JP4593957B2 - Electro-optical detector - Google Patents

Description

  The present invention relates to an electro-optical detection device that detects the presence and concentration of a subject present in a biological fluid, and more particularly to an electro-optical detection device that is used by being embedded in a living body.

  In the field of diabetes treatment, it is important to control the patient's blood glucose level within the normal range in order to prevent complications such as diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy caused by diabetes It is. In order to control the blood glucose level of such patients, it is performed by monitoring the glucose concentration in the body over time, and it is recommended to measure many times every day, and continuous measurement is the most effective. It is said that.

  Conventionally, in order to monitor glucose concentration in a living body, blood is collected at regular intervals and measured, or an electrode sensor to which an enzyme that reacts with glucose such as glucose oxidase is attached is placed percutaneously in the body. And the method of measuring has been performed.

  However, in order to obtain continuous data, the blood sampling method is not practical because it requires great labor and pain for the subject. In addition, there is a situation where the electrode sensor can be continuously measured only for about three days.

  Technological development for continuously measuring the glucose concentration in a living body has been made for a long time. Schultz et al. Have reported a glucose sensor capable of continuous measurement using a microdialysis technique (Non-patent Document 1). In this method, concanavalin A is bound to the inner side of the dialysis tube connected to the tip of the optical fiber, and FITC-modified dextran is bound to concanavalin A, and FITC is formed by competitive reaction with glucose flowing from the outside through the dialysis tube. It utilizes the fact that dextran dissociates and the fluorescence intensity in the solution in the dialysis tube changes.

  On the other hand, a device that inputs and outputs a signal from a device embedded in a living body using wireless is disclosed (see Patent Documents 1 and 2). According to this technique, as a method of continuously measuring changes in glucose concentration in the body without damaging the living body, a detection device having an indicator layer that reversibly reacts with glucose and changes in fluorescence characteristics is placed in the living body. The glucose concentration is measured by implantation and changes in the amount of fluorescence, and data is derived outside the body by electromagnetic waves.

  Moreover, as what can be utilized for the indicator layer of such a detection apparatus, what covalently bonded to polystyrene the fluorescent substance reversibly couple | bonded with glucose, such as phenyl boronic acid, is proposed (refer patent document 3).

  In addition, various biological sugar components exist in biological components, and a fluorescent substance that can be specifically reversibly bound by glucose has also been proposed (see Patent Document 4).

  Furthermore, as an excitation light source for causing fluorescence to be emitted from these fluorescent materials, a smaller light source and a detection device that are easily embedded in the body have been proposed (see Patent Document 5).

  Although various detection devices and fluorescent substances have been proposed in this way, no device capable of continuously monitoring the glucose concentration in the body with high accuracy has been realized so far.

  One of the reasons is that the amount of fluorescent light emitted from the fluorescent material is very small with respect to the amount of excitation light. This is because in the case of a detection device that measures fluorescence, it is difficult to completely prevent excitation light from entering the detector, and erroneous detection due to excitation light occurs.

  In a general fluorescence spectrophotometer, the irradiation axis of the excitation light is set at a position of 90 ° with respect to the optical axis of the fluorescence to be measured, and further, the wavelength width of the excitation light and the wavelength of the fluorescence to be measured are measured by a prism or a diffraction grating. By preventing the wavelength widths from overlapping, the excitation light signal is designed not to be added to the fluorescence signal. When the excitation light enters the fluorescence detector, the signal from the excitation light is added as a bias to the fluorescence that changes depending on the analyte, so the change in signal relative to the analyte concentration change is relatively small and the response is Because it gets worse, it is designed in such a structure to avoid this.

  However, in a detection device in which downsizing is important in order to be able to be embedded, it is not possible to take a complicated structure like these fluorescence spectrophotometers.

Conventionally, in order to solve such problems, a detector is installed between the indicator layer and the light source to prevent direct excitation light from being incident on the detector, and to further prevent the excitation light from being incident on the detector. There has been proposed a detection device having a configuration utilizing the above (see Patent Document 6).
U.S. Pat. No. 4,550,731 U.S. Pat. No. 4,253,466 US Pat. No. 5,137,833 US Pat. No. 5,503,770 US Pat. No. 5,039,490 US Pat. No. 5,157,262 Diabetes Care Vol. 5 (1982) p. 245-253

  However, since the difference between the excitation light wavelength and the fluorescence wavelength of a fluorescent substance is generally about 0 to 100 nm as a peak wavelength, the emission spectrum of a light-emitting diode often used as a light source and the fluorescence wavelength to be measured overlap. There is a problem that it is very difficult to design a fluorescent material so that it does not become. In addition, since the excitation light is reflected or scattered in a small space and enters the detector, it is difficult to cut the excitation light to a level that can be ignored as compared with fluorescence using only an optical filter.

  On the other hand, since the fluorescence from the indicator layer is weakly diffused light, it is effective for highly sensitive measurement of glucose concentration in the living body to shorten the distance between the detector surface and the indicator layer as much as possible. However, when the indicator layer is brought closer, the emission portion of the excitation light is limited by the positional relationship with the detector, so that it is difficult to efficiently irradiate the entire area of the indicator layer with the excitation light, and the amount of emitted fluorescence is reduced. Furthermore, as described above, the addition of a bias signal to the detector due to the reflection and scattering of the excitation light causes a problem that the change in the detector signal with respect to the change in the glucose concentration is reduced and the sensitivity is lowered.

  Accordingly, an object of the present invention is to provide an electronic device capable of improving the sensitivity to a change in the concentration of a subject and monitoring the concentration of the subject in a living body more reliably in a small and transcutaneously implantable electro-optical detection device. An optical detection device is provided.

