JP4996235B2 - Trace magnetic drug detection device and magnetic drug detection method - Google Patents

Trace magnetic drug detection device and magnetic drug detection method Download PDF

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JP4996235B2
JP4996235B2 JP2006347574A JP2006347574A JP4996235B2 JP 4996235 B2 JP4996235 B2 JP 4996235B2 JP 2006347574 A JP2006347574 A JP 2006347574A JP 2006347574 A JP2006347574 A JP 2006347574A JP 4996235 B2 JP4996235 B2 JP 4996235B2
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JP2008157786A (en
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典英 佐保
明 佐々木
弘之 田中
晃 塚本
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Hitachi Healthcare Manufacturing Ltd
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Abstract

A technique of measuring detectable trace magnetic particles with high sensitivity and high efficiency three-dimensionally by a magnetic method using a SQUID magnetic sensor. Disk-shaped sample holders are rotated and inserted from the outside of a magnetic shield into the inside thereof one by one. Magnetizing means magnetizes the standardized specimen outside the magnetic shield. A magnetic sensor detects a magnetic field generated from the magnetized standardized specimen inside the magnetic shield. Thus, the detection of the magnetic field and the magnetization are performed in parallel to each other. The specimen is continuously cut, and the magnetic sensor measures the magnetic field generated from the magnetized standardized specimen before and after the cutting.

Description

本発明は、微量磁性薬剤検出装置及び磁性薬剤検出方法に関するものである。   The present invention relates to a trace magnetic drug detection device and a magnetic drug detection method.

近年、ＤＤＳ（Drug Delivery System）によって癌患部への薬剤の集積効率を高めることで患者への投薬量を低減する治療が検討されてきている。この治療は副作用が軽減されるため患者に優しく、癌患部を効率的に殺滅する将来の医療技術として有望視されている。   In recent years, treatments for reducing dosage to patients by increasing the efficiency of drug accumulation in cancer affected areas by DDS (Drug Delivery System) have been studied. This treatment is gentle on patients because of reduced side effects, and is promising as a future medical technique for efficiently killing cancerous areas.

血液中に投与された薬剤を患部まで誘導する手段の１つとして、例えば図１に示すようなものがある。これは材質がフェライトで、粒子径が１００ナノメートル前後の磁性粒子５０の周りに直接もしくは間接的に微小薬剤５１を結合させた磁性薬剤を血液中に投薬し、体外に配置した磁気誘導手段で、患者の動脈血管の分岐部において所定の方向に磁性薬剤を誘導するものである。これにより、患部近傍に磁性薬剤を人為的に集積効率を高めて誘導することが可能である。このＤＤＳにおいては、ナノサイズの磁性薬剤粒子が患部付近に定量的に集積したか計測することが、磁気誘導手段および磁性薬剤自身の開発研究評価に必要不可欠となる。   One means for guiding a drug administered into the blood to the affected area is, for example, as shown in FIG. This is a magnetic induction means in which a magnetic drug in which a minute drug 51 is bound directly or indirectly around a magnetic particle 50 having a particle diameter of around 100 nanometers, directly or indirectly, is dispensed into blood and disposed outside the body. The magnetic drug is guided in a predetermined direction at the branch of the arterial blood vessel of the patient. Thereby, it is possible to artificially increase the accumulation efficiency of the magnetic drug in the vicinity of the affected area and guide it. In this DDS, it is indispensable for the development research evaluation of the magnetic induction means and the magnetic drug itself to measure whether the nano-sized magnetic drug particles are quantitatively accumulated in the vicinity of the affected part.

一方、免疫検査の一般的な方法として、検出対象とする抗原に選択的に結合する検出用抗体を蛍光酵素等の光学マーカーで標識して、抗原−抗体の結合反応を光学マーカーからの光信号を検出し、抗原の種類及び量を検出する光学的方法がある。しかし、光学的方法では、細胞内部の光源に関し、光源外部の細胞が光の透過を阻害してしまい、検出感度が十分ではない。したがって、定量的計測が十分行えず、また、検出感度を低下させる未結合の光学マーカーを完全に洗い流す工程が必要であった。   On the other hand, as a general method of immunoassay, a detection antibody that selectively binds to an antigen to be detected is labeled with an optical marker such as a fluorescent enzyme, and an antigen-antibody binding reaction is detected by an optical signal from the optical marker. And an optical method for detecting the type and amount of the antigen. However, in the optical method, regarding the light source inside the cell, the cell outside the light source inhibits light transmission, and the detection sensitivity is not sufficient. Therefore, quantitative measurement cannot be performed sufficiently, and a process of completely washing away unbound optical markers that reduce detection sensitivity is required.

