ORDER FOR THE OPERATION OF A BIOSENSOR AND ORDER FOR THE DETERMINATION OF BLOOD GLUCOSE CONTENT

Description

[0001] The present invention relates to a fiber optic arrangement for operating a biosensor. The biosensor is particularly, although not exclusively, suitable for determining the glucose content in blood. The invention therefore also relates to an arrangement for determining the glucose content in blood.

[0002] Optical sensors are used, among other things, to evaluate fluorescent radiation. In many cases, an optical arrangement provides both excitation radiation and evaluates the radiation emitted by a suitable phosphor. The intensity of the emitted fluorescent radiation can be a measure of a parameter to be monitored.

[0003] For example, DE 10 2015 101 847 B4 describes an arrangement for examining a sample that can be excited by electromagnetic radiation. To separate the excitation radiation from the emitted measuring radiation, the arrangement has a first dichroic beam splitter with a first and a second prism, which are connected to one another at their base surfaces, and with a dichroic layer arranged between the base surfaces of the two prisms. A light source supplies electromagnetic radiation suitable for exciting the sample, which is coupled into the entrance surface of the first prism. Part of the radiation is reflected by the dichroic layer towards the sample, which is positioned behind an exit surface of the first prism. A detector serves to detect the electromagnetic measuring radiation emitted by the sample, passed through the beam splitter and exiting it at a measuring surface.A disadvantage of such arrangements is the sensitive and comparatively large structure, which makes their use in everyday situations and by untrained personnel impossible.

[0004] In Müller AJ, Knuth M, Nikolaus KS, Krivänek R, Küster F, Hasslacher C. "First clinical evaluation of a new percutaneous optical fiber glucose sensor for continuous glucose monitoring in diabetes". Journal of Diabetes Science and Technology 2013; 7(1):13-23. 2013 Jan 01, an arrangement with a glucose-sensitive sensor is described, which is designed as a biosensor at the end of an optical fiber. For this purpose, one or more fluorescent phosphors are arranged on the fiber and excited by excitation radiation. The excitation radiation is supplied by an LED and coupled into the fiber via a lens. In the specific application, the intensity of the emitted fluorescence radiation depends on the glucose content in the blood of a tissue into which the fiber can be implanted. The emitted fluorescence radiation is guided in the fiber to a detector, which evaluates it.In principle, such a biosensor is suitable for quasi-continuous blood glucose measurement, so that the values ​​provided can be fed, for example, into an insulin dosing unit to administer insulin to a patient as needed. However, the delivery of the excitation radiation and the evaluation of the fluorescence radiation emitted by the biosensor are technically difficult to implement in such small units, forcing the patient to carry a larger device.

[0005] DE 694 08 976 T2 describes a glucose monitor that includes a light source, a sensor, and a processor. The light source emits excitation light directed at the sample to induce fluorescence of glucose in the sample. The excitation light causes the sample to generate return light, which includes fluorescent light produced by any glucose in the sample. The sensor monitors the returning light and generates two signals representing the intensity of the light within two spectral wavelength bands. The first signal indicates the intensity of the returning light with a wavelength within a first wavelength band. The second signal indicates the intensity of the light within a second wavelength band. The processor processes the two electrical signals to determine the glucose concentration in the sample.The optical components used are fibers or waveguides for light transmission, a dichroic filter for separating the excitation light from the return light, an aperture with a slit, and a prism.

[0006] US 4,344,438 discloses a solution for in vivo measurement of the concentration of low-molecular-weight plasma components. It shows a fluorescence-based glucose sensor with a catheter-type measurement chamber, with the detection device and the light source device in optical contact with the chamber via optical fibers. The excitation light from the source passes through a filter to a semi-silvered mirror and is then focused onto the end of an optical fiber. In one embodiment, these components can be miniaturized by using an LED for the light source and a photodiode for the light detector, and by implanting the entire assembly into the body.

[0007] WO 2014 / 116597 A1 describes an optical system for detecting fluorescent light from a biological sample. The optical coupler used comprises a fiber for contacting a fluorescent body, a light-emitting diode, several filters, and a photodiode.