  The object of the present invention is achieved by the following means.

(1) In an electro-optical detection device that is embedded in a living body and measures a subject in the living body, a housing that keeps the inside liquid-tight, and a transparent layer that keeps the inside liquid-tight together with the housing and transmits light An indicator layer that includes fluorescent indicator molecules that are in close contact with the outer surface of the transparent layer and change in fluorescence characteristics in accordance with the concentration of the analyte; and the indicator layer inside the housing with the transparent layer interposed therebetween And a detector that converts the fluorescence from the indicator layer into an electrical signal, a plurality of light emitting units that are sandwiched between the indicator layer and the detector and emit excitation light, and An electro-optical detection device comprising: a light-shielding layer that is provided on the detector side of the light-emitting unit and shields light from the light-emitting unit toward the detector.

  (2) The light emitting unit is provided between the indicator layer and the detector to guide light emitted from a light source provided in the housing other than between the indicator layer and the detector. It is a waveguide opening surface of the optical waveguide.

  (3) The optical waveguide is an optical fiber having a circular cross section having a diameter of 0.02 to 1 mm.

  (4) The waveguide opening surface is characterized by comprising one or more light emitting surfaces continuously or intermittently in a length of 1 to 20 mm in the axial direction.

  (5) The light shielding layer has a concave shape in which a reflection surface is formed on the inner side, and the optical waveguide is disposed on the inner side of the concave shape.

  (6) The light shielding layer is a metal pipe having an opening that is opened so that light from the waveguide opening surface is directed only in the direction of the indicator layer.

  (7) The light shielding layer is a plating layer provided on a side surface of the optical waveguide other than the opening surface of the waveguide.

  (8) The light emitting section and the light shielding layer are provided between the transparent layer and the detector.

  (9) The light emitting unit and the light shielding layer are installed in a space provided inside the transparent layer.

  (10) The space is viewed with a liquid having the same refractive index as that of the transparent layer.

  (11) The light emitting unit is a light emitting element.

  (12) The transparent layer is made of quartz glass.

  (13) The transparent layer is a fluororesin.

  (14) The transparent layer has a thickness of 0.05 to 1.2 mm.

  (15) The indicator layer has a cover layer that does not transmit the excitation light.

  (16) The indicator layer includes a hydrogel layer that is disposed between the cover layer and the transparent layer and includes the fluorescent indicator molecule.

  (17) The cover layer includes carbon black.

  (18) The hydrogel layer has a thickness of 5 to 30 μm.

  (19) The indicator layer is characterized in that an outer surface has a height of 0.1 to 1 mm from an end of the housing around the indicator layer.

  According to the present invention, a transparent layer is disposed between the indicator layer and the detector, and a light emitting unit that emits excitation light is provided between the indicator layer and the detector, and light directed from the light emitting unit to the detector is shielded. Since the light shielding part is provided, the excitation light is not guided to the detector by reflection, refraction, and scattering inside the apparatus, and the fluorescence from the indicator layer can be efficiently guided to the detector. The detection sensitivity with respect to the concentration change is improved, and the glucose concentration in the living body can be monitored more reliably.

  Embodiments of the present invention will be described below with reference to the drawings.

  FIG. 1 is a perspective view showing an external appearance of an electro-optical detection device (hereinafter referred to as a detection device) according to the present invention, FIG. 2 is a partially broken perspective view showing an internal structure of the detection device, and FIG. 4 is a cross-sectional view taken along line AA in FIG. 1, and FIG. 4 is an enlarged cross-sectional view of portions such as an indicator layer, an optical waveguide, and a detector in the cross section shown in FIG.

  First, a schematic configuration of this detection apparatus will be described.

  This detection device 1 has a housing 11 that keeps its inside liquid-tight in appearance, a window portion 12 that exposes only the indicator layer, and an antenna portion 13 that communicates with a system outside the body.

  The inside of the detection device 1 is in contact with a bodily fluid in the body, and is provided so as to close the window portion 12 in order to keep the inside of the indicator layer 21 that senses the glucose concentration and to keep the inside liquid-tight. The layer 22, the light source 23 that emits the excitation light, the optical waveguide 24 that guides the light from the light source 23 to the indicator layer 21, the detector 25 that detects the fluorescence from the indicator layer 21, and the signal data from the detector 25 An integrated circuit 26 that processes the above and a battery 27 that is an internal power source are mounted.

  The indicator layer 21 is disposed in close contact with the outer side of the transparent transparent layer 22 that does not allow liquid to pass through. The transparent layer 22, together with the housing 11, makes the inside of the detection device 1 liquid-tight from the outside of the detection device 1.

  The detection device 1 guides light from the light source 23 through an optical waveguide 24 serving as a light emitting unit, and irradiates the indicator layer 21 as excitation light, whereby the indicator layer 21 exhibits fluorescence corresponding to the glucose concentration, The fluorescence is converted into an electric signal by the detector 25.

  The optical waveguide 24 is installed so as to be sandwiched between the indicator layer 21 and the detector 25. The light guided from the light source 23 is not irradiated to the detector 25 side by the light shielding layer 41, but only the indicator layer 21.

  The detector 25 is a light receiving element that receives the fluorescence from the indicator layer 21 and converts it into an electrical signal corresponding to the amount of received light.

  The integrated circuit 26 processes the electrical signal from the detector 25, temporarily stores it, and transmits it to the system outside the body from the antenna unit 13 installed on the outer surface of the housing in a timely manner.

  The antenna unit 13 is provided inside the antenna unit 13 so as to be embedded in a resin or the like so that the antenna coil 28 does not come into contact with body fluid.