光学的方法を上回る検出感度を得る方法として、近年、ＳＱＵＩＤ (超電導量子干渉素子：Superconducting Quantum Interference Device)磁気センサーを用い、微量な磁気微粒子を定量的に検出する磁気的方法が提案されている。この磁気的方法では、微量な磁気微粒子を、非常に高感度なＳＱＵＩＤ磁気センサーを用いて検出する。   In recent years, a magnetic method for quantitatively detecting a minute amount of magnetic fine particles using a SQUID (Superconducting Quantum Interference Device) magnetic sensor has been proposed as a method for obtaining detection sensitivity exceeding that of an optical method. In this magnetic method, a very small amount of magnetic fine particles are detected using a very sensitive SQUID magnetic sensor.

微量な磁気微粒子を検出する方法について、以下に説明する、（１）磁化率の測定、
（２）残留磁気の測定に基づく方法が提案されている。 A method for detecting a minute amount of magnetic fine particles will be described below. (1) Measurement of magnetic susceptibility;
(2) A method based on measurement of residual magnetism has been proposed.

以下、（１），（２）について説明する、
（１）磁化率を測定する方法：
ＳＱＵＩＤ磁気センサーの磁束検出方向と直角な方向から、微量な磁気微粒子を磁化させる直流磁界を印加し、ＳＱＵＩＤ磁気センサーの磁束検出領域内を移動する微量な磁気微粒子より生じた磁界の変化を測定している（例えば、特開２００１−３３４５５号公報を参照）。 Hereinafter, (1) and (2) will be described.
(1) Method for measuring magnetic susceptibility:
A DC magnetic field that magnetizes a small amount of magnetic fine particles is applied from a direction perpendicular to the magnetic flux detection direction of the SQUID magnetic sensor, and the change in the magnetic field generated by the small amount of magnetic fine particles moving in the magnetic flux detection region of the SQUID magnetic sensor is measured. (For example, refer to JP 2001-33455 A).

また、微量な磁気微粒子に対して交流磁界を印加し、その信号をＳＱＵＩＤ磁気センサーを用いて磁気微粒子を検出している（例えば、特開２００１−１３３４５８号公報を参照）。
（２）残留磁気を測定する方法：
磁気微粒子のサイズが大きくなると、磁気微粒子の残留磁気は緩和しなくなる。SQUID磁気センサーから離れた場所で微量な磁気微粒子に０.１Ｔ 程度の磁界を印加し、磁気微粒子に残留磁化を発生させる。この後に、試料を乗せた基板を移動し残留磁化をSQUID 磁気センサーで測定する（例えば、特表平１０−５１３５５１号公報を参照）。 Further, an alternating magnetic field is applied to a very small amount of magnetic fine particles, and the magnetic fine particles are detected by using a SQUID magnetic sensor (see, for example, Japanese Patent Laid-Open No. 2001-133458).
(2) Method for measuring residual magnetism:
When the size of the magnetic fine particles increases, the residual magnetism of the magnetic fine particles does not relax. A magnetic field of about 0.1 T is applied to a minute amount of magnetic fine particles at a location away from the SQUID magnetic sensor, and residual magnetization is generated in the magnetic fine particles. Thereafter, the substrate on which the sample is placed is moved, and the residual magnetization is measured with a SQUID magnetic sensor (see, for example, Japanese Patent Publication No. 10-513551).

また、特開２００４−０６８６４５号公報記載された微量な磁気微粒子を検出する磁気的方法に関する具体例を説明しておく。   A specific example of a magnetic method for detecting a minute amount of magnetic fine particles described in JP-A-2004-068645 will be described.

図２は、微量な磁気微粒子を用いた従来技術の磁気微粒子検査装置を説明する図である。
図２は従来技術になる磁気微粒子検査装置の一部構成を示す断面を含む図であり、装置の測定時における構成要素の配置状態を説明するものである。
複数の円盤型試料ホルダー２は、非磁性の円盤型試料ホルダー３（以下、単に、試料ホルダー３という）により円周上に固定されている。試料ホルダー３は回転機構４によって回転する。回転機構４は、移動ステージ５上で３次元方向に移動可能に保持されている。移動ステージ５上での回転機構４の移動により、試料ホルダー３は磁気シールド１の内部へ移動され位置調整される。 FIG. 2 is a diagram for explaining a conventional magnetic particle inspection apparatus using a minute amount of magnetic particles.
FIG. 2 is a diagram including a cross-section showing a partial configuration of a magnetic particle inspection apparatus according to the prior art, and explains the arrangement state of components during measurement of the apparatus.
The plurality of disk-type sample holders 2 are fixed on the circumference by a non-magnetic disk-type sample holder 3 (hereinafter simply referred to as a sample holder 3). The sample holder 3 is rotated by the rotation mechanism 4. The rotating mechanism 4 is held on a moving stage 5 so as to be movable in a three-dimensional direction. By moving the rotating mechanism 4 on the moving stage 5, the sample holder 3 is moved into the magnetic shield 1 and its position is adjusted.

