JP5002266B2 - Body fluid collection device - Google Patents

Description

  The present invention relates to a body fluid collecting device for analyzing and quantifying components contained in body fluids such as blood, lymph, and intercellular fluid. More specifically, the present invention relates to a bodily fluid collecting apparatus that is more convenient and accurate and has a high merit for the subject, such as being less contaminated with contamination even when self-collecting bodily fluids.

  In recent years, with the increase in social health awareness and lifestyle-related diseases due to changes in eating habits and lifestyles, the importance of health checkups and medical checkups has increased along with the progress of examination methods. On the other hand, due to the increase in medical expenses due to the declining birthrate and aging population, the momentum for grasping one's own health condition is increasing. In fact, in addition to measuring blood glucose levels, other biochemical tests such as liver function tests, immunological tests such as infectious diseases and tumor markers, etc. are collected in the name of postal medical examinations, and blood is collected by themselves and sent to the appropriate laboratory. The mailing system is starting to work.

  Furthermore, the development of devices for in-situ inspection of body fluids collected by themselves using microfabrication technology and microfluidic control technology has been promoted. With respect to such a test microdevice, the following techniques are disclosed as examples of techniques related to collection of body fluids and collected body fluid samples.

Japanese Patent Application Laid-Open No. 2002-263085 discloses a method and apparatus for collecting a trace amount of blood that can complete a series of blood collection operations by simply pressing the collection mechanism against the skin surface of the blood collection site with a finger or the like. Japanese Patent Laid-Open No. 2003-083958 discloses that the outer periphery of a syringe is surrounded by a cylinder so as to maintain airtightness, the inside of the cylinder is negatively pressured to suck the skin, and the needle is punctured by raising the skin into a convex shape. A blood collection method is disclosed. According to the publication, the syringe can be surely positioned and fixed by this puncturing method. Japanese Patent Laid-Open No. 2000-185034 discloses a configuration in which a blood collection needle having a hollow portion inside a bowl body formed of silicone in a minute needle shape, a pump portion, and an analysis portion are arranged on the same substrate. A blood collection analyzer is disclosed.
JP 2002-263085 A Japanese Patent Laid-Open No. 2003-083958 JP 2000-185034 A

As described above, in the bodily fluid collection device according to the prior art, the liquid transport element, the analysis element, and the puncture means such as the collection needle are interlocked so that the collected body fluid such as blood does not touch the outside, and the body fluid It is devised so that only a small amount of sample is required. However, in these apparatuses, the puncture means basically performs puncture by approaching the skin or mucous membrane surface of the living body, and the body fluid taken out from the body after the puncture is sucked by a special mechanism provided on the apparatus side. Therefore, the configuration of the apparatus is often complicated. Therefore, it is considered extremely useful to provide a body fluid sampling device that satisfies at least the following required performance.
(1) The psychological barrier to puncture is reduced, and the subject can actively and voluntarily control the pain associated with puncture.
(2) The bodily fluid taken out from the body by the puncturing means can be transported into the apparatus with a simple configuration without providing any special suction means or suction mechanism on the apparatus side.

  An object of the present invention is to provide a body fluid sampling device and a body fluid analyzer having a configuration that satisfies the required performance.

The body fluid collection device of the present invention is a body fluid collection device for collecting body fluid from a body fluid collection surface of a living body,
A housing having an internal region that can be sealed;
A pressing portion to the body fluid collection surface provided in a part of a partition wall that partitions the internal region from the outside;
A puncture means disposed in the internal region, for piercing the body fluid collection surface and leaching the body fluid to the body fluid collection surface;
Negative pressure generating means for generating a negative pressure in the internal region;
Have
The puncturing means is provided at a position where the body fluid collection surface can be pierced by forming a through-hole through the pressure portion by pressing the body fluid collection surface to the pressing portion,
The negative pressure generating means is to have a mechanism for generating a negative pressure in the interior region with the elimination of the pressing force when the body fluid sampling surface is separated from the pressing portion,
The bodily fluid collecting device according to claim 1, wherein the bodily fluid to be exuded on the bodily fluid collecting surface is collected through a through hole formed through the pressing portion .

  By adding a body fluid analyzing means to this body fluid collecting device, a body fluid analyzing device with a body fluid collecting function can be provided.