  Hereinafter, the detection apparatus will be described in detail.

(housing)
The housing 11 may be anything as long as the inside can be kept liquid-tight, and is preferably made of metal or resin from the viewpoint of workability. In particular, in consideration of embedding in the living body percutaneously, for example, a titanium material having a proven record in biocompatibility is most preferable.

  The housing 11 is composed of two parts 11a and 11b on the upper and lower sides in the drawing, and the two parts 11a and 11b are engaged and joined to keep the inside liquid-tight.

  As shown in the figure, the housing 11 is manufactured to have a rounded shape with no corners, and the window 12 is covered with a cover layer (described later in detail) that comes into contact with the living body. It is made to be in a more indented position. Thereby, when it embeds in the living body, a mechanical stimulus is received by the housing 11 and the cover layer can be made difficult to receive a strong stress. In addition, inflammation in the vicinity of the cover layer can be suppressed, encapsulation by a thick collagen tissue can be suppressed, and a change in glucose concentration can be continuously measured more stably with good response.

  As for the size of the housing 11, that is, the size of the entire detection device 1, the maximum portion including the antenna unit 13 is preferably about 25 mm × 10 mm × 5 m. This is because the inspection device is embedded in the body, and the smaller one is preferable because the degree of invasion at the time of implantation is small. However, if it is too small, it is necessary to make the internal components small. For example, in the case of a battery, if the battery is too small, the capacity of the battery becomes too small and cannot be used for a long time.

  In the housing 11, the transparent layer 22 is fixed to the periphery of the window portion 12 of the housing 11 with an adhesive 50, and the integrated circuit 26 and the detector 25 are disposed on the spacer substrate 51. In this way, a predetermined distance 32 (details will be described later) is maintained between the detector 25 and the transparent layer 22. As described above, by maintaining the predetermined distance 32 between the detector 25 and the transparent layer 22 by the spacer substrate 51 and the spacer 52, a soft package made of resin other than metal is used as a member forming the housing. Even in this case, the predetermined interval 32 can always be maintained.

(Indicator layer)
The indicator layer 21 can be made of a hydrogel that allows body fluids to enter. In addition, the indicator layer 21 preferably includes at least two hydrogel layers that can diffuse at least glucose molecules as a subject from the body fluid and do not diffusely reflect the excitation light.

  In order to have such characteristics, the indicator layer 21 includes a fluorescent light emitting layer 47, and may be configured to include a cover layer 46 and a fluorescent light emitting layer 47 as shown in FIG.

  The cover layer 46 includes an absorbing material that absorbs excitation light so as to completely cover and cover the fluorescent light emitting layer 47 from the body tissue, and is disposed so as to completely cover the window portion 12. Thereby, the cover layer 46 can prevent the excitation light that has passed through the transparent layer 22 from leaking outside, and can prevent external light from entering the inside of the detection device. Therefore, the cover layer 46 can be used by the detector 25 to detect such light even when there is a slight amount of light reaching the detection device 1 through the skin or subcutaneous tissue when the detection device 1 is embedded in the body. It plays a role in preventing detection.

  Such a cover layer 46 includes a hydrogel and an absorbent that absorbs excitation light, and the same hydrogel as the fluorescent light-emitting layer 47 can be used.

  As the absorbent, the fluorescent indicator molecule itself can be used so as to have a high concentration up to a concentration at which almost no excitation light is transmitted. In this case, it is only necessary to increase only the concentration of the fluorescent indicator molecule by substantially the same procedure as that for producing the fluorescent light emitting layer 47 described later.

  The cover layer 46 may be manufactured by fixing a dye that absorbs excitation light from the light source 23 but does not emit fluorescence to the hydrogel. As such a dye, for example, carbon black that is inexpensive and well absorbs light of many wavelengths can be used in consideration of deterioration of the dye in the body.

  The fluorescent light emitting layer 47 is disposed on the body fluid side surface of the transparent layer 22. The fluorescent light emitting layer 47 includes a fluorescent indicator molecule that reversibly binds to glucose and changes in fluorescence characteristics depending on the glucose concentration. The fluorescent light emitting layer 47 is provided at least partially in close contact with the transparent layer 22.

  The fluorescent indicator molecules in the fluorescent light-emitting layer 47 may be any substance that reversibly binds to glucose and changes the fluorescence characteristics depending on the glucose concentration. As such a fluorescent indicator molecule, for example, a molecule having a functional group capable of binding to glucose at two phenyl boronic acid moieties and capable of binding to a hydrogel polymer chain is suitable.

  5 and 6 are diagrams showing examples of molecular structures of substances having such characteristics. Here, the substance having the molecular structure shown in FIG. 5 is called G1, and the substance having the molecular structure shown in FIG. 6 is called G2.

  These substances are introduced into polymers forming various hydrogels as follows, for example.

  G1 is a polyacrylamide copolymer containing acrylic acid, a hydrogel or water-soluble polymer containing a carboxyl group in the side chain such as polyalginic acid, 1-ethyl-3- (3-dimethylaminopropyl) carbodidiimide), or It can be introduced by an amino coupling method in which N-hydroxysuccinimide is additionally used. Alternatively, 2-isocyanatoethyl methacrylate having an isocyanate group may be bonded to a terminal amino group and then bonded to an acrylic monomer such as acrylamide to produce a hydrogel.

  As for G2, fluorescent indicator molecules can be introduced by binding to hydrogels or aqueous polymers having amino groups such as gelatin, collagen, polylysine and chitosan by amino coupling method.