微量な磁気微粒子の磁気信号を検出する高温超電導ＳＱＵＩＤ１１（以下、単に、
ＳＱＵＩＤ１１という）は、サファイアロッド９及び銅ロッド１０を介して、液体窒素７によって超電導転移温度以下に冷却され、真空断熱容器の外槽６ａ，真空断熱容器の内槽６ｂから構成される真空断熱容器６によって外部と熱的に遮断されている。真空断熱容器６は、ＳＵＳやＦＲＰ等の非磁性材料から構成される。真空断熱容器６の内槽６ｂの内部へ排気・供給ポート８を通して、気化した窒素の排気，液体窒素の供給が行われる。
ＳＱＵＩＤ昇温用光源１３は、ＳＱＵＩＤ１１を加熱しトラップ磁束の除去に使用される。 A high-temperature superconducting SQUID 11 (hereinafter simply referred to as a magnetic signal of a minute amount of magnetic fine particles)
SQUID 11) is cooled to a superconducting transition temperature or lower by liquid nitrogen 7 through sapphire rod 9 and copper rod 10, and is composed of an outer tank 6 a of a vacuum heat insulating container and an inner tank 6 b of a vacuum heat insulating container. 6 is thermally shielded from the outside. The vacuum heat insulating container 6 is made of a nonmagnetic material such as SUS or FRP. Exhaust of vaporized nitrogen and supply of liquid nitrogen are performed through the exhaust / supply port 8 into the inner tank 6b of the vacuum heat insulating container 6.
The SQUID temperature raising light source 13 is used to heat the SQUID 11 and remove the trap magnetic flux.

ＳＱＵＩＤ１１は、環境磁気雑音の入力を低減するために、磁気シールド１によって囲まれている。磁気シールド１は、パーマロイ等の高透磁率材料から構成され、磁気シールド１ａ，１ｂ，１ｃから構成される３層構造をもっている。なお、磁気シールドの効率をより向上させるために、磁気シールド１を多層構造とすることが望ましい。   The SQUID 11 is surrounded by the magnetic shield 1 in order to reduce the input of environmental magnetic noise. The magnetic shield 1 is made of a high magnetic permeability material such as permalloy, and has a three-layer structure made up of magnetic shields 1a, 1b, and 1c. In order to further improve the efficiency of the magnetic shield, it is desirable that the magnetic shield 1 has a multilayer structure.

磁気シールド１（１ａ，１ｂ，１ｃ）の一部には切欠き穴１９が形成されている。測定時には、円盤型試料ホルダー２及び試料ホルダー３の一部は切欠き穴１９から円盤型試料ホルダー２の交換時、又はＳＱＵＩＤ１１の制御回路の調整時には試料ホルダー３及び円盤型試料ホルダー２は完全に磁気シールド１の外部に露出した状態となる。   A notch 19 is formed in a part of the magnetic shield 1 (1a, 1b, 1c). At the time of measurement, a part of the disk-type sample holder 2 and the sample holder 3 is completely replaced when the disk-type sample holder 2 is replaced from the notch 19 or when the control circuit of the SQUID 11 is adjusted. The magnetic shield 1 is exposed to the outside.

本構成により、永久磁石又は磁場印加用コイルの発する磁場のＳＱＵＩＤ１１に対する影響が低減される。よって、磁気シールド１の内部にある円盤型試料ホルダー２内の微量な磁気微粒子の磁気信号をＳＱＵＩＤ１１によって測定しながら、磁気シールド１の外部にある他の円盤型試料ホルダー２内の微量な磁気微粒子に磁場を印加し、試料ホルダー３を回転させることによって、磁気シールド１の内部にある円盤型試料ホルダー２内の微量な磁気微粒子から発生する磁場の測定と、磁気シールド１の外部にある他の円盤型試料ホルダー２内の微量な磁気微粒子の磁化とを、同時にもしくは並行して行う。   With this configuration, the influence of the magnetic field generated by the permanent magnet or the magnetic field application coil on the SQUID 11 is reduced. Therefore, while measuring the magnetic signal of a minute amount of magnetic fine particles in the disk type sample holder 2 inside the magnetic shield 1 with the SQUID 11, the minute amount of magnetic fine particles in another disk type sample holder 2 outside the magnetic shield 1 is measured. By applying a magnetic field to the sample holder 3 and rotating the sample holder 3, the magnetic field generated from the minute amount of magnetic fine particles in the disk-shaped sample holder 2 inside the magnetic shield 1 is measured, and other magnetic elements outside the magnetic shield 1 are measured. Magnetization of a minute amount of magnetic fine particles in the disk-shaped sample holder 2 is performed simultaneously or in parallel.

