and the photodetector 30b. Figure 10 In a variant of the illustrated embodiment, the spectral filter located between the focusing lens 30a and the photodetector 30b of each of the two detectors 30', 30'' is omitted. Figure 10 In another variant of the illustrated embodiment, the spectral filter is located before rather than after the focusing lens 30a.

[0209] Figure 11 The optical architecture of the sensor system of the present invention shown in the embodiment is suitable for dual excitation (i.e., two light sources 21', 21'') and dual emission (i.e., two detectors 30', 30''). Figure 11 The optical architecture of the embodiment and Figure 10 The optical architecture of the embodiment differs in that the light source device includes two light sources 21', 21'', which emit different excitation wavelengths to excite different fluorophores (fluorescent markers) of fluorescently labeled particles in the capillary. The optical waveguide device includes corresponding waveguides 10a', 10a'' for the excitation beams from the respective light sources 21', 21''.

[0210] Similarly, the two detectors 30' and 30'' of the detector device D each include a spectral filter 30c located between the focusing lens 30a and the photodetector 30b. Here, the separator 31 can separate the emitted signal light into a first part and a second part, wherein the first part of the emitted signal light includes emitted signal light from a fluorophore excited by light of one of the two light sources at a wavelength of light, and the second part of the emitted signal light includes emitted signal light from a fluorophore excited by light of the other of the two light sources at a wavelength of light.

[0211] Figure 12 The optical architecture of the sensor system of the present invention shown in the embodiment is suitable for dual excitation (i.e., two light sources 21', 21'') and single emission (i.e., one detector 30). Figure 12 The optical architecture of the embodiment and Figure 8 The optical architecture of the embodiment differs in that the light source device includes two light sources 21', 21'', which emit different excitation wavelengths to excite different fluorophores (fluorescent markers) of fluorescently labeled particles in the capillary.

Claims

1. A sensor system for fluorescence detection of fluorescently labeled particles in a liquid within a capillary, wherein the sensor system comprises a capillary mounting module, an optical head, a sliding plate, a light source adapted to deliver excitation light to the optical head, and a detector adapted to receive emitted signal light from the optical head. The optical head is mounted on or can be mounted on the sliding plate. The capillary mounting module includes a housing and a sliding plate receiving device. The housing includes a recess for mounting the capillary and a reading window leading to the capillary. The sliding plate receiving device is adapted to receive the sliding plate, allowing the sliding plate to slide from an offline position to an online position. The optical head includes an optical port for allowing light to pass through the reading window into and out of the capillary. The optical head includes a flange adjacent to the optical port. When the sliding plate is mounted with the optical head, the sliding plate is in an offline position when the flange is a certain distance away from the housing; and in an online position when the flange is in contact with the housing.

2. The sensor system of claim 1, wherein the sliding plate receiving device and the sliding plate are engaged or capable of being engaged via one or more sliders and rails, the sliders and rails respectively forming part of the sliding plate receiving device of the sliding plate and the capillary mounting module.

3. The sensor system according to claim 1 or claim 2, wherein the optical head includes a spherical lens at least partially located in the optical aperture, wherein when the optical head or a sliding plate mounted on the optical head is in an online position, the spherical lens is in contact with the outer surface of the capillary, preferably, when the sliding plate mounted with the optical head is in an online position, the spherical lens is in contact with the capillary.

4. The sensor system according to any one of the preceding claims, wherein when the optical head or a sliding plate mounted on the optical head is mounted to the sliding plate receiving device, the flange protrudes toward the housing, preferably, the flange is located near the optical port, more preferably, the flange completely or partially surrounds the optical port.

5. The sensor system according to any one of the preceding claims, wherein the sensor system includes a safety measure configured to prevent excitation light from being emitted via the optical port, the safety measure preferably being configured to prevent excitation light from being emitted via the optical port by comprising a pin device located at the housing of the capillary mounting module and an engagement opening in the optical head, wherein the pin device engages with the optical head via the engagement opening when the sliding plate mounted with the optical head is in an online position, wherein the sensor system is configured to prevent excitation light from being emitted via the optical port unless the pin device engages with the optical head.