  Polymers that form hydrogels include polysaccharides such as cellulose, dextran, alginic acid, pullulan and curdlan and their derivatives, polyamino acids such as gelatin and polyglutamic acid, acrylics such as polyacrylamide, polyacrylic acid and poly N-isopropylacrylamide. Water-soluble polymers and copolymers, modified polymers obtained by modifying a part of their side chains by esterification, polyethylene glycol, polyvinyl pyrrolidone and mixtures thereof can be used.

  In the substance into which these fluorescent indicator molecules are introduced, the fluorescence characteristics due to the excitation light increase when the glucose concentration increases (that is, the luminous intensity due to fluorescence increases).

  The thickness of the fluorescent light emitting layer 47 is 2 μm to 100 μm, more preferably 5 μm to 30 μm. In the case of 2 μm or less, this is not preferable because the amount of fluorescent indicator molecules in the fluorescent light-emitting layer 47 decreases and the amount of fluorescence due to binding to glucose becomes too small. On the other hand, when the thickness exceeds 100 μm, it is not preferable because it becomes too thick considering the size of the entire detection device 1 and the entire device must be enlarged.

  Such an indicator layer 21 is preferably provided on the transparent layer 22 at a position that is recessed by about 0.1 mm to 1 mm inside the detection device 1 from an end portion around the window portion 12 of the housing 11. Thereby, when inserting the detection apparatus 1 in a body, or at the time of handling, the possibility that the biological tissue or the surgical instrument hits the window 11 and the indicator layer 21 is destroyed can be reduced. Moreover, when the detection apparatus 1 is pushed from the outside of the body, the possibility that the indicator layer 21 is broken due to stress from the living tissue can be reduced.

(Transparent layer)
The transparent layer 22 may be a material that does not transmit light, particularly excitation light and fluorescence, and a material that does not transmit water (body fluid in the living body). Examples of such a material include shelf silicate glass, synthetic glass, quartz glass, synthetic quartz glass, acrylic resin such as polycarbonate, polyester, and polymethacrylate, cyclic polyolefin, and fluorine resin. Of these, quartz glass, synthetic quartz glass, and amorphous fluororesin are preferred because they have good durability in the body and good transmission of excitation light with a low wavelength.

  The adhesion between the indicator layer 21 and the transparent layer 22 is important from the viewpoint of reaching the stable detector 25 of the emitted fluorescence energy. In the case of the transparent layers 22 made of various kinds of glass, the indicator layer 21 may be bonded after coating with a silane coupling agent.

  The silane coupling agent used varies depending on the components of the hydrogel used for the indicator layer 21. For example, when an acrylic hydrogel is used and the indicator layer 21 is polymerized and synthesized on the transparent layer 22, a silane coupling agent having an acryloyl group such as γ-methacryloxypropyltrimethoxysilane can be used. When a hydrogel having a polyamino group such as gelatin is used, a silane coupling agent having an epoxy group such as γ-glycidoxypropyltrimethoxysilane can be used. In addition, when a polysaccharide such as cellulose is bound as a hydrogel, it may be aminated and then bound in the same manner as a polyamino acid, or the terminal reducing sugar moiety may be linked with γ- (2aminoethyl) aminopropyltrimethyl. It may be bonded to the transparent layer 22 treated with methoxysilane.

  On the other hand, when a fluororesin is used as the transparent layer 22, the hydrogel is aminated with an electron beam, a carboxyl group or a hydroxyl group is introduced, a silane coupling agent is used in the same manner as glass, or an introduced amino group is introduced. And acrylic acid can be amide-bonded with carbodiimide, and an acrylic polymer can be polymerized to adhere the indicator layer 21 and the transparent layer 22 together.

(light source)
The light source 23 emits excitation light applied to the indicator layer 21. For example, a light emitting diode (LED) or a semiconductor laser element can be used.

  The wavelength of the light source 23 is adjusted to the excitation wavelength of the fluorescent indicator molecule. The excitation light wavelength suitable for the fluorescent indicator molecule described above is 350 to 450 nm, and for example, a commercially available gallium nitride LED can be used.

  Light from the light source 23 is guided to the optical waveguide 24 and emitted to the indicator layer 21.

  One light source 23 may be provided, or a plurality of light sources 23 may be provided as many as the number of optical waveguides 24 described later.

(Optical waveguide)
FIG. 7 is a partial perspective view showing an example of the optical waveguide 24.

  As shown in FIGS. 3 and 4, the optical waveguide 24 is disposed from the light source 23 to between the detector 25 and the indicator layer 21. The light guided from the light source 23 is emitted from the waveguide opening surface 31 toward the indicator layer 21, and is irradiated to the indicator layer 21 through the transparent layer 22 as excitation light.

  In this example, the optical waveguide 24 is disposed under the transparent layer 22 so as to be separated into a plurality of pieces. This is because the front surface of the indicator layer 21 is uniformly irradiated with excitation light. In such an arrangement, a plurality of light sources 23 are provided, or a plurality of optical waveguides 24 are provided from one light source 23.

  Such an optical waveguide 24 is obtained by processing an optical fiber, for example. As shown in FIG. 7, the optical fiber 61 is tapered (cut obliquely as shown) so as to gradually reduce the cross-sectional area in the distal direction. Is. As a result, the core layer 62 of the optical fiber 61 is exposed from the cladding layer 63. Light is emitted from the exposed core layer 62.

  The waveguide opening surface 31 is light emitting surface light, and the length in the optical fiber axial direction may be set so as to sufficiently illuminate the indicator layer 21, but is preferably about 1 to 20 mm. If it is less than 1 mm, radiation of excitation light may be insufficient, which is not preferable. On the other hand, the maximum value may be adjusted to the length of the indicator layer 21. However, if the maximum value is longer than 20 mm, the entire apparatus may be increased accordingly, which is not preferable.