特開２００１−３３４５５号公報JP 2001-33455 A 特開２００１−１３３４５８号公報JP 2001-133458 A 特表平１０−５１３５５１号公報Japanese National Patent Publication No. 10-513551 特開２００４−０６８６４５号公報Japanese Patent Laid-Open No. 2004-068645

癌細胞を含有する細胞組織（以下、検査細胞組織と称す）中に、例えば磁気的誘導等の手段で薬剤成分を担架された状態でデリバリーされた微量な磁気微粒子が、どの程度の量で集積され、２次元および３次元的にどのように分布しているかを磁気的方法により測定できる微量磁性微粒子測定検査装置の実用化のためには、検査細胞組織の試料の効率的な測定が要求される。従来技術の磁気的方法では、いかに微量な磁気微粒子を測定するかに主眼が置かれ、２次元および３次元的な微量な濃度分布を計測するための方法の具体的な提案は従来なされていない。   In a cell tissue containing cancer cells (hereinafter referred to as a test cell tissue), for example, how much a minute amount of magnetic fine particles delivered in a state where a drug component is suspended by means such as magnetic induction is accumulated. Therefore, in order to put into practical use a minute magnetic particle measuring and testing apparatus that can measure the distribution in two dimensions and three dimensions by a magnetic method, efficient measurement of a sample of a test cell tissue is required. The The prior art magnetic method focuses on how to measure a minute amount of magnetic fine particles, and no concrete proposal has been made for a method for measuring a two-dimensional and three-dimensional minute concentration distribution. .

従来の磁気的方法では、細胞組織試料あるいは微量な磁気微粒子サンプルを収納する円盤容器上に、単数もしくは複数個固定して測定する方法が採られており、それぞれの試料の個別の計測を実施するのみであった。   In the conventional magnetic method, a method of measuring one or a plurality of samples on a disk container containing a cell tissue sample or a minute amount of magnetic fine particle sample is employed, and individual measurement of each sample is performed. It was only.

前述の従来技術では、光学顕微鏡で検査細胞組織の母体端面のスライス面を薄くスライスしながらその顕微鏡観察画像を取得し、検査細胞組織の母体の各断層断面画像を映像的に再構成し、２次元および３次元の画像を可視化する電子的多層画像構成手段を具備しているが、微量な磁性粒子を計測することを目的とするものではない。   In the above-described prior art, a microscopic observation image is obtained while thinly slicing the slice surface of the matrix end surface of the examination cell tissue with an optical microscope, and each tomographic cross-sectional image of the matrix of the examination cell tissue is visually reconstructed. Although electronic multilayer image forming means for visualizing three-dimensional and three-dimensional images is provided, it is not intended to measure a minute amount of magnetic particles.

本発明の目的は、磁気微粒子とＳＱＵＩＤ磁気センサーを用いて、微量な磁気微粒子を磁気的方法により、高感度に効率的に２次元および３次元的な微量な濃度分布を検出可能な微量磁性微粒子計測技術を提供することにある。   An object of the present invention is to use a magnetic fine particle and a SQUID magnetic sensor to detect a minute amount of magnetic fine particles by a magnetic method and to detect a two-dimensional and three-dimensional minute concentration distribution efficiently with high sensitivity. To provide measurement technology.