  According to the present invention, it is possible to provide a body fluid collecting device that satisfies at least the required performances (1) and (2) mentioned above. As a result, testing of infectious diseases, health conditions, and illness conditions can be performed easily and with few psychological barriers for the subject, either by the subject himself or by a person in charge at a hospital or laboratory, etc. Will be able to. In addition, the body fluid collecting device of the present invention can puncture by the self-collection of the blood collection person himself, for example, when blood collection is performed from the fingertip, so that it is possible to perform blood collection processing with one hand without the need for a special support. . In this case, it is possible to assign a blood collection site on the surface film (103 in FIG. 1) in which the puncture needle is previously stored, and then apply force to puncture and collect blood. It is possible to collect body fluid. Furthermore, since the bodily fluid collecting device of the present invention collects bodily fluid through the membrane (103 in FIG. 1), the air contact time of the bodily fluid is extremely short, and the deterioration of the bodily fluid due to oxygen in the air can be minimized. As a result, an accurate inspection can be performed.

  A preferred embodiment of the body fluid sampling device of the present invention will be described with reference to FIG. FIG. 1 is a diagram schematically showing a configuration of a body fluid sampling device of the present invention, (A) is a longitudinal sectional view thereof, and (B) is a plan view thereof. This liquid collection device has a configuration in which the puncture means 102 is arranged on the support 104 in the inner region of the housing 101 so as to face the membrane 103 that forms a pressing portion against the body surface as a liquid collection surface of the living body. . Further, a check valve 105 is installed in a part of the housing 101 to allow a gas flow from the inside to the outside and to prevent a gas flow from the outside to the inside.

  The puncture means 102 only needs to have a protrusion whose tip can be pierced into the body surface. A needle or the like can be used as the puncturing means. In the case of a needle, a stainless needle is most commonly used, but any material needle can be used as long as sufficient strength and safety are ensured for puncturing. For example, silicone or reinforced plastic needles may be used in some cases. The puncturing means only needs to have a puncture function at the tip thereof sufficient to extract body fluid such as blood by piercing the body surface, and guide the body fluid that has exuded to the body surface to the inside of the housing. What further has the structure made easy is preferable. When a needle is used, a hollow structure needle having a hole penetrating to the support 104 or a structure for guiding body fluid such as a continuous minute groove reaching the support 104 on the side surface is provided in the axial (length) direction of the needle. The needle applied to is preferred. In addition, the diameter, length, tip structure, number of arrangement on the support, and arrangement state of the needle can be appropriately selected according to the type and size of the body surface such as the fingertip, the type of body fluid, and the like.

  Puncturing means 102 is supported by support 104. In the example shown in the figure, the support 104 is also provided with a function of storing the body fluid introduced. Usually, a hard sponge-like substance, a porous substance, or a film-like substance having sufficient strength to support the puncture means 102 is used for the support 104.

  The film 103 forms part of a partition wall that separates the internal region and the outside of the casing 101 and forms a pressing portion to the body surface. The film 103 is formed of an elastic body. When the film 103 is pressed by a body surface such as a fingertip, the film 103 is bent by the pressure applied to the film 103 from the body surface, and the film 103 is in a bent state. Has a repulsive force to return to the state before bending. Due to this bending, two operations are performed simultaneously: an operation for obtaining a negative pressure in the internal region of the apparatus and an operation for piercing the body surface with the puncturing means. The pressing operation of the membrane 103 to the body surface can be performed by pressing from at least one side of the apparatus and the body surface.

  In the operation for obtaining the negative pressure, first, the membrane 103 is bent toward the inner region side of the apparatus, so that a positive pressure state is formed on the inner region side. As a result, a volume of gas (air) corresponding to the amount of deflection of the membrane 103 toward the device internal region side is discharged from the internal region to the outside through the check valve 105. From that state, when the body surface that is applying pressure to the membrane 103 is moved away from the membrane 103, the pressure applied to the membrane 103 by the body surface is released, and the membrane 103 is not yet bent by its elastic repulsion. Try to return to the state. At that time, the check valve 105 allows communication from the internal region to the outside and has a function of preventing the inflow of gas from the outside to the internal region. Negative pressure is generated.

  In the puncturing operation on the body surface, the membrane 103 reaches the tip of the puncturing means 102, and the puncturing means 102 penetrates the membrane 103 by further pressurization and punctures the body surface. As a result, body fluid such as blood exudes from the body surface.

  The exuded body fluid is held between the body surface and the outer surface of the membrane 103. On the other hand, when the tip of the puncture means 102 penetrates the membrane 103 at the time of pressing, a through hole is opened in the membrane 103, and body fluid is caused by the negative pressure generated in the apparatus as described above through the through hole. Effectively induced. That is, when the external air flows into the membrane 103 through the through hole opened by the puncture means 102 to compensate for the negative pressure in the internal region of the apparatus, the body fluid that has exuded from the body surface simultaneously It is sent inside the device.

