JP3784014B2 - Puncture needle - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a puncture needle used when blood or body fluid is collected from a living body.
[0002]
[Background]
With the increase in sensitivity and miniaturization of analyzers, necessary and sufficient analysis information can be obtained with a very small amount of sample. In particular, microanalysis of blood and other biological components provides valuable information for the purpose of health management and disease diagnosis, and the development of μ-TAS (Total Analysis System) and Lab on a chip makes it easier for individuals and medical institutions. It is becoming possible to obtain biological information.
[0003]
As a sampling method for collecting blood or body fluid from a living body, a method using an injection needle is generally used. However, since it is painful at the time of puncture, a more comfortable sampling method without anxiety is desired. For example, Patent Document 1 discloses an apparatus and method for sampling blood using a hollow microneedle. Similarly, Patent Document 2 discloses a device that includes a plurality of hollow needles having a small diameter and collects blood by changing the pressure in the hollow needle.
[0004]
Non-Patent Document 1 discloses a painless needle in which a hollow stainless steel tube having an outer diameter of 70 μm is nitrided and cured, the tip is polished by chemical mechanical polishing, and further sharpened by electrolytic polishing.
[0005]
Patent Document 3 discloses a blood collection needle in which a slit is formed in the longitudinal direction of the blood collection needle from the bevel surface in a tubular blood collection needle having a bevel surface for the purpose of causing blood to bleed on the skin without pain.
[0006]
Patent Documents 4 to 8 show a hollow microneedle array and a manufacturing method thereof. Further, Patent Document 9 discloses a hollow or porous microneedle using a micromold.
[0007]
The above is an apparatus or method for collecting blood and the like by puncturing the skin with a needle, but Patent Documents 10 to 11 show apparatuses for collecting and collecting body fluid without puncturing.
[0008]
[Patent Document 1]
JP2001-258868
[Patent Document 2]
Japanese Patent Laid-Open No. 07-132119 [Patent Document 3]
Japanese Patent Laid-Open No. 08-187237 [Patent Document 4]
US Pat. No. 6,256,533 [Patent Document 5]
US Pat. No. 6,311,612 [Patent Document 6]
US Pat. No. 6,379,324 [Patent Document 7]
US Pat. No. 6,451,240 [Patent Document 8]
US Pat. No. 6,471,903 [Patent Document 9]
US Pat. No. 6,334,856 [Patent Document 10]
Japanese Patent Laid-Open No. 04-060208 [Patent Document 11]
US Pat. No. 6,340,354 [Non-Patent Document 1]
A. Oki et. al, “Electrophoresis” 22, (2001), p. 341,
[0009]
[Problems to be solved by the invention]
The present invention has been made in view of the problems of the prior art as described above, and the puncture needle used when collecting blood or body fluid from a living body is almost without using a conventional hollow puncture needle. An object of the present invention is to provide a puncture needle that can quickly and safely collect body fluid without feeling pain.
[0010]
[Means for Solving the Problems]
That is, the present invention relates to a puncture needle for puncturing a living body to collect a body fluid, the needle body having a closed tip, and an outer surface of the needle body, and the body after the needle body is punctured A puncture needle comprising a body fluid adhering portion having a helical recess for removing the body fluid attached to the needle body and storing the attached body fluid.
[0014]
Next, a preferred embodiment of the puncture needle of the present invention is shown.
The puncture needle of the present invention is a liquid in the body of a human body, an animal, etc., and is used for taking out body fluids such as blood, lymph and tissue fluids from the skin. The puncture needle has a diameter of 10 to 60 μm and is punctured. It is characterized in that the ratio of the diameter and the length of the needle is 1: 2 to 1:20.
[0015]
The body fluid adhering portion of the puncture needle forms one or more spiral grooves having a width and depth less than half of the diameter of the puncture needle in the length direction of the puncture needle on the outer periphery of the puncture needle Is preferred.
[0016]
The piercing end for piercing the skin at the tip of the puncture needle is preferably cylindrical, conical or beveled.
The puncture needle is preferably formed integrally with the puncture device by being connected to means such as sample storage / pretreatment / concentration / separation / detection.