上記目的は、非磁性物質と結合した微少な磁気微粒子を含有する微量磁性薬剤を含む細胞組織の検体を収納する試料ホルダーを円周上に保持する円盤型試料ホルダーと、前記円盤型試料ホルダーをその中心軸の回りに回転させる回転手段と、前記検体を前記円盤型試料ホルダー上で昇降させる昇降手段と、前記検体の一部を切削除去する切削手段と、前記検体の一部を切削除去した部分を拡大撮影する画像取得手段と、前記検体を磁化する磁化手段と、磁化された標識化検体から発生する磁場を検出する磁気センサーと、前記磁気センサーを囲む磁気シールドとを有し、前記複数の円盤型試料ホルダーは前記円盤型試料ホルダーの回転により順次前記磁気シールドの外部から内部に挿入されるよう構成され、前記磁化手段は前記標識化検体を前記磁気シールドの外部で磁化し、前記磁気センサーは磁化された前記標識化検体から発生する磁場を前記磁気シールドの内部で検出し、前記磁場の検出と前記磁化とが並行して実行され、前記検体を連続的に切削し、切削前後に前記磁気センサーで磁化された前記標識化検体から発生する磁場を計測するよう構成するとともに、前記磁場を検出する際に、前記切削工程前後に計測された結果から、その差分を演算するよう構成したことを特徴とする微量磁性薬剤検出装置により達成される。
また、上記目的は、非磁性物質と結合した微少な磁気微粒子を含有する微量磁性薬剤を含む細胞組織の検体を収納する試料ホルダーを円周上に保持する円盤型試料ホルダーと、前記円盤型試料ホルダーをその中心軸の回りに回転させる回転手段と、前記検体を前記円盤型試料ホルダー上で昇降させる昇降手段と、前記検体の一部を切削除去する切削手段と、前記検体の一部を切削除去した部分を拡大撮影する画像取得手段と、前記検体を磁化する磁化手段と、磁化された標識化検体から発生する磁場を検出する磁気センサーと、前記磁気センサーを囲む磁気シールドとを有し、前記複数の円盤型試料ホルダーは前記円盤型試料ホルダーの回転により順次前記磁気シールドの外部から内部に挿入されるよう構成され、前記磁化手段は前記標識化検体を前記磁気シールドの外部で磁化し、前記磁気センサーは磁化された前記標識化検体から発生する磁場を前記磁気シールドの内部で検出し、前記磁場の検出と前記磁化とが並行して実行され、前記検体を連続的に切削し、切削前後に前記磁気センサーで磁化された前記標識化検体から発生する磁場を計測するよう構成するとともに、前記切削工程前後に前記磁場を計測する際に、検体を上昇させた後に切削を実行し、その後計測する前に検体を降下させて、検体を切削前の位置に戻して切削後の計測を実行し、その後再度検体を切削後の位置に上昇させ、前記切削後の検体を磁化する構成としたことを特徴とする微量磁性薬剤検出装置により達成される。 The object is to provide a sample holder for holding a sample holder for storing a specimen of a cell tissue containing a trace amount of a magnetic drug containing minute magnetic fine particles combined with a non-magnetic substance on the circumference, and the disc type sample holder. Rotating means for rotating around the central axis, elevating means for raising and lowering the specimen on the disk type sample holder, cutting means for cutting and removing a part of the specimen, and removing a part of the specimen A plurality of image acquisition means for magnifying a portion; magnetizing means for magnetizing the specimen; a magnetic sensor for detecting a magnetic field generated from the magnetized labeled specimen; and a magnetic shield surrounding the magnetic sensor; the disk-shaped sample holder is configured to be inserted from the outside to the inside of sequentially the magnetic shield by the rotation of the disk-shaped sample holder, wherein the magnetizing means the labeled analyte Magnetized in serial magnetic shield outside, the magnetic sensor detects a magnetic field generated from the labeled analyte which is magnetized in the interior of the magnetic shield, and detecting said magnetization of said magnetic field is performed in parallel, the The specimen is continuously cut and configured to measure the magnetic field generated from the labeled specimen magnetized by the magnetic sensor before and after cutting, and measured before and after the cutting process when detecting the magnetic field. This is achieved by a trace magnetic drug detecting device characterized in that the difference is calculated from the result .
Further, the object is to provide a disk-shaped sample holder for holding a sample holder for storing a specimen of a cellular tissue containing a trace amount of a magnetic drug containing minute magnetic fine particles combined with a non-magnetic substance on the circumference, and the disk-shaped sample. Rotating means for rotating the holder around its central axis, elevating means for raising and lowering the specimen on the disc-shaped sample holder, cutting means for cutting and removing a part of the specimen, and cutting a part of the specimen An image acquisition means for magnifying the removed portion; a magnetization means for magnetizing the specimen; a magnetic sensor for detecting a magnetic field generated from the magnetized labeled specimen; and a magnetic shield surrounding the magnetic sensor; The plurality of disk-type sample holders are configured to be sequentially inserted from the outside to the inside of the magnetic shield by the rotation of the disk-type sample holder, and the magnetization means is the labeling The body is magnetized outside the magnetic shield, the magnetic sensor detects the magnetic field generated from the magnetized labeled specimen inside the magnetic shield, and the detection of the magnetic field and the magnetization are performed in parallel. The specimen is continuously cut and the magnetic field generated from the labeled specimen magnetized by the magnetic sensor before and after the cutting is measured, and the specimen is measured when the magnetic field is measured before and after the cutting process. After cutting, perform cutting, lower the specimen before measurement, return the specimen to the position before cutting, perform measurement after cutting, then raise the specimen again to the position after cutting, This is achieved by a trace magnetic drug detection device characterized in that the specimen after cutting is magnetized.