  In the optical waveguide 24, when the optical fiber 61 is installed, the side covered with the clad layer 63 that contacts the detector 25 may be further installed in the concave light shielding layer 41 that does not transmit light. . When installing in the light shielding layer 41, you may use the optical fiber which does not have a clad layer.

  Normally, the optical fiber 61 has little light leakage from the clad layer 63, but here the light is blocked by the light shielding layer 41 in order to prevent such slight light leakage from coming out to the detector 25 side. is doing. The inner side 43 (the side facing the optical fiber 61) of the light shielding layer 41 is preferably a reflective surface that reflects light so that more light can be emitted toward the indicator layer 21.

  Excitation light from the light source 23 is introduced from the left side of the optical fiber 61 shown in FIG. 7 and radiated upward from the waveguide opening surface 31 of the optical fiber 61.

  The cross section of the optical fiber 61 is generally circular, although it is generally commercially available, but it is not necessarily circular.

  For example, when a glass with heat resistance is used for the transparent layer 22 and a germanium-containing glass waveguide having a higher refractive index than that of the transparent layer 22 is produced by a CVD method, the cross section of the optical waveguide 24 deposited on a portion without a photomask is Generally square.

  When the CVD method is used in this way, it is necessary to scrape a part of the produced optical waveguide and surround it with a concave light shielding layer 41 having a width of several microns around the optical waveguide. In this case, as the light shielding layer 41, for example, a black paint may be applied, but it is preferable to perform metal plating by masking a portion through which fluorescence passes with a masking filter or a resin coat.

  The optical fiber 61 itself is a general type in which a cladding layer 63 having a refractive index lower than that of the core layer 62 is provided on a core layer 62 of acrylic resin, cyclic polyolefin resin, quartz glass, synthetic glass, fluororesin or the like that does not absorb excitation light. An optical fiber 61 having a composition can be used. In particular, the optical fiber 61 used as the core layer 62 made of synthetic quartz or amorphous fluororesin is preferable in order to efficiently induce the excitation action.

  The size of the cross section of the optical fiber 61 can be appropriately changed according to the size of the entire detection device 1 and the area of the detector 25 for obtaining the required sensitivity, and the cross section need not be circular. The maximum length of the cross section is suitably 0.02 mm to 1 mm. Moreover, the cross-sectional shape has the longest width | variety by the side of the indicator layer 21, and becomes short as it goes to the detector 25 side. As a result, the rate at which the optical fiber 61 obstructs the fluorescence from the indicator layer 21 is reduced, and the fluorescence reaches the detector 25 efficiently.

  Note that the method of forming the waveguide opening surface 31 of the optical fiber 61 includes, for example, a method in which the clad layer 63 is shaved all around and the shape like the tip of a pencil other than the method of taper-cutting the side surface as shown in FIG. It may be. In this case, the inner side of the light shielding layer 41 (the side facing the optical fiber 61) is particularly preferably a reflecting surface that reflects light.

  FIG. 8 is a perspective view for illustrating the shape of another waveguide opening surface 31.

  As shown in the figure, the shape of the waveguide opening surface 31 may be a defect portion that intermittently reaches the core layer 62 in the axial direction of the optical fiber 61 and may be used as the waveguide opening surface 31.

  The light shielding layer 41 may be any material that does not transmit at least excitation light. For example, the heat shielding material such as polyester, polycarbonate, polyolefin such as polyethylene or polypropylene, polyamide, polyurethane, polyacrylate, polyetheretherketone, or a copolymer thereof. Plastic resin or thermosetting resin mixed with carbon black, titanium oxide or the like so as not to transmit light, or metal plated or metal-deposited on them, stainless steel, copper, aluminum, titanium, magnesium, gold, etc. , And various other alloys, ceramics, and composite members of resin and metal or ceramics can be used. Among these, metal is more preferable because it can reflect excitation light in the direction toward the indicator layer 21 while reliably blocking excitation light.

FIG. 9 is a perspective view showing an example of a metal light shielding layer. The light shielding layer 41 is formed by, for example, cutting a part of a side surface of a stainless steel pipe 91 made of SUS316 as shown in FIG. 31 has an opening that is opened so that the light from 31 is directed only in the direction of the indicator layer 21. Further, the stainless pipe 91 is sealed so that one end portion 92 is not leaked with silver brazing or a carbon black-containing silicone caulking agent.

  The inner surface of the metal pipe can be easily roughened so as to easily diffuse the excitation light, and there is an advantage that the excitation light is more efficiently emitted to the entire surface of the indicator layer 21.

  The size of the light shielding layer 41, particularly the inner dimension of the light shielding layer 41, depends on the size of the optical fiber 61 and the axial distance of the indicator layer 21 to be irradiated, but the inner diameter of the optical fiber 61 The length obtained by adding 50 to 200 μm to the maximum length of the cross section is required to be 2 to 20 mm larger than the length equivalent to the axial distance of the indicator layer 21 to be irradiated. Therefore, the maximum length of the inner cross section of the light shielding layer 41 is about 120 μm to 1.4 mm according to the cross section of the optical fiber 61.

  If the inner diameter is less than the maximum length of the cross section of the optical fiber 61 plus 50 μm, it is difficult to insert the optical fiber 61 inside the light shielding layer 41, which is not preferable. In other words, the light shielding layer 41 and the optical fiber 61 are in close contact with each other. On the other hand, it is not preferable to increase the cross-sectional maximum length of the optical fiber 61 beyond 200 μm because a gap is formed between the light shielding layer 41 and the optical fiber 61, and light leakage occurs from the gap. The length in the axial direction is a length that does not cause light leakage and is determined in consideration of the size of the entire detection device, and is not particularly limited.