[0017]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
Pain when a needle is punctured into the skin is a sensation of pain points scattered on the skin, and it is said that there are 100 to 200 pain points per square centimeter of skin. The pain at the time of puncture is a great stress for the subject, and sampling with less pain or no pain is strongly desired. There are several methods and devices for reducing pain as described in the background art, but methods that are essentially painless can be broadly divided into sampling that does not stimulate the pain point, or sampling that is paralyzed.
[0018]
On the other hand, for quick and safe sampling, it is desirable that no special pretreatment is performed on the subject or the living body. Therefore, the sampling apparatus and method for producing a needle that is thinner than the pain point interval of the skin and using this for collecting body fluid such as blood enables collection of a biological sample that is substantially painless and has little stress.
[0019]
However, the less painful or painless puncture needles disclosed so far are hollow fine needles and require a sufficient hollow diameter to sample a biological sample through the hollow portion of the needle. Furthermore, the mechanical strength of the needle is required so that the needle does not break during puncturing. For this purpose, it is desired to produce a hollow tube having a sufficient thickness with a hard material. In order to satisfy the required performance as such a puncture needle, it is difficult to use an extremely thin hollow tube of 50 μm or less, and it is also difficult to produce such a hollow tube in the process. .
[0020]
In order to solve such a problem, the puncture needle of the present invention has a recess for holding and passing a body fluid such as blood on the outer peripheral portion of the puncture needle without using a hollow tube. The present invention provides a fine puncture needle.
[0021]
A more specific shape of the puncture needle is a puncture needle having a diameter of 10 to 60 μm and a ratio of the diameter to the length of 1: 2 to 1:10.
[0022]
In addition, the cross-sectional shape of the concave portion provided on the outer peripheral portion of the puncture needle is such that the width and depth thereof are half or less of the diameter of the puncture needle, and the concave portion is formed in a spiral shape on the outer peripheral portion of the puncture needle. Good. Further, if the diameter of the puncture needle is 50 μm or less, the piercing end may be cylindrical, but if the piercing end is conical, sampling without a sense of pressure can be further performed during puncturing.
[0023]
These puncture needles can be directly produced, for example, by dry etching of a silicon substrate. Alternatively, a columnar structure can be formed on the substrate by electrolytic plating using a photoresist or the like as a mold. Further, a puncture needle having a complicated structure, for example, a puncture needle having a spiral recess, can be produced by using an optical modeling method. Furthermore, a mold can be formed by stereolithography, and finally a puncture needle having a desired shape can be produced by electrolytic plating.
[0024]
Next, the present invention will be described with reference to the drawings. 1 to 4 shown below, FIG. 3 shows a puncture needle of the present invention, and FIGS. 1, 2, and 4 show reference examples of the puncture needle.
FIG. 1 is a schematic view showing an example of the puncture needle of the present invention. In the puncture needle of the present invention, a cylindrical needle body 102 is formed on a base 101, the diameter of the needle body 102 is 10 to 60 μm, and the ratio of the diameter and length of the needle body 102 is 1: 2-1. : 20 is desirable. The needle body 102 punctured into the skin holds body fluid such as blood on its surface, and body fluid can be taken out by extracting the needle body 102. The base 101 is for holding the needle body 102, and the shape thereof does not have to be a disc shape, and an optimum shape for the manufacturing process and the purpose of use is selected.
[0025]
FIG. 2 is a schematic view showing another example of the puncture needle of the present invention. FIG. 2 shows an example of a puncture needle in which a linear recess 203 is formed on the outer periphery of the needle body 202. As in FIG. 1, the puncture needle has a cylindrical needle body 202 formed on a base body 201, and a linear recess 203 having a width and depth less than half of the diameter of the needle body 202 is formed on the outer periphery thereof. Has been. This linear recess allows a biological sample such as blood to be held or passed out of the skin and efficiently sampled. The width and depth of the linear recess 203 are designed so that the mechanical strength of the needle body 202 can be practically sufficiently secured and a necessary amount of sample can be collected.
[0026]
FIG. 3 is a schematic view showing another example of the puncture needle of the present invention. FIG. 3 shows an example of a puncture needle in which a spiral recess 303 is formed in the outer peripheral portion 304 of the needle body 302. As in FIG. 1, the puncture needle has a cylindrical needle body 302 formed on a base body 301, and a helical recess 303 having a width and depth less than half the diameter of the needle body 302 on its outer peripheral portion 304. Is formed.