6. The sensor system according to any one of the preceding claims, wherein the light source device comprises at least one light source and an input terminal of a supply optical waveguide device, the input terminal being arranged to receive a beam of light comprising excitation light from the at least one light source and propagate it to a second end of the supply optical waveguide device. The optical head includes optical devices forming an excitation optical path for the excitation light, the excitation optical path including, along the path, the second end of the supply optical waveguide device, a first collimator device, a dichroic mirror, a converging lens device, and a spherical lens, wherein the spherical lens is at least partially located in the optical aperture. The detector device includes a receiving section and at least one detector. The receiving section includes an output terminal of a receiving optical waveguide, which is arranged to propagate and deliver the emission signal light emitted by excited fluorescently labeled particles in the liquid in the capillary to the receiving section of the detector device. The optical head includes optical devices that form an emission signal light path for the emission signal light emitted by the excited fluorescent labeled particles, the emission signal light path including the spherical lens, the converging lens device, the dichroic mirror, the second collimator device and the input end of the receiving waveguide device.

7. The sensor system of claim 6, wherein the first collimator device is adapted to collimate light received from the second end of the supply optical waveguide device, wherein the light received from the second end of the supply optical waveguide device is preferably divergent light, optionally due to propagation into the free space of the first collimator device, and / or wherein the first collimator device is adapted to diverge the light before collimating the light.

8. The sensor system according to claim 6 or claim 7, wherein the second collimator device is adapted to focus the transmitted signal light to feed the transmitted signal light to the input of the receiving optical waveguide device, wherein the second collimator device is adapted to collimate the transmitted signal before diverging the light and then focus the transmitted signal light to the input of the receiving optical waveguide device.

9. The sensor system according to any one of claims 6 to 8, wherein the supply optical waveguide device and / or the receiving optical waveguide device independently comprise at least one of optical fiber, planar waveguide, silicon-on-insulator (SOI) waveguide and / or liquid optical waveguide.

10. The sensor system according to any one of claims 6 to 9, wherein the first collimator device is adapted to receive and collimate the excitation light and transmit the collimated excitation light to the dichroic mirror, wherein the dichroic mirror is adapted to reflect the collimated excitation light toward the spherical lens via the converging lens device, wherein when the sliding plate mounted with the optical head is in an online position, the converging lens device and the spherical lens converge the light beam to have a focal point in the wall portion including the outer surface contact point of the capillary, thereby causing the light beam to diverge in the liquid volume in the capillary to excite fluorescently labeled particles in the liquid volume.

11. The sensor system according to any one of claims 6 to 10, wherein the converging lens device is adapted to converge the excitation light and transmit the converged excitation light to the spherical lens.

12. The sensor system according to any one of claims 6 to 11, wherein the spherical lens is adapted to receive emission signal light emitted from excited fluorescently labeled particles in a liquid, preferably receiving emission signal light emitted from excited fluorescently labeled particles in the liquid volume, wherein the emission signal light propagates to the spherical lens in the form of divergent emission signal light, wherein the spherical lens causes the emission signal light to be transmitted toward the dichroic mirror via the converging lens device, wherein the spherical lens and the converging lens device are adapted to cause the emission signal light to diverge to have a beam diameter not exceeding the diameter of the converging lens device, and to cause the emission signal light to be transmitted toward the dichroic mirror in the form of convergent emission signal light, wherein the dichroic mirror is adapted to allow the convergent emission signal light to optionally pass toward the second collimator device via a mirror, wherein the second collimator device receives the convergent emission signal light and couples the light into the input end of the receiving optical waveguide device, wherein the first collimator device is preferably physically coupled to the input end of the receiving optical waveguide device.

13. The sensor system according to any one of claims 3 to 12, wherein the spherical lens has a diameter of 3 mm or greater, for example 3.5 mm or greater, for example up to 8 mm, preferably about 4 mm.

14. The sensor system according to any one of claims 3 to 13, wherein the spherical lens has a refractive index of 1.45 to 2 at λ = 589 nm, preferably the spherical lens comprises sapphire, ruby ​​and / or fused silica or one or more of the above materials, wherein the spherical lens optionally comprises a coating layer, such as an anti-reflective coating layer.

15. The sensor system according to any one of the preceding claims, wherein the light source device is adapted to generate and deliver the excitation light in the form of pulsed light, for example, pulsed light at a selectable frequency, such as pulsed light with a frequency of at least 1 kHz.

16. The sensor system according to any one of claims 6 to 15, wherein the optical device forming the excitation optical path for the excitation light comprises at least one excitation filter located between the first collimator device and the dichroic mirror, wherein the at least one excitation filter preferably has a selective bandpass that allows the excitation wavelength for the fluorescently labeled particles to pass through.

17. The sensor system according to any one of claims 6 to 16, wherein the dichroic mirror has at least one reflection bandwidth for selectively reflecting the wavelength of the excitation light, and at least one transmission band for transmitting the wavelength of the emitted signal light.