[0008] EP 2 989 975 A1 discloses a fiber optic glucose sensor comprising an element with proximal and distal end regions, wherein the proximal end region is configured for coupling to an optical device comprising an excitation light source and a detector. The distal end can be positioned in a blood vessel and comprises a cavity and a reflective surface, wherein the cavity comprises an indicator system.

[0009] DE 43 22 734 A1 and DE 43 41 086 A1 disclose an optical Y-coupler consisting of a continuous optical waveguide with a polymer cladding and a laterally merging optical waveguide with a polymer cladding. The continuous optical waveguide runs straight at the junction point, while the laterally merging optical waveguide runs at an angle α that is smaller than the critical angle for total internal reflection in the continuous optical waveguide. The continuous optical waveguide has a diameter of 50 to 6000 µm.

[0010] US 6,553,164 shows a waveguide-based Y-coupler consisting of 4 individual sub-elements.

[0011] DE 694 14 139 T2 describes a coupling arrangement between a multimodal light source and an optical fiber using an intermediate fiber, which is designed as an optical multimode intermediate fiber. The intermediate fiber has a partial region with the cross-section and a tapered partial region. A Y-coupler is formed by the tapered intermediate fiber.

[0012] US 2004 / 0072358 A1 describes a glucose detection device comprising a sensor, a light source, and a photodetector connected by an optical fiber. Furthermore, a Y-coupler is used, which is formed by an optical fiber split into two strands.

[0013] Based on US 2004-0072358 A1, one object of the present invention is to provide an improved arrangement for operating a biosensor. The arrangement should both provide the excitation radiation and be capable of detecting the measurement signals generated by the sensor with high sensitivity. A small, integrable structure, a secure mechanical connection to the biosensor, and high optical reliability should be achieved. Furthermore, one object is to provide an improved arrangement for determining the glucose content, particularly in blood, which allows for mobile, quasi-continuous measurement of the glucose content. These and other objects are achieved by an arrangement for operating a biosensor according to the appended claim 1.

[0014] The arrangement according to the invention for operating a biosensor has an excitation light source that generates at least one excitation beam for the biosensor. The arrangement further comprises a coupling fiber, to whose entrance surface the excitation beam is coupled. Furthermore, an optical Y-coupler is provided, which has an excitation arm connected to the exit surface of the coupling fiber, a detector arm connected to an optical detector, and a sensor base connectable to the biosensor. The detector arm and the sensor base preferably have a common main beam axis. The beam axis of the excitation arm extends to the main beam axis of the detector arm at an angle in the range of 5° to 70°, preferably 5° to 30°.The excitation arm has an elongated, conical shape, wherein the diameter of the excitation arm at the entry point into the detector arm is less than two-thirds of the diameter of the detector arm at this connection point, preferably less than half, particularly preferably less than one-third of the diameter of the detector arm.

[0015] The excitation light source is preferably formed by an LED chip that emits excitation radiation of, for example, 595 nm. The excitation radiation is adapted to the biosensor in terms of wavelength and optical power and can, for example, also contain two wavelengths if desired for the respective excitation purpose. The emission plane of the LED chip is preferably positioned at a distance from the input surface of the coupling fiber that is 0.1 to 10 times the diameter of the coupling fiber.

[0016] According to a preferred embodiment, the excitation light source is a planar, diffusely radiating emitter. Emission preferably occurs from a thin layer, as is the case with a thin-film LED, for example. Therefore, the excitation light source is particularly preferably formed by a thin-film LED.

[0017] The coupling fiber is preferably a PMMA fiber or a sapphire fiber, which, for example, has a spherical, aspherical, or flat entrance surface facing the excitation light source. The coupling fiber preferably has a constant diameter over its length in the range of 0.1 to 2 mm, more preferably 0.3 to 0.7 mm, particularly preferably 0.5 mm, and a length that is preferably 7 times to 13 times the distance between the excitation light source and the entrance surface of the coupling fiber, for example, 5 to 15 mm, particularly preferably 10 mm. The entrance surface of the coupling fiber is preferably spaced approximately 0.8 to 1.2 mm, particularly preferably approximately 1 mm, from the excitation light source, with the excitation beam preferably traveling in air at this distance. This distance ensures that only "flat beams" are coupled into the coupling fiber, i.e., beams that form only a small angle relative to the central axis of the coupling fiber.The emitting area of ​​the excitation light source preferably corresponds to 10 to 60% of the cross-sectional area of ​​the coupling fiber.