[0027]
FIG. 4 is a schematic view showing another example of the puncture needle of the present invention. FIG. 4 shows an example of a puncture needle in which the tip 405 of the needle body 402 is processed into a conical shape. As in FIG. 1, the puncture needle has a needle body 402 having an isotropic etching surface 404 with a tip 405 sharpened in a conical shape on a base body 401, and the outer periphery thereof has a diameter less than half of the diameter of the needle body 402. A linear or helical recess 403 having a width and a depth is formed.
[0028]
As the material of the puncture needle, an inorganic material such as silicon, nickel, or chromium, or an organic material such as polystyrene or polymethyl methacrylate can be used. In addition, it is non-toxic because it punctures directly into a living body, it does not change material due to autoclave heating, ultraviolet irradiation, or γ-ray irradiation so that it can be sterilized. The manufacturing process is desired. Further, it is desirable that the surface of the puncture needle is hydrophilic.
[0029]
If necessary, it is also possible to coat only the surface of the puncture needle using a dip method or a sputtering method.
[0030]
Next, the puncture device of the present invention will be described.
A puncture device according to the present invention includes the puncture needle described above, and a puncture force applying means for applying a force to puncture a living body with respect to the puncture needle.
[0031]
Specifically, in order to make the puncture needle as painless as possible when puncturing the puncture device of the present invention, it is not a hollow needle but a needle having a rod-shaped cross-section that has an extremely small diameter, and is provided on the outer surface of the needle when pulled out after puncturing. A bodily fluid such as blood is attached to the recessed portion or the hydrophilic processed portion, and the bodily fluid is transferred to the biochip.
[0032]
The puncture device according to the present invention comprises a collecting means for collecting blood from within a living body, a filtering means for filtering at least the collected blood to obtain plasma, or a separating means for separating serum from the blood, and analyzing substances in the blood Analysis means, flow path means for connecting each of these means, movement means for moving blood components existing in each of these means, and output means for taking out information from the analysis means, Control means for controlling the operation of at least one of the means, and holding means for holding the blood component in the substrate.
[0033]
FIG. 5 is a schematic view showing an example of the puncture device of the present invention. The apparatus shown in FIG. 5 introduces blood into a microcapillary 503 on a quartz substrate 501 via a puncture needle 502 for collecting blood. At this time, an anticoagulant (sodium citrate, EDTA, heparin, etc.) stored in the liquid reservoir 504 so that blood does not coagulate in the capillary 503 can be appropriately supplied into the capillary 503 by pressing the rubber stopper 505. Good. Next, it is introduced into the filtering means 506 to separate plasma and blood cells from the blood. The separated plasma is introduced into the analysis means 507. It introduce | transduces into the analysis means 507 by the electroosmotic flow produced by applying an electric field between the electrodes 508 and 509, and detects the density | concentrations, such as pH, a sodium ion, potassium ion, glucose, in plasma. In the figure, a plurality of analysis means are provided, and the concentration of each of the above components can be analyzed at a time.
[0034]
In the present invention, the bodily fluid adhering to the bodily fluid adhering portion of the puncture needle is supplied to the puncture device using the collecting means. The collecting means can be performed by applying a negative pressure to the body fluid adhering portion of the puncture needle, applying a physical force, or utilizing a force when air is blown. It is preferable that the physical force is a force used when wiping the body fluid adhered to the body fluid adhesion portion.
[0035]
The puncture needle of the present invention can be reused by washing after being used once. As the cleaning liquid for the puncture needle when reusing, a denaturant is used. Examples of the denaturant include sodium salt, potassium salt, lithium salt or ammonium salt of thiocyanic acid, guanidinium hydrochloride, hydrochloride of guanidinium derivative, urea and the like. Used. Such a denaturing agent is preferably used in combination with a surfactant. As the surfactant, twin, triton-based nonionic surfactants, sodium deoxycholate, or the like is used. As the buffer solution, phosphate buffer solution, Tris buffer solution, acetate buffer solution and the like are used.
[0036]
【Example】
Hereinafter, the present invention will be described in more detail with reference to examples.
In addition, the dimension, shape, material, and manufacturing process conditions in the following examples are examples, and can be arbitrarily changed as design matters as long as they satisfy the requirements of the present invention. In Examples 1 to 4 shown below, Example 3 shows an example of the puncture needle of the present invention, and Examples 1, 2 and 4 show reference examples.