前記細胞組織の検体を氷結固形化する冷却手段を前記円盤型試料ホルダーに具備することにより達成される。   This is achieved by providing the disk-type sample holder with cooling means for freezing and solidifying the specimen of the cell tissue.

前記冷却手段を液体冷媒で構成されることにより達成される。   This is achieved by configuring the cooling means with a liquid refrigerant.

前記冷却手段をドライアイスで冷却される液体冷媒で構成されることにより達成される。   This is achieved by configuring the cooling means with a liquid refrigerant cooled with dry ice.

前記冷却手段を電子冷却手段で冷却される液体冷媒で構成されることにより達成される。   This is achieved by configuring the cooling means with a liquid refrigerant cooled by an electronic cooling means.

前記冷却手段を電子冷却手段で冷却される非磁性蓄熱物質で構成されることにより達成される。   This is achieved by configuring the cooling means with a non-magnetic heat storage material cooled by an electronic cooling means.

前記冷却手段を電子冷却手段で冷却される非磁性ホルダーで構成されることにより達成される。   This is achieved by configuring the cooling means with a non-magnetic holder cooled by an electronic cooling means.

前記切削手段で切削後発生する切片を除去，回収する清掃手段を具備することにより達成される。   This is achieved by providing a cleaning means for removing and collecting a section generated after cutting by the cutting means.

また、上記目的は、非磁性物質と結合した微少な磁気微粒子を含有する微量磁性薬剤を含む細胞組織の検体を収納する試料ホルダーを円周上に保持する円盤型試料ホルダーと、前記円盤型試料ホルダーをその中心軸の回りに回転させる回転工程と、前記検体を前記円盤型試料ホルダー上で昇降させる昇降工程と、前記検体の一部を切削除去する切削工程と、前記検体の一部を切削除去した部分を拡大撮影する画像取得工程と、前記検体を磁化する磁化工程と、磁化された標識化検体から発生する磁場を検出する工程とが連続的もしくはプログラム化されて実行されることを特徴とする磁性薬剤検出方法であって、前記磁場を検出する工程で、切削工程前後に計測された結果から、その差分を演算する演算工程がなされることを特徴とする磁性薬剤検出方法により達成される。 Further, the object is to provide a disk-shaped sample holder for holding a sample holder for storing a specimen of a cellular tissue containing a trace amount of a magnetic drug containing minute magnetic fine particles combined with a non-magnetic substance on the circumference, and the disk-shaped sample. A rotating step of rotating the holder about its central axis, a lifting step of raising and lowering the specimen on the disk-type sample holder, a cutting step of cutting and removing a part of the specimen, and a part of the specimen being cut An image acquisition process for magnifying the removed portion, a magnetization process for magnetizing the specimen, and a process for detecting a magnetic field generated from the magnetized labeled specimen are performed continuously or programmed. magnetic a magnetic agent detection method, in the step of detecting the magnetic field, to the results measured before and after the cutting process, characterized in that the calculation step of calculating a difference is made to It is achieved by the agent detection methods.