[0018] An advantageous embodiment is characterized by the coupling fiber having no curvature in the axial longitudinal direction, i.e., its longitudinal axis is straight. For example, the coupling fiber can be made of a rigid material or be guided in a non-curved sleeve.

[0019] According to a preferred embodiment, the exit surface of the coupling fiber is coupled to the excitation arm of the optical Y-coupler via a cut-off filter. This filter can filter out the wavelengths from the excitation radiation that correspond to the fluorescence wavelengths emitted by the biosensor, making them more easily detectable as measurement signals at the detector. The cut-off filter is formed, for example, as a carrier glass with applied filter layers. The exit surface of the coupling fiber can be glued to this carrier glass, although the glueing can also be done directly onto the filter layers.

[0020] A particularly preferred embodiment is characterized by a specially adapted beam guide that allows for optimized use of the available optical power. For this purpose, the aforementioned "flat beams" are coupled into the coupling fiber. "Flat beams" are defined as beams with a small angular deviation in the propagation direction. The use of such beams also allows for the efficient use of the cut-off filter, which cuts out certain wavelengths from the excitation radiation, thus preventing them from distorting the measurement result. The aim is for the excitation radiation to strike the surface of the cut-off filter as perpendicular as possible. This is achieved when the excitation radiation propagates through the coupling fiber at the smallest possible angular deviation from the longitudinal axis of the coupling fiber and thus strikes the cut-off filter with the smallest possible angular deviation from the perpendicular to the surface of the cut-off filter.Preferably, the excitation radiation in the coupling fiber runs at an angle <40° to the surface normal of the cut-off filter or to the core axis of the coupling fiber, particularly preferably at an angle <30°, in particular <25°.

[0021] An advantageous embodiment of the arrangement is characterized in that the diameter of the excitation arm decreases continuously from its entrance surface, which is optically coupled to the exit surface of the coupling fiber, towards the connection point with the detector arm (so-called tapered fiber). The excitation arm thus has the shape of an elongated truncated cone. At the connection point, i.e., at the position where the excitation arm, detector arm, and sensor base of the Y-coupler converge, the diameter of the coupling arm is thus significantly smaller than at its entrance surface. Preferably, the diameter of the excitation arm is reduced by more than half along its longitudinal extent. In particular, the excitation arm has a diameter in the range of 0.1 to 0.2 mm at the connection point with the detector arm.The tapering of the excitation arm serves primarily to form an optical valve, which enables the coupling of the excitation radiation into the sensor base, but at the same time minimizes the unwanted escape of the fluorescence radiation returned by the biosensor into the excitation arm.

[0022] According to a preferred embodiment, a piece of colored glass is located between the coated carrier glass, which adjoins the exit surface of the coupling fiber, and the entrance surface of the excitation arm. This piece supports the filtering effect of the cut-off filter. The piece of colored glass is designed like a waveguide and can also have a conical shape. A piece of colored glass is colored optical filter glass, such as that offered by Schott AG.

[0023] The Y-coupler is preferably made of plastic, particularly PMMA or PC. 3D printing or injection molding processes are suitable for this purpose. The diameter of the detector arm and the sensor base are preferably constant, for example, in the range of 0.4 to 0.6 mm, particularly 0.5 mm. The sensor base can advantageously have a longitudinal curvature at an angle of approximately 90° to allow for easy connection to the biosensor at its exit surface when the biosensor has been implanted into the tissue essentially perpendicular to the patient's skin surface.

[0024] A suitable embodiment has an additional piece of colored glass in the shape of a waveguide, which is arranged between the detector and the exit surface of the detector arm. This piece of colored glass, in turn, fulfills filtering functions. Furthermore, it is advantageous to arrange a lens and a filter in front of the detector to collimate the fluorescence radiation coming from the detector arm and to filter out any excitation radiation that may still be present.

[0025] The detector can preferably be implemented as a photodiode or a similar component. If multiple fluorescence wavelengths are to be detected, it may be advantageous to combine a beam splitter with several photodetectors of different sensitivities.