  When a needle having a hollow structure is used as the puncture means 102, body fluid can be efficiently introduced into the apparatus from both the gap between the side surface of the needle and the membrane 103 and the hollow portion of the needle. In addition, when a needle having a minute groove extending continuously in the axial direction is used on the side surface, a minute passage for bodily fluid can be provided in the gap between the side surface of the needle and the membrane 103, and the body fluid can be passed through the minute passage. It can be effectively guided into the device. Furthermore, since the membrane 103 is formed of an elastic body, the body fluid that has exuded to the contact portion of the body surface, the membrane 103 and the puncture means 102 can be satisfactorily retained, and the introduction of the exuded body fluid into the apparatus is ensured. Can be done.

As described above, the following phenomena (1) and (2) occur in an instant by pressing the film 103.
(1) When the membrane 103 is pressed, the internal air escapes from the back valve 105 by the amount pressed.
(2) When the pressure is released, the membrane 103 returns and at the same time the body fluid exuded by the puncture is introduced into the inside from the micropores of the membrane 103 formed by the puncture means 102.

  As the elastic body constituting the film 103, a rubber-like material having elasticity such as silicone rubber can be suitably used.

  Further, by forming the support 104 with a porous material such as a sponge, body fluid introduced into the internal region of the apparatus can be easily collected in the support. After collecting the body fluid, the entire support 104 can be taken out of the apparatus and used as a sample for various tests.

  By disposing the body fluid analyzing means in the body fluid collecting device, a body fluid analyzing device with a body fluid collecting function can be obtained. FIG. 2 shows a preferred example of such an analyzer. 2A is a longitudinal sectional view of the analyzer, and FIG. 2B is a plan view of the analyzer. This apparatus also has a puncturing means 202, a membrane 203, a support 204, and a check valve 205, and these functions are the same as those in FIG. In this apparatus, in addition to the strength sufficient to support the puncture means 202, a filter function for separating blood cells is added to the support 204 in order to cope with the case where blood is used as a body fluid sample as a specimen. ing. As a specific material for constituting the support body with a filter function, any structure can be used as long as it has submicron-sized micropores that do not allow blood cells to pass therethrough and can form a body fluid passage. It may be a body or material. Usually, inorganic materials such as porous silica materials and glass filters, and organic materials such as cellulose derivatives and polysulfone filtration filters are used. In addition, the surface of these materials may be coated with a hydrophilic polymer or the like so that the substance to be inspected in the body fluid as a specimen does not adsorb.

  The filtered bodily fluid (plasma if the bodily fluid sample is blood) reaches the support 204 that also serves as a filtration filter, moves into the liquid transport path 206 by capillary action, and contacts the reaction / detection unit 207. In FIG. 2, the reaction / detection unit 207 is described as a separate member from the liquid conveyance path 206, but the liquid conveyance path 206 and the reaction / detection unit 207 are integrated, for example, as in general immunochromatography. There may be a method. When the reaction / detection unit 207 is configured as a separate member from the liquid transport path 206, the liquid transport path 206 is a micro liquid transport path having a diameter of several hundred micrometers to several tens of micrometers. If the liquid transport path 206 and the reaction / detection unit 207 are integrated as in general immunochromatography, the liquid transport path 206 becomes a so-called test strip filter (filter paper or polymer film). .

  The reaction / detection unit 207 can be variously configured depending on the analysis object, and a plurality of the reaction / detection units 207 can be provided in the liquid transport path 206. For example, when analyzing a tumor marker protein (AFP, PSA, CEA, etc.) in a body fluid as a target, a sandwich immunoassay method can be used. In that case, a labeled secondary antibody is disposed between the support 204 and the reaction / detection unit 207. By arranging the labeled secondary antibody in this way, the body fluid moves through the liquid transport path 206, reaches the reaction / detection unit 207, and is a portion of the primary antibody fixed on the reaction / detection unit 207. A primary antibody-target-secondary antibody complex is formed. If the label of the secondary antibody is an enzyme, it can be used as an enzyme immunization (EIA or ELISA) apparatus that provides an enzyme substrate by a method not shown and optically detects the substrate converted by the enzyme. If the label of the secondary antibody is an enzyme or a catalyst, and the product resulting from the conversion of the enzyme substrate or the precursor on which the catalyst acts by the enzyme or the catalyst produces luminescence, chemiluminescence immunoassay (CLIA) ) Can be used as a device. When a fluorescent material is used as a label, it can be used as a fluorescence immunoassay (FIA) apparatus for performing analysis by measuring a tendency generated by excitation light generated from a light source (not shown). Further, it can be used as an electrochemiluminescence immunoassay (ECLIA) apparatus in which a ruthenium complex such as ruthenium tribipyridine is used as a label and analysis is performed by a method of generating light emission by an electrolytic reaction on an electrode.