[0037]
Example 1
In this example, the puncture needle shown in FIG. 1 was produced.
First, a silicon substrate was prepared as a base.
Next, a photoresist (AZ-P4620: manufactured by Clariant) was applied to the silicon substrate by a spin coating method so as to have a film thickness of 8 μm. The photoresist was baked, exposed and developed to produce a circular resist pattern having a diameter of 10 μm on the silicon substrate.
[0038]
Next, the silicon substrate was dry etched using the resist pattern as an etching mask. Etching was performed perpendicular to the substrate surface while using C ₄ F ₈ gas and SF ₆ gas as the etching gas and protecting the etching side walls by alternately flowing the above two kinds of gases. The etching depth was 100 μm. As a result, the ratio of the diameter and length of the puncture needle was 1:10.
[0039]
Next, after the entire substrate surface was protected with a photoresist, dicing was performed, and one puncture needle made of silicon and the holding substrate were taken out.
Next, the resist film was removed by immersing the extracted puncture needle and holding substrate in acetone and isopropyl alcohol. The removed puncture needle was observed with a scanning electron microscope, and it was confirmed that the puncture needle was designed as designed.
[0040]
Next, the prepared puncture needle was washed with ethyl alcohol and then sterilized and dried with ultraviolet rays. This was directly punctured into the human body to confirm that there was no pain. Further, the extracted puncture needle was observed with an optical microscope, and it was confirmed that blood components were retained in the outer peripheral portion and the concave portion of the puncture needle.
[0041]
It was also confirmed that the puncture needle shown in FIG. 2 could be produced by making the photoresist pattern serving as an etching mask a pattern having the cross-sectional shape of the needle body 202 of FIG. At this time, the diameter of the needle was 60 μm, the width and depth of the recess 203 were 10 μm, and the length of the needle was 300 μm.
[0042]
In the manufacturing method of this embodiment, since a photolithography method is used, a puncture needle having an arbitrary cross-sectional shape can be manufactured. Further, by using photolithography and dry etching, a large number of needles can be manufactured at the same time, and the manufacturing cost can be reduced. Further, by controlling the etching depth of dry etching, it is possible to form a needle having an arbitrary length. It is also possible to form a tapered puncture needle by adjusting the pressure during dry etching, the gas ratio, and the like.
[0043]
Example 2
In this example, the puncture needle of FIG. 2 was produced by a process different from that of Example 1.
First, a glass substrate was prepared. A 50 nm thick titanium thin film serving as an adhesion layer was formed by sputtering. Next, a gold thin film having a thickness of 300 nm was formed on the titanium thin film in the same manner as a seed layer for the subsequent plating step.
[0044]
Next, a photoresist (PMER P-GH3000PM: manufactured by Tokyo Ohka Kogyo Co., Ltd.) having a thickness of 50 μm was formed on the substrate on which the titanium and gold thin films were formed by using a spin coating method. At this time, the thickness of the photoresist is set larger than the length of the puncture needle to be produced.
[0045]
Next, a negative pattern having a cross-sectional shape of the needle main body 202 (diameter: 20 μm, recess width and depth: 5 μm each), that is, a mold pattern was formed by photolithography.
[0046]
Next, electrolytic nickel plating is performed on the above substrate using a plating bath mainly composed of nickel sulfamate, nickel chloride, and boric acid at a bath temperature of 50 ° C., a cathode current density of 10 A / dm ² , and a pH of 4.2. Went. As a result, nickel grew in a columnar shape on the surface of the gold thin film formed on the substrate where no resist pattern was formed. When the length of the columnar nickel structure became the desired length of the puncture needle, the substrate was lifted from the plating bath.
[0047]
Next, after washing with water, it was separated into a puncture needle made of individual nickel and a support substrate by dicing.
Next, the resist on the substrate was removed using a dedicated resist stripping solution.
Finally, the exposed needle part was washed with ethyl alcohol and then sterilized and dried with ultraviolet rays to complete the puncture needle shown in FIG.
[0048]
When the extracted puncture needle was observed with a scanning electron microscope, it was confirmed that a puncture needle having a cross-sectional shape as designed could be produced. The length of the puncture needle was 40 μm, and the ratio of the diameter and length of the puncture needle was 1: 2.