[0026] According to the invention, the sensor base serves not only for mechanical coupling to the sensor fiber but also for beam deflection. A toric surface is preferably formed in the sensor base for this purpose.

[0027] An arrangement according to the invention for determining the glucose content, in particular in the blood, comprises a biosensor and an arrangement for its operation according to one of the embodiments described here.

[0028] Further advantages and details of the invention will become apparent from the following description of preferred embodiments, with reference to the drawings. Fig. 1 shows a schematic diagram of a first embodiment of an arrangement according to the invention for operating a biosensor; Fig. 2 shows a schematic diagram of a second embodiment of the arrangement for operating the biosensor; Fig. 3 shows an optical beam path in a sensor base for beam deflection and coupling into or out of the sensor fiber with low optical losses.

[0029] Fig. 1shows a simplified side view of an arrangement for operating a biosensor. The biosensor is formed here as a sensor fiber 01, equipped at its free end with immobilized, glucose-sensitive fluorescent phosphors 02. When excited by excitation radiation, these fluorescent phosphors emit fluorescent radiation whose intensity depends on the glucose concentration in a medium in which the end of the biosensor is positioned. The medium can, in particular, be blood.

[0030] The arrangement for operating the biosensor has an LED chip 03 as the excitation light source, preferably a thin-film LED. The LED chip 03 emits the excitation radiation and couples it at a shallow angle into a coupling fiber 04. The angle between the excitation radiation and the core of the coupling fiber is preferably <30°. For this purpose, the LED 03, in the illustrated embodiment, is positioned approximately 1 mm from the entry surface of the coupling fiber 04. The entry surface of the coupling fiber can be designed as a freeform, spherical, aspherical, or flat surface. The coupling fiber 04 has, for example, a diameter of 0.5 mm and a length of 10 mm. The exit surface of the coupling fiber 04 is attached to a carrier glass 07 with an adhesive 06.The carrier glass 07 is equipped with one or more filter layers 08 to act as a cut-off filter and filter out the wavelength of the fluorescence radiation emitted by the fluorescent phosphors 02 from the excitation radiation. In the propagation direction of the excitation radiation, the carrier glass 07 is followed by a first piece of colored glass 09, which supports the effect of the cut-off filter. The first piece of colored glass 09 is designed in the shape of a waveguide and, on the opposite side, connects to an excitation arm 11 of an optical Y-coupler 12. The excitation arm 11 and the first piece of colored glass 09 have a cross-section that tapers in the direction of radiation. The diameter of the excitation arm 11 at its end facing away from the coupling fiber 04 is therefore, for example, only 0.1 to 0.2 mm.

[0031] The Y-coupler 12 also has a detector arm 13 and a sensor base 14. At a connection point 16, the excitation arm 11 enters the material that otherwise extends from the detector arm 13 to the sensor base 14. At the connection point 16, the detector arm 13 and the excitation arm 11 form an angle in the range of 5° to 70°, preferably 5° to 30°, particularly preferably approximately 15°. The main beam axes of the detector arm 13 and the sensor base 14 run coaxially in the embodiment shown. In modified versions, the main beam axes of the detector arm and the sensor base can also run at an angle to one another, for example with an angular change of 10° to 40°. The sensor base 14 is designed to be flexible or curved at its end facing away from the connection point 16 in order to be able to be connected to the sensor fiber 01. The detector arm 13 and the sensor base 14 have a diameter of, for example, 0.5 mm.

[0032] The excitation radiation is guided from the LED chip 03 via the coupling fiber 04, the excitation arm 11, and the sensor base 14 into the sensor fiber 01, where it excites the fluorescent phosphors 02. The fluorescent radiation emitted by these phosphors travels through the sensor fiber 01 back to the sensor base 14 of the Y-coupler 12 and then, for the most part, into the detector arm 13. A second piece of colored glass 17, formed in the shape of a waveguide, is attached to the end of the detector arm 13 facing away from the connection point 16. An optical lens 18 is provided to collimate the fluorescent radiation emerging from the exit surface of the second piece of colored glass 17. This lens is followed by a further filter 19 to allow only the fluorescent radiation to pass through to a subsequent detector 21.