  In addition, a thin film or pattern of metal that causes plasmon resonance such as gold or silver is disposed on the surface of the reaction / detection unit 207, and an analysis means in which a capturing body such as an antibody against the target is immobilized on the thin film or pattern. A configuration is also possible. With such a configuration, it can also be used as a plasmon resonance method apparatus. In an analyzer using this plasmon resonance, a body fluid containing a target (substance to be detected) is brought into contact with a capturing body on a metal, whereby the amount or concentration can be optically detected.

  For example, when ions such as potassium ions, sodium ions, potassium ions, and calcium ions in body fluids are used as objects, the ion selective electrodes of the respective ions are arranged in the region 207 of the liquid transport path 206, and Analyze by changes in electrical signal.

  In addition, when organic low-molecular compounds such as glucose and lactic acid in body fluids are to be detected, an enzyme electrode in which an oxidoreductase such as glucose oxidase, glucose dehydrogenase, or lactate dehydrogenase is immobilized on an electrode substrate is mounted. Place. By adopting a configuration using an enzyme electrode, it is generally possible to use a method of analyzing the exchange of electrons on the electrode by a current value. Further, if the enzyme to be immobilized is an enzyme such as ALP or γ-GTP, a method of optically detecting a product in which the substrate is converted can be used.

  On the other hand, the liquid recovery unit 208 is a part that recovers the liquid for which the reaction / detection has been completed, and may be a simple hollow container or a liquid absorbent material. By providing the liquid transport path 206 with a capillary structure having the size described above, it is possible to transport the liquid in the direction of the liquid recovery unit 208. Furthermore, when the membrane 203 is pressed, when the air is released from the reverse support valve 205 and the membrane 203 returns to its original state, the left side of the housing is partitioned, so the negative pressure is slightly increased in the left portion, and the liquid It is considered that waste liquid from the transport path 206 to the liquid recovery unit 208 can be more effectively performed. In addition, in order to effectively perform the waste liquid, the liquid recovery unit 208 is sealed, the opening is only partly provided, and a reverse support valve is provided in that part. Means may be provided.

Hereinafter, the present invention will be described more specifically with reference to examples. In addition, this invention is not limited only to a following example.
Example 1
An embodiment in the case of blood collection of the body fluid collection device of the present invention will be described with reference to FIGS. 1 and 4 (flow chart). First, an index finger or a middle finger is placed on the membrane 103 of the body fluid collecting device shown in FIG. At this time, the bottom surface of the apparatus may be fixed on a desk or the like, or may be supported by the thumb. Next, a finger placed on the film 103 is pressed strongly. The degree and time of the pressing are such that the puncture means (in this case, the puncture needle) 102 penetrates the membrane 103 and further penetrates the skin of the fingertip to bleed out a sufficient amount of blood to meet the purpose of blood collection ( Displacement) and time. At that time, the air inside the apparatus is released to the outside from the check valve 105 by the amount by which the fingertip is pressed and the membrane 103 is deformed. After a sufficient blood volume is secured, the fingertip pressed against the membrane 103 is slowly restored. When the film 103 that has been deformed by returning the fingertip to its original state returns to its original state by its elastic repulsive force, an internal negative pressure is generated. Due to this internal negative pressure, blood exuded from the fingertip is fed into the apparatus through a through-hole provided by the puncture needle 102 and reaches the support 104. The body fluid (blood) collection operation is completed when the body fluid infiltrates into the support body 104.

(Example 2)
An embodiment in the case of blood analysis of the body fluid analyzer of the present invention will be described with reference to FIGS. In this example, γ-GTP (γ-glutamyl transpeptidase) serving as an index of liver function as an enzyme component in blood is analyzed. For the analysis of γ-GTP, L-γ-glutamyl-p-nitroanilide and glycylglycine are used as substrates. Analysis of γ-GTP is possible by optically measuring the absorption at 440 nm of L-glutamylglycylglycine and p-nitroaniline produced by reaction with γ-GTP using these as substrates. To be implemented. Therefore, the housing 209 in this embodiment is formed using a material that is transparent to light including a wavelength for detection and has no absorption near 400 nm, for example, glass.