18. The sensor system according to any one of claims 6 to 17, wherein the converging lens device comprises: A biconvex lens having two identical or different convex surfaces; a plano-convex lens (PCX lens) having a flat surface facing the spherical lens; a doublet lens, such as a doublet comprising a positive lens and a negative lens, wherein the negative lens is closer to the spherical lens than the positive lens; or any combination thereof.

19. The sensor system according to any one of claims 6 to 18, wherein the converging lens device comprises an achromatic lens and / or apochromatic lens.

20. The sensor system according to any one of claims 6 to 19, wherein the optical head includes a mirror positioned to reflect emitted signal light from the converging lens device toward the second collimator device, the mirror preferably being a dielectric mirror having a reflection bandwidth that includes at least the wavelength of the emitted signal light, more preferably being a broadband dielectric mirror having a reflection bandwidth spanning at least 200 nm, for example at least 300 nm, for example 400-700 nm.

21. The sensor system according to any one of the preceding claims, wherein the detector device includes a receiving portion, at least one detector, and an output terminal of a receiving optical waveguide device, the output terminal being optically connected to the optical head for receiving emitted signal light from the optical head, wherein the receiving portion includes at least one emitted filter for filtering noise in the emitted signal light.

22. The sensor system of claim 21, wherein the at least one detector comprises a photodetector, such as a photodiode, avalanche photodiode, silicon photomultiplier, phototransistor, phototransistor and / or photomultiplier tube, preferably, the at least one detector comprises a photomultiplier tube module adapted to detect the intensity of the emitted signal light of the selected wavelength as a function of time, preferably, the at least one detector comprises a focusing lens for focusing at least a portion of the emitted signal light onto a detection portion of the at least one detector.

23. The sensor system of claim 20 or claim 21, wherein the receiving portion includes a beam splitter adapted to separate the emitted signal light wavelength into at least two emitted signal light portions, wherein the detector device includes a detector for each of the plurality of emitted signal light portions, wherein each detector is arranged to receive and detect the corresponding emitted signal light portion.

24. The sensor system according to claim 20 or claim 23, wherein the optical head includes a beam splitter adapted to separate the emitted signal light wavelength into at least two emitted signal light portions, wherein the beam splitter of the optical head is located in the emitted signal light path, preferably between the converging lens device and the second collimator device.

25. The sensor system according to any one of the preceding claims, wherein the detector device communicates with a computer system to receive data representing detected emitted signal light.

26. The sensor system according to any one of the preceding claims, wherein the light source device comprises at least one light source and an input terminal of a supply optical waveguide device, the input terminal being arranged to receive excitation light from the at least one light source, wherein the supply optical waveguide device is in optical communication with the optical head to deliver the excitation light to an optical element of the optical head, the optical element forming an excitation optical path for the excitation light to excite fluorescently labeled particles in a portion of the liquid in the capillary, wherein the light source is preferably a light-emitting diode (LED).

27. The sensor system according to any one of claims 6 to 26, wherein the light source device comprises at least two different light sources for generating excitation beams for corresponding fluorophores of particles of liquid in the capillary.

28. The sensor system of claim 27, wherein the supply optical waveguide device includes a corresponding transmission waveguide for a corresponding excitation beam, preferably, the optical device in the optical head forming an excitation optical path for the excitation light includes an excitation filter for each corresponding excitation beam, preferably located between the first collimator device and the dichroic mirror.

29. The sensor system according to claim 27 or claim 28, wherein the dichroic mirror is a multi-pass dichroic mirror.

30. The sensor system according to any one of claims 27 to 29, wherein the sensor system is adapted to perform fluorescence resonance energy transfer (FRET) measurements.

31. The sensor system according to any one of claims 26 to 30, wherein the sensor system has a dual-excitation and dual-emission optical architecture adapted to perform dual-excitation and dual-emission fluorescence measurements.

32. The sensor system according to any one of claims 6 to 31, wherein the optical head includes an optical transmission module, wherein the optical transmission module includes a portion of an optical device forming an excitation optical path for the excitation light, the portion including a second end of the supply optical waveguide device, a first collimator device, and optionally including an optional excitation filter, and includes a portion of an optical device forming the emission signal optical path, the portion including the second collimator device and the input end of the receiving optical waveguide device.

33. The sensor system according to any one of claims 6 to 32, wherein the optical head includes a projection and collection module, wherein the projection and collection module includes a portion of an optical device forming an excitation optical path for the excitation light, the portion including the dichroic mirror, the converging lens device and the spherical lens, and includes a portion of an optical device forming the emission signal optical path, the portion including the spherical lens, the converging lens device and optionally including an optional reflector.

34. The sensor system of claim 33, wherein the light transmission module and the projection and collection module are detachable from each other.

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