[0033] Fig. 2 shows a modified embodiment of the arrangement for operating the biosensor, which initially has the structure according to Fig. 1largely coincides. One difference is that the detector is divided into two sub-detectors 21a and 21b, which serve to detect different wavelengths of the fluorescent radiation. For this purpose, a beam splitter 22 is located behind the filter 19 in the beam direction. This beam splitter splits the fluorescent radiation into two partial beams depending on the wavelength, which are then fed to the respective sub-detectors 21a, 21b. The second piece of colored glass 17 supports the effect of the filter 19.

[0034] Fig. 3shows an example of the optical beam path in the excitation arm 11, in the detector arm 13, in the area of ​​the connection point 16 and especially in the sensor base 14. The sensor base 14 serves to deflect the beam and couple it into or out of the sensor fiber and at the same time creates the possibility of a distance of several 100 µm between the sensor base and the sensor fiber, which significantly simplifies positioning. As already shown in the Figures 1 and 2 As can be seen, the sensor base 14 is preferably curved or bent in order to be easily connected to the sensor fiber 01 and to realize a beam deflection. The entrance surface on the excitation arm 11 and the exit surface on the sensor base 14 are thus at an angle of more than 45°, preferably approximately 90°, to each other. The connection point 16 is particularly preferably optically designed in the manner of a funnel, as the beam path in Fig. 3 clarified.

[0035] The funnel-shaped design of the connection point 16 also offers a significant advantage for the optical return path, i.e., the path of the fluorescent light guided from the sensor fiber 01 back to the detector 21. The beam guidance shown minimizes optical losses up to the point where the excitation arm meets the detector arm. The comparatively low emissions emanating from the fluorescent phosphors 02 can thus be particularly well analyzed at the detector. This allows a distance of several hundred µm to be achieved between the sensor base and the sensor fiber, which is a significant advantage for practical setups.

[0036] Preferably, a lens 23 is formed on the side of the sensor base 14 facing the sensor fiber 01, preferably integrated into the material of the sensor base. The lens 23 is located behind the toric surface in the direction of the excitation radiation in order to focus the excitation radiation onto the input end face of the sensor fiber 01. The lens can be formed as a spherical or aspherical lens and can optionally be anti-reflective.

[0037] Particularly preferably, the numerical aperture which results after the lens 23 on the sensor base 14 in the direction of the sensor fiber 01 is adapted such that it essentially corresponds to the numerical aperture of the sensor fiber.

[0038] According to a preferred embodiment, the excitation arm 11 widens in diameter in the area of ​​the connection point 16, as can be seen on the steel profile in Fig. 3This expansion is preferably achieved by a linear, or alternatively, a non-linear, increase in diameter in the direction of the sensor base 14. The surface lines of the resulting cone of expansion in the longitudinal section can thus be of any shape.

[0039] In the area of ​​the curvature of the sensor base, the beams are deflected, preferably on a toric surface 24, which can be mathematically described as follows: z = C ∗ y 2 1 + 1 − C 2 ∗ 1 + KK ∗ y 2 where the first radius of the toric surface refers to the X-axis (radius around an axis in the X-direction) (R_um_X; C = 1 / R_um_X); KK = conic constant; the Y-coordinate is inserted in the formula as y and the Z-coordinate is obtained for the case that the toric surface has its origin at the point Y=0 and Z=0 and is not rotated 45° counterclockwise; the second radius of the toric surface refers to the Y-axis (radius around an axis in the Y-direction), in the case that the toric surface is not rotated 45° counterclockwise.

[0040] Reflection at the toric surface preferably occurs as total internal reflection. For example, an additional reflective layer can be applied in this area. This is useful. If the refractive index of the material in the sensor base is too low, total internal reflection is not possible. In this case, an additional reflective layer can be applied to the toric surface.