  With respect to the surface of the waveguide opening surface 31, a part of the surface 42 of the transparent layer 22 in contact with the waveguide opening surface 31, and the inner surface of the light shielding layer 41, the excitation light is appropriately scattered. Make it a rough surface that is not a mirror surface.

  This can be easily done with a paper file of about 2000, but in the case of the aforementioned CVD or a waveguide as small as 20 μm, a method of partially etching with light such as a YAG laser is preferable.

  As a result, the excitation light causes irregular reflection and refraction on the rough surface, and is emitted as diffused light from the waveguide opening surface 31, so that the surface of the indicator layer 21 in FIG. 4 can be illuminated more widely and uniformly. At this time, the light shielding layer 41 is installed in close contact so as to cover the transparent layer 22 and the optical fiber 61.

  At this time, there may be a space between the concave shaped light shielding layer 41 and the installed optical fiber 61. Preferably, however, the optical fiber 61 vibrates due to vibration of an inspection device or the like, and the indicator layer 21 for excitation light. In order to suppress a change in the intensity of irradiation, the optical fiber 61 may be fixed inside the concave light shielding layer 41 and / or the transparent layer 22. For fixing, when an adhesive is used or a plastic optical fiber 61 is used, heat welding may be performed.

  FIG. 10 is a cross-sectional view showing another example of a method for fixing the optical waveguide 24 and the light shielding layer 41.

  In the example shown in FIG. 10, the hole 101 into which the concave light shielding layer 41 can be inserted as it is is formed in the transparent layer 22, and the same refractive index as that of the transparent layer 22 is formed in the gap between the concave light shielding layer 41 and the hole 101. It is made by pouring a standard refraction liquid such as silicone oil or an acrylic thermosetting resin into it.

  As a result, the distance from the indicator layer 21 to the detector 25 can be shortened, and the weak fluorescence can be made more efficient than when the waveguide opening surface 31 is simply brought into close contact with the surface of the transparent layer 22 on the detector 25 side. Can be measured.

  However, in that case, care should be taken so that the surface of the waveguide opening surface 31 does not protrude above the concave light shielding layer 41 and the concave light shielding layer 41 does not tilt in the rotational direction with respect to the axis. It is.

  Although the above uses the member formed in the concave shape as the light shielding layer 41, the light shielding layer 41 may be one in which the optical fiber 61 is metal-plated.

  When the light shielding layer 41 by plating is used, metal waveguide that does not transmit light may be applied to the entire surface of the optical fiber, and then the waveguide opening surface 31 may be formed. In this case, the plated portion becomes the light shielding layer 41.

  Thereby, the optical waveguide 24 can be made more compact. Specifically, for example, compared to the case where a metal pipe is used as the light shielding layer 41, a place where the diameter has to be larger by about 0.1 mm than the maximum diameter of the optical fiber 61 is plated. Since the thickness is about several μm, it is possible to secure a more optical path when the fluorescence from the indicator layer 21 passes to the detector 25 side, and more efficiently transmit the fluorescence from the indicator layer 21 to the detector 25 side. it can.

  Furthermore, if plating is used, the distance between the indicator layer 21 and the detector 25 can be reduced by the distance of the thickness of the metal pipe.

  Furthermore, according to the present invention, as described above with reference to FIG. 10, the waveguide opening surface 31 of the optical fiber 61 is embedded in the transparent layer 22, the detector 25 and the indicator layer 21 are brought closer to each other, and the faint fluorescent light is more effectively emitted. It can be collected in the detector 25. It is clear that this effect is higher than that of using the above-described concave light shielding layer 41 obtained by processing a metal pipe, and depending on the thickness of the transparent layer 22, the fluorescence energy emitted to the detector 25 side is 80%. % Or more can reach the detector 25.

  The plating may be any material that can easily reflect the excitation light. For example, gold, silver, aluminum, nickel, or the like can be used. As a plating method, a general plating method such as electroless plating or post-deposition electroplating can be used.

  The surface of the optical fiber 61 during plating may be scraped off from the cladding layer 63, and there is no need to mirror-polish the surface when scraping off, and the excitation light emitted from the waveguide opening surface 31 is more uniform. In addition, the surface roughness of the waveguide opening surface 31 and the way of shaving may be adjusted so that the indicator layer 21 is efficiently radiated.

  Alternatively, only the portion of the transparent layer 22 with which the waveguide opening surface 31 is in contact may be roughened with a laser or a rotating grindstone to a depth of 1 to 50 μm, and then the waveguide opening surface 31 may be adhered or bonded.

(Detector)
The detector 25 may be a light receiving element capable of converting the light to be measured into an electric signal continuously or periodically, preferably over one year. For example, a commercially available silicon photodiode, phototransistor, etc. Can be used.

  As the detector 25, the size of the light receiving surface for converting fluorescence into an electrical signal is currently on the market, and it may be used as it is. In addition, even if it is a magnitude | size other than this, what is necessary is just to select an appropriate thing from the sensitivity, power consumption, and magnitude | size requested | required as the detection apparatus 1, and it is not limited.

  The detector 25 and the transparent layer 22 are installed with a slight gap 32 (see FIG. 4). This is to allow the optical waveguide 24 to be installed at the interval 32 and to allow the detector 25 to efficiently receive the fluorescence from the indicator layer 21. The space 32 (that is, the surface of the transparent layer 22 on the detector 25 side) is filled with a gas having a refractive index of approximately 1 or a gas such as nitrogen gas.