  Next, the flow from actual blood collection to analysis will be described. First, as in the first embodiment, the index finger or middle finger is placed on the membrane 203 of the body fluid analyzer shown in FIG. At this time, the bottom surface of the apparatus may be fixed on a desk or the like, or may be supported by the thumb. Next, a finger placed on the film 203 is strongly pressed. The degree of pressing is such that the puncture means (in this case, the puncture needle) 202 penetrates the membrane 203 and further penetrates the skin of the fingertip to bleed out a sufficient amount of blood to meet the purpose of blood collection (displacement amount). , Time is needed. At that time, the air inside the apparatus is released to the outside from the check valve 205 by the amount that the fingertip is pressed and the membrane 203 is deformed. FIG. 3 illustrates this aspect.

  After a sufficient blood volume is secured, the fingertip pressed against the membrane 203 is slowly returned to its original position. The deformed membrane 203 returns to its original state by returning the fingertip to the original state, and blood exuded from the fingertip is fed into the apparatus through the through-hole provided by the puncture needle 202 and reaches the support 204. The body fluid (blood) is collected by infiltration. At this point, the analyzer is placed in a constant temperature bath (not shown) at 37 ° C. In addition, this analyzer is in the state which can be arrange | positioned in a thermostat at this time.

The blood infiltrating the support 204 is filtered to become plasma, moves to the liquid transport path 206 by capillary action, and reaches the reaction / detection unit 207. The reaction / detection unit 207 is preloaded with L-γ-glutamyl-p-nitroanilide and glycylglycine, which are substrates for γ-GTP, and the amount thereof depends on γ-GTP in general blood. There is a large excess over the amount by which the reaction is carried out. The reaction / detection unit 207 is designed to hold only a certain amount of plasma components. After a certain period of time, this device is attached to an absorptiometer (not shown), the absorbance at 440 nm is measured, and the concentration is obtained from a pre-measured calibration curve, so that the γ-GTP analysis operation in blood can be performed. Complete. Note that there is no problem even if the thermostat and the absorptiometer used in this embodiment are integrated.

It is a figure which shows typically the structure of an example of the bodily fluid sampling device of this invention, (A) is the longitudinal cross-sectional view, (B) is the top view. It is a figure which shows typically the structure of an example of the analyzer with a bodily fluid collection | recovery function of this invention, (A) is the longitudinal cross-sectional view, (B) is the top view. It is a figure which shows the use condition of the body fluid analyzer in Example 2. FIG. It is a figure which shows the flowchart of the bodily fluid collection process in Example 1. FIG. It is a figure which shows the flowchart of the bodily fluid collection | recovery and analysis process in Example 2. FIG.

Explanation of symbols

101 ... Guide plate
102 ・ ・ ・ ・ Puncture means (needle)
103 ... Membrane
104 ・ ・ ・ ・ Support
105 ・ ・ ・ ・ Check valve
201 ... Guide plate
202 ・ ・ ・ ・ Puncture means (needle)
203 ... Membrane
204 ・ ・ ・ ・ Support
205 ・ ・ ・ ・ Check valve
206 ... Liquid transfer path
207 ... Reaction / detection section
208 ・ ・ ・ ・ Liquid recovery unit
209 ・ ・ ・ ・ Case
210 ... Fingertip

Claims (4)

A body fluid collecting device for collecting body fluid from a body fluid collecting surface of a living body,
A housing having an internal region that can be sealed;
A pressing portion to the body fluid collection surface provided in a part of a partition wall that partitions the internal region from the outside;
A puncture means disposed in the internal region, for piercing the body fluid collection surface and leaching the body fluid to the body fluid collection surface;
Negative pressure generating means for generating a negative pressure in the internal region;
Have
The puncturing means is provided at a position where the body fluid collection surface can be pierced by forming a through-hole through the pressure portion by pressing the body fluid collection surface to the pressing portion,
The negative pressure generating means is to have a mechanism for generating a negative pressure in the interior region with the elimination of the pressing force when the body fluid sampling surface is separated from the pressing portion,
The bodily fluid collecting device, wherein the bodily fluid to be exuded on the bodily fluid collecting surface is collected through a through hole formed through the pressing portion . The negative pressure is generated by providing the casing with a check valve that is formed of an elastic film and that allows the internal region and the outside to communicate with each other and that allows only gas from the internal region to flow outside. Configure means
The body fluid collecting device according to claim 1, wherein The puncture means is provided at a position of the inner region facing a body fluid collection surface that presses the membrane through the elastic membrane.
The bodily fluid collection device according to claim 2, wherein It further has means for analyzing the body fluid
Body fluid sampling device according to any one of claims 1 to 3, characterized in that.

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