[0041] This design ensures that the excitation radiation travels from the excitation arm 11 through the widened portion in the area of ​​the connection point 16 and the toric surface 24 to the lens 23 in the material of the excitation arm. Only at the lens 23 does a transition to air or gas occur, and then into the sensor fiber 01. Reference symbol

[0042] 01Sensor fiber 02Fluorescent phosphors 03LED chip / LED 04Coupling fiber 05-- 06Adhesive 07Carrier glass 08Filter layers 09First colored glass piece 10-- 11Excitation arm 12Y-coupler 13Detector arm 14Sensor base 15-- 16Connection point 17Second colored glass piece 18Lens 19Filter 20-- 21Detector 22Beam splitter 23Aspherical lens 24Toric surface

Claims

1. An arrangement for operating a biosensor (01) emitting radiation, comprising: - an excitation light source (03), which generates at least one excitation radiation for the biosensor; - a coupling fiber (04), at the entry surface of which the excitation radiation is coupled in; - an optical detector (21); and - an optical Y-coupler (12) including an excitation arm (11), which is connected to the exit surface of the coupling fiber (04), a detector arm (13), which is connected to the optical detector (21), and a sensor foot (14), which can be connected to the biosensor (01); wherein the excitation arm (11) having a conical shape, wherein the radiation axis of the excitation arm (11) forms an angle in the range of 5° to 70° with the main radiation axis of the detector arm (13) at a connecting point (16) between the detector arm (13) and the excitation arm (11), wherein the diameter of the excitation arm (11) at the connecting point (16) to the detector arm (13) being less than two thirds of the diameter of the detector arm (13), and wherein the excitation arm (11) has a cross-section tapering in the direction of radiation.

2. The arrangement according to claim 1, characterized in that the diameter of the excitation arm (11) at the connecting point (16) is less than half as large as at the entry surface thereof.

3. The arrangement according to claim 1 or 2, characterized in that the detector arm (13) and the sensor foot (14) have a shared main radiation axis.

4. The arrangement according to any one of claims 1 to 3, characterized in that the excitation light source is an LED chip (03), the emission plane of which is positioned at a distance of 0.1 to 10 times the diameter of the coupling fiber from the entry surface of the coupling fiber (04).

5. The arrangement according to claim 4, characterized in that the coupling fiber (04) has a length that is 7 times to 13 times the distance between the excitation light source (03) and the entry surface of the coupling fiber (04), in particular in the range of 7 to 13 mm.

6. The arrangement according to claim 4, characterized in that the entry surface of the coupling fiber (04) is designed as a planar, spherical, aspherical or free-form surface.

7. The arrangement according to any one of claims 1 to 6, characterized in that a cut-off filter (07, 08), which filters the wavelength of the radiation emittable by the biosensor (01) out of the excitation radiation, is arranged between the exit surface of the coupling fiber (04) and the entry surface of the excitation arm (11).

8. The arrangement according to any one of claims 1 to 7, characterized in that the coupling fiber (04) is designed with a rectilinearly extending longitudinal axis.

9. The arrangement according to claim 7 or according to claim 8 referenced to claim 7, characterized in that the cut-off filter is composed of a carrier glass (07) including optical filter layers (08) applied thereon, wherein the exit surface of the coupling fiber (04) preferably being glued to the filter layers (08).

10. The arrangement according to any one of claims 1 to 9, characterized in that a lens (18) is arranged between the exit surface of the detector arm (13) and the detector (21) for collimating the radiation emitted by the biosensor (01), wherein an optical filter (19), which blocks incoming fractions of the excitation radiation, is arranged between the lens (18) and the detector (21).

11. The arrangement according to any one of claims 1 to 10, characterized in that a colored glass piece (17) in waveguide form is arranged at the exit-side end of the detector arm (13).

12. The arrangement according to any one of claims 1 to 11, characterized in that the sensor foot (14) comprises a curved section, in which a beam deflection is carried out at an angle of more than 45°, and preferably of approximately 90°.

13. The arrangement according to claim 12, characterized in that a beam-deflecting, toric surface (24) is formed in the sensor foot (14).

14. An arrangement according to any one of claims 1 to 13, characterized in that it is still designed for determining the glucose content, in particular of blood, and comprising the biosensor (01, 02), which can be implanted into tissue and emits radiation upon excitation.;15. The arrangement according to claim 14, characterized in that the biosensor is formed as an optical fiber (01), which includes glucose-sensitive fluorescent luminophores (02) at the exit surface thereof, which upon excitation by the excitation radiation emit fluorescent radiation having a fluorescent wavelength.