  The fluorescent indicator molecules in the indicator layer 21 receive excitation light, exhibit fluorescence according to the glucose concentration, and radiate it as diffuse light to the surroundings. The emitted fluorescence passes through the transparent layer 22, passes through the gap, is applied to the detector 25, and is converted into an electrical signal. At this time, the light emitted from the waveguide opening surface 31 is emitted only in the direction opposite to the detector 25, and as a result, the detector 25 is not directly irradiated with the excitation light.

  On the other hand, the surface of the transparent layer 22 on the detector 25 side is in contact with air having a refractive index of 1 or a gas such as nitrogen gas. Therefore, the total reflection angle of the excitation light at the interface 44 between the transparent layer 22 and the indicator layer 21 is necessarily larger than the total reflection angle at the interface 45 of the opposite transparent layer 22, and as a result, at the interface 44. It is substantially avoided that the totally reflected excitation light is irradiated on the detector 25, and the detector 25 can efficiently receive the fluorescent component from the indicator layer 21.

  By having this interval 32, coupled with the above-described light shielding layer 41, it is possible to reliably prevent the excitation light from entering the detector 25 and to receive the fluorescence efficiently by the detector 25. For example, the interval 32 is preferably 0.1 to 1.0 mm.

  Basically, the shorter interval 32 is preferable because the entire detection apparatus can be made smaller. However, by making the distance longer than the wavelength of the excitation light, the influence of the evanescent wave upon reflection can be ignored. Therefore, it is preferable. Therefore, the lower limit is preferably about 0.1 mm. The upper limit value is a distance for providing a space allowing the convex portion by the optical waveguide 24 and the light shielding portion 41 when assembling the detection device, while considering the size of the entire device. 24 and the light shielding part 41 are preferably set to about 1 mm, which is about the maximum value of the thickness. There may be a space between the optical fiber 61 and the transparent layer 22.

  Further, an optical filter that shields only the excitation light wavelength may be further provided on the surface of the detector 25. According to the present embodiment, as described above, due to the structure, only the fluorescence is received by the detector 25. However, it is assumed that manufacturing accuracy and unfortunately mixed dust and dirt are present. This is for preventing the irregular reflection of the excitation light from entering the detector 25. Therefore, the optical filter in front of the detector is not essential.

(Integrated circuit)
FIG. 11 is a block diagram illustrating a functional configuration of the integrated circuit.

  The integrated circuit 26 includes an amplifier 201, an analog / digital converter (A / D converter 202), a memory 203, a transmitter 204, and a CPU 205. In the operation of the integrated circuit 26, the amplifier 201 amplifies the electric signal from the detector 25, and the A / D converter 202 converts the amplified analog electric signal into a digital signal. The memory 203 temporarily stores this digital signal. The temporarily stored digital data is sent from the memory directly to the transmitter 204 according to the instruction of the CPU 205, and is transmitted from the transmitter 204 to the system outside the body through the antenna coil 28 in the antenna unit 13 installed on the outer surface of the housing. The

  Here, the integrated circuit 26 includes the CPU 205 and the memory 203, thereby enabling transmission of data indicating the detected glucose concentration in various forms. For example, the data from the detector 25 is continuously stored in the memory 203 and transmitted at a stage where it is accumulated to some extent or at predetermined time intervals, or bidirectional communication with an external system is performed, resulting in poor transmission. In some cases, data in the memory 203 is retransmitted in response to a command from the CPU 205. In addition, the memory 203 stores various settings such as an identification code (ID) for specifying the individual user, and these are read together with the data and transmitted together with the data when transmitting the data. May be. Further, the transmission frequency may be set in the memory 203 so that the set frequency of the transmitter can be changed to the frequency stored in the memory.

  Correspondingly, the external system includes an external antenna that receives a signal from the integrated circuit 26, a device that analyzes the received signal, and displays a glucose concentration.

  The integrated circuit 26 stores the data once in the memory 203 and then transmits the data. However, the present invention is not limited to this. For example, the integrated circuit 26 simply converts an analog signal from the detector 26 into a digital signal, and then directly transmits the data. You may make it transmit. In this case, a CPU and a memory are not always necessary. Further, after the electrical signal from the detector 25 is amplified, it may be transmitted directly to an external system as an analog signal. In this case, the A / D converter, the memory, and the CPU are not necessarily required.

  As described above, according to the present embodiment, the light from the light source 23 is guided by the optical waveguide 24 provided between the indicator layer 21 and the detector 25, and the optical waveguide 24 is connected to the detector 25. Since the light shielding layer 41 for preventing light leakage is provided, the light entering the detector 25 is structurally prevented, so that only fluorescence can be reliably received, and detection accuracy is improved. Can do it. Moreover, since the space | interval 32 was opened between the transparent layer 22 holding the indicator layer 21, and the detector 25, the penetration | invasion of the excitation light to the detector 25 can be suppressed from the relationship of the refractive index of light. ing.

  Note that the present invention is not limited to the embodiment described above. Hereinafter, the embodiment of the present invention will be further described. However, since the basic structure is the same as that of the above-described embodiment, only portions different from the above-described embodiment will be described.

  For example, the detection device 1 without the battery 27 may be used. A solar cell is provided in the detection device 1 instead of the battery 27, and the solar cell generates power by irradiating light from outside the body and uses it as a power source. By embedding the detection apparatus 1 itself in a shallow place in the skin, it is possible to generate sufficient power with light from outside the body.

  Also, by incorporating an electromagnetic induction coil, it is possible to generate an electromotive force in the coil by electromagnetic induction by applying a low frequency or a high frequency from the outside, and use it as a power source. In this case, the electromagnetic induction coil may also function as an antenna.