また、上記目的は、非磁性物質と結合した微少な磁気微粒子を含有する微量磁性薬剤を含む細胞組織の検体を収納する試料ホルダーを円周上に保持する円盤型試料ホルダーと、前記円盤型試料ホルダーをその中心軸の回りに回転させる回転工程と、前記検体を前記円盤型試料ホルダー上で昇降させる昇降工程と、前記検体の一部を切削除去する切削工程と、前記検体の一部を切削除去した部分を拡大撮影する画像取得工程と、前記検体を磁化する磁化工程と、磁化された標識化検体から発生する磁場を検出する工程とが連続的もしくはプログラム化されて実行されることを特徴とする磁性薬剤検出方法であって、切削工程前後に計測される工程で、検体を上昇させる工程後に切削工程が実行され、その後計測される工程前に検体を降下させる工程を実行させ、検体を切削前の位置に戻して切削後の計測される工程を実行し、その後再度検体を切削後の位置に上昇させる工程が実施され、前記切削後の検体を磁化する磁化工程を実施する工程を有することを特徴とする磁性薬剤検出方法により達成される。 Further, the object is to provide a disk-shaped sample holder for holding a sample holder for storing a specimen of a cellular tissue containing a trace amount of a magnetic drug containing minute magnetic fine particles combined with a non-magnetic substance on the circumference, and the disk-shaped sample. A rotating step of rotating the holder about its central axis, a lifting step of raising and lowering the specimen on the disk-type sample holder, a cutting step of cutting and removing a part of the specimen, and a part of the specimen being cut An image acquisition process for magnifying the removed portion, a magnetization process for magnetizing the specimen, and a process for detecting a magnetic field generated from the magnetized labeled specimen are performed continuously or programmed. a magnetic agent detection method and, in the process to be measured before and after the cutting step, the cutting step after the step of raising the specimen is performed, to lower the sample before step that is subsequently measured To execute the extent, run the process to be measured after cutting back the specimen position before cutting, is subsequently step of raising the specimen again to the position after cutting performed, to magnetize the sample after the cutting magnetization It is achieved by a magnetic drug detection method characterized by comprising a step of performing a step.

前記円盤型試料ホルダーをその中心軸の回りに回転させる回転工程とその回転の半径方向に移送する半径方向移動工程を組み合わる工程が必要に応じてなされることにより達成される。   This is achieved by performing, as necessary, a step of combining a rotating step of rotating the disk-shaped sample holder around its central axis and a radial moving step of transferring in the radial direction of the rotation.

前記円盤型試料ホルダーをその中心軸の回りに回転させる回転工程と正逆方向の切り返し回転工程が必要に応じてなされることにより達成される。   This is achieved by performing a rotation process for rotating the disk-shaped sample holder about its central axis and a turn-back rotation process in the forward and reverse directions as necessary.

本発明によれば、磁気微粒子とＳＱＵＩＤ磁気センサーを用いて、微量な磁気微粒子を磁気的方法により、高感度に効率的に２次元および３次元的な微量な濃度分布を検出可能な微量磁性微粒子計測技術を提供できる。   According to the present invention, a minute amount of magnetic fine particles and a SQUID magnetic sensor can be used to detect a minute amount of magnetic fine particles by a magnetic method with high sensitivity and efficiently detecting a two-dimensional and three-dimensional minute concentration distribution. Can provide measurement technology.

以下、本発明の一実施例を添付した図にしたがって説明する。   Hereinafter, an embodiment of the present invention will be described with reference to the accompanying drawings.

本発明の実施例で説明する微量磁性薬剤検出装置及び磁性薬剤検出方法では、図１に示すような微量な磁性薬剤が適用される。また、本実施例による微量磁性薬剤検出装置において、磁場検出を行う近傍で使用される構成要素は、非磁性材料で構成されることが計測への磁気雑音の混入抑制の点から望ましい。   In the trace magnetic drug detection device and the magnetic drug detection method described in the embodiments of the present invention, a trace magnetic drug as shown in FIG. 1 is applied. In addition, in the trace magnetic drug detection device according to the present embodiment, it is desirable that the constituent elements used in the vicinity of performing magnetic field detection be made of a nonmagnetic material from the viewpoint of suppressing magnetic noise from being mixed into the measurement.

図３は、本実施例の微量磁性薬剤検出装置の構成を示す断面図であり、ＳＱＵＩＤ及び冷却系の構成を示す図である。
図３において、例えばイットリューム系の高温超電導材で構成れたＳＱＵＩＤセンサー６１は、円盤型試料ホルダー６２内細胞組織試料である検査細胞組織６３の端面とSQUID1との距離を小さくし、磁気信号の検出感度及び空間分解能を高くするために、円盤型試料ホルダー６２にＳＱＵＩＤ６１を接近して配置した構成とする。円盤型試料ホルダー６２にＳＱＵＩＤ６１を接近して配置するために、ＳＱＵＩＤ６１を液体窒素６４により直接冷却するのではなく、熱伝導率の高い銅ロッド６５及びサファイアロッド６６を介して
ＳＱＵＩＤ６１を間接的に冷却する構造を採用している。ＳＱＵＩＤ６１と銅ロッド６５との間にサファイアロッド６６を介することにより、銅ロッド６５から発生する磁気雑音の影響を低減する効果がある。 FIG. 3 is a cross-sectional view showing the configuration of the trace magnetic drug detection device of the present embodiment, and shows the configuration of the SQUID and the cooling system.
In FIG. 3, for example, a SQUID sensor 61 made of an yttrium-based high-temperature superconducting material reduces the distance between the end surface of the test cell tissue 63, which is a cell tissue sample in the disc-shaped sample holder 62, and SQUID1, and generates a magnetic signal. In order to increase the detection sensitivity and the spatial resolution, the SQUID 61 is arranged close to the disc-shaped sample holder 62. In order to place the SQUID 61 close to the disc-shaped sample holder 62, the SQUID 61 is not cooled directly by the liquid nitrogen 64 but is indirectly cooled via the copper rod 65 and the sapphire rod 66 having high thermal conductivity. The structure to be adopted is adopted. By interposing the sapphire rod 66 between the SQUID 61 and the copper rod 65, there is an effect of reducing the influence of magnetic noise generated from the copper rod 65.