[0049]
In the manufacturing method of this embodiment, a puncture needle mold is manufactured by using a photolithography method, and thus a puncture needle having an arbitrary cross-sectional shape can be manufactured. In addition, a large number of needles can be manufactured at the same time, and the manufacturing cost can be reduced. Further, in the manufacturing method of this example, the material of the puncture needle can be selected from materials that can be electroplated or electrolessly plated. is there.
[0050]
Example 3
In this example, the puncture needle shown in FIG. 3 was produced.
In this example, “micro modeling method” was used as a manufacturing method. The micro stereolithography method is, for example, [A. Bertsch et al. : Proc. Of the IEEE International Workshop on Micro Electro Mechanical Systems (1998) p. 18], [K. Ikuta et al: Proc. Of the IEEE International Workshop on Micro Electro Mechanical Systems, (1998) p. 290]. In this manufacturing method, a liquid ultraviolet curable resin is irradiated with an ultraviolet beam, and a desired position is cured while the XY stage is operated, thereby processing a cross-sectional shape of one layer. After one layer of processing is completed, the Z stage is lowered by one layer and further processing is performed. By repeating the above steps, it is possible to finally form a structure having an arbitrary shape.
[0051]
In this example, SU-8 (manufactured by Micro Chemical Corp.) was used as an ultraviolet curable resin, and an optical modeling method was performed using a UV lamp having a wavelength of 365 nm as a light source. By manipulating the XYZ stage while irradiating the SU-8 with a UV lamp, the shape of the puncture needle shown in FIG. 3 could be produced.
[0052]
After removing uncured SU-8, the exposed needle part was washed with ethyl alcohol and then sterilized and dried with ultraviolet rays to complete the puncture needle shown in FIG .
When the extracted puncture needle was observed with a scanning electron microscope, it was confirmed that a puncture needle having a cross-sectional shape as designed could be produced .
In this example, a puncture needle was produced using a micro stereolithography method. As a result, it becomes possible to form a puncture needle having an arbitrary shape such as a puncture needle having a helical recess formed on the outer peripheral portion.
[0053]
Moreover, although the needle | hook main body was produced by the micro stereolithography method in the present Example, a puncture is carried out by forming a mold by the micro stereo lithography method, plating this mold like Example 2, and removing the mold after plating. A needle may be formed. In this case, it is possible to form a puncture needle made of a material other than the ultraviolet curable material, and it is possible to widen the selection range of the material.
[0054]
Example 4
In this example, the puncture needle shown in FIG. 4 was produced. First, a cylindrical puncture needle was prepared in the same manner as in Example 1. Next, the tip of 10 μm was immersed in an aqueous solution in which HF (hydrofluoric acid) and HNO ₃ (nitric acid) were mixed at a volume ratio of 1: 2, and the tip was processed into a conical shape by isotropic etching. This was observed with a scanning electron microscope, and it was confirmed that a puncture needle as designed was made.
[0055]
【The invention's effect】
As described above, according to the present invention, it was possible to provide a puncture needle capable of collecting a biological sample quickly and safely with almost no pain when sampling blood or body fluid from a living body.
[Brief description of the drawings]
FIG. 1 is a schematic view showing a reference example of a puncture needle .
FIG. 2 is a schematic view showing a reference example of a puncture needle .
FIG. 3 is a schematic view showing an embodiment of the puncture needle of the present invention.
FIG. 4 is a schematic view showing a reference example of a puncture needle .
FIG. 5 is a schematic view showing an example of the puncture device of the present invention.
[Explanation of symbols]
101, 201, 301, 401 Substrate 102, 202, 302, 402 Needle body 203, 303, 403 Recess 304 Outer periphery 404 Isotropic etching surface 405 Tip 501 Substrate 502 Puncture needle 503 Microcapillary 504 Liquid reservoir 505 Rubber stopper 506 Filtration Means 507 Analytical means 508,509 Electrode

Claims (2)

A puncture needle for puncturing a living body to collect a body fluid, the needle body having a closed tip, and an outer surface of the needle body, and puncturing the body of the needle into the body, A puncture needle comprising: a body fluid adhering portion having a helical recess for removing the adhering body fluid and storing the adhered body fluid .   The puncture needle according to claim 1 or 2, wherein a diameter of the puncture needle is 10 to 60 µm, and a ratio of a diameter and a length of the puncture needle is 1: 2 to 1:20.

Images