  In addition, the integrated circuit 26 and the battery 27 may be provided in a device outside the body, communicated with the body through lead wires, and the antenna coil 28 may be omitted.

  Further, a light source 23 that emits excitation light may be directly disposed between the detector 25 and the transparent layer 22.

  FIG. 12 is an enlarged cross-sectional view showing an example when the light source 73 is directly installed between the detector 25 and the transparent layer 22.

  As described above, when the light source 73 is directly installed between the detector 25 and the transparent layer 22, the LED chip serving as the light source 73 has a concave reflection surface on the LED chip side, and light leaks to the detector 25 side. It is installed on the non-light shielding member 76.

  For example, an LED chip that is currently on the market is approximately 0.35 mm square in a non-packaged state (not sealed with resin), so that even such a structure can be sufficiently reduced in size. . Further, in this case, the concave light shielding member 76 is made of a metal that conducts electricity, and as one electrode of the LED, fine electric wiring that communicates with this electrode is applied on the detector surface, while the transparent layer 22 It is also possible to provide a wiring structure for the LED automatically when this structure is assembled by applying fine wiring to the portion in contact with the LED chip to form the other electrode of the LED.

  Furthermore, in the above-described embodiment, glucose is detected as an analyte. However, the present invention is not limited to this, and other in-vivo substances can be detected as an analyte by changing the indicator molecule. . For example, the orange-red fluorescence of tris (4,7-diphenyl-1,10-phenanthroline) ruthenium (II) percolate can be used to measure the oxygen concentration in the body. Further, hydroxypyrenetrisulfonic acid can be used for measuring the concentration of carbon dioxide gas. When these are used, for example, they may be adsorbed to the hydrogel molecules of the indicator layer, or, similarly to G1 and G2 described above, functionally bondable functional groups may be connected and covalently bonded. .

  Furthermore, it goes without saying that the present invention can be variously modified by those skilled in the art, and these modified examples are also included in the scope of the technical idea of the present invention.

  The present invention can be used for continuously or intermittently detecting a subject embedded in a living body.

It is a perspective view which shows the external appearance of the electro-optical detection apparatus by this invention. It is a partially broken perspective view which shows the internal structure of a detection apparatus. It is sectional drawing which follows the AA line in FIG. It is an expanded sectional view of parts, such as an indicator layer in the cross section shown in FIG. 3, an optical waveguide, and a detector. It is drawing which shows the molecular structure of an example of a fluorescent indicator molecule. It is drawing which shows the molecular structure of an example of a fluorescent indicator molecule. It is a fragmentary perspective view which shows an example of optical waveguide itself. It is a perspective view for showing the shape of the other waveguide opening side. It is a perspective view which shows an example of metal light shielding layers. It is sectional drawing which shows the other example of the fixing method of an optical waveguide and a light shielding layer. It is a block diagram which shows the function structure of an integrated circuit. It is an expanded sectional view showing an example at the time of installing a light source directly between a detector and a transparent layer.

Explanation of symbols

1 ... detection device,
11 ... Housing,
12 ... window,
13 ... antenna part,
21 ... Indicator layer,
22 ... transparent layer,
23. Light source,
24: Optical waveguide,
25. Detector,
26: integrated circuit,
27 ... Battery,
28 ... Antenna coil,
31 ... Waveguide opening surface,
32 ... interval,
41 ... light shielding layer,
46 ... cover layer,
47. Fluorescent light emitting layer,
61 ... Optical fiber,
62 ... core layer,
63 ... cladding layer,
91 ... Stainless steel pipe,
73: Light source (LED chip).

Claims (9)

In an electro-optical detection device that is embedded in a living body and measures a subject in the living body,
A housing that keeps the interior fluid-tight;
A transparent layer that keeps the inside liquid-tight with the housing and transmits light;
An indicator layer that includes fluorescent indicator molecules that are in close contact with the outer surface of the transparent layer and change in fluorescence characteristics in accordance with the concentration of the analyte;
A detector that is provided inside the housing at a position facing the indicator layer across the transparent layer, and that converts the fluorescence from the indicator layer into an electrical signal;
A plurality of light emitting units that are sandwiched between the indicator layer and the detector and emit excitation light;
A light shielding layer that is provided on the detector side of the light emitting unit and shields light from the light emitting unit toward the detector;
An electro-optical detection device comprising:   The light emitting unit is an optical guide provided between the indicator layer and the detector for guiding light emitted from a light source provided in the housing other than between the indicator layer and the detector. 2. The electro-optical detection device according to claim 1, wherein the detection surface is a waveguide opening surface of the waveguide.   3. The electro-optical detection device according to claim 2, wherein the optical waveguide is an optical fiber having a circular cross section having a diameter of 0.02 to 1 mm.   3. The electro-optical detection device according to claim 2, wherein the waveguide opening surface is composed of one or more light emitting surfaces continuously or intermittently in a length of 1 to 20 mm in the axial direction.   3. The electro-optical detection device according to claim 2, wherein the light shielding layer has a concave shape with a reflection surface formed inside, and the optical waveguide is disposed inside the concave shape.   The said light shielding layer is a metal pipe which has an opening part opened so that the light from the said waveguide opening surface may go only to the said indicator layer direction, It is any one of Claims 2-5 characterized by the above-mentioned. The electro-optical detection device described.   6. The electro-optical detection device according to claim 2, wherein the light shielding layer is a plating layer provided on a side surface of the optical waveguide other than the waveguide opening surface.   The electro-optical detection device according to claim 2, wherein the light emitting unit and the light shielding layer are provided between the transparent layer and the detector.   The electro-optical detection device according to claim 2, wherein the light emitting unit and the light shielding layer are installed in a space provided inside the transparent layer.

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