真空断熱容器６７の外槽６７ａ，内槽６７ｂはＳＵＳやＦＲＰ等の非磁性材料で構成される。また、円盤型試料ホルダー６２内の微量な磁気微粒子とＳＱＵＩＤ６１の距離を小さくするために、ＳＱＵＩＤ６１と検査細胞組織６３の端面との間は、厚さ１mm以下の薄いサファイアウインドウ６８で隔てられている。磁場を高効率で検出するためには、
ＳＱＵＩＤ６１と検査細胞組織６３の端面の内部底面との距離は１.５mm 以下であることが望ましい。液体窒素６４は補給配管６９から補充される。外槽６７ａ，内槽６７ｂとの間は断熱真空空間である。 The outer tank 67a and the inner tank 67b of the vacuum heat insulating container 67 are made of a nonmagnetic material such as SUS or FRP. Further, in order to reduce the distance between the minute amount of magnetic fine particles in the disc-shaped sample holder 62 and the SQUID 61, the SQUID 61 and the end surface of the test cell tissue 63 are separated by a thin sapphire window 68 having a thickness of 1 mm or less. . In order to detect magnetic fields with high efficiency,
The distance between the SQUID 61 and the inner bottom surface of the end surface of the test cell tissue 63 is preferably 1.5 mm or less. Liquid nitrogen 64 is replenished from a replenishment pipe 69. A space between the outer tank 67a and the inner tank 67b is an adiabatic vacuum space.

検査細胞組織６３は非磁性材料で作製された円盤型試料ホルダー６２に固定された円筒状のサファイア支持筒７０内をスライドできるように挿入されている。これにより、上下移動機構７１で支持された上下移動体７２に端部を支持された上下ロッド７３により、検査細胞組織６３は円筒状のサファイア支持筒７０内を上下に昇降制御される。円盤型試料ホルダー６２内には、例えばドライアイス等で冷却されたアルコールや不凍液等の冷媒
７４が満たされているため、その冷熱で円筒状のサファイア支持筒７０は−８０℃の低温に冷やされ、検査細胞組織６３は氷結して固形化されている。 The test cell tissue 63 is inserted so as to be slidable in a cylindrical sapphire support cylinder 70 fixed to a disc-shaped sample holder 62 made of a nonmagnetic material. As a result, the test cell tissue 63 is controlled to move up and down in the cylindrical sapphire support cylinder 70 by the vertical rod 73 whose end is supported by the vertical movement body 72 supported by the vertical movement mechanism 71. Since the disk-shaped sample holder 62 is filled with a refrigerant 74 such as alcohol or antifreeze cooled with dry ice, the cylindrical sapphire support cylinder 70 is cooled to a low temperature of −80 ° C. by the cold heat. The test cell tissue 63 is frozen and solidified.

サファイア支持筒７０内面には、検査細胞組織６３との摩擦係数を低減するためにフッ素樹脂等の低摩擦係数を有する物質がコーティングされていることが望ましい。上下ロッド７３と円盤型試料ホルダー６２はベロー７５で気密的に一体化され、冷媒７４が漏れ出さないようにされている。また、サファイア支持筒７０下部と円盤型試料ホルダー６２は接着剤で気密的に一体化されている。円筒状のサファイア支持筒７０には、その内部に冷媒７４が入り込み検査細胞組織６３をより良く冷却するために、導入口を設けることが望ましい。   The inner surface of the sapphire support cylinder 70 is preferably coated with a material having a low friction coefficient such as a fluororesin in order to reduce the friction coefficient with the test cell tissue 63. The upper and lower rods 73 and the disk-shaped sample holder 62 are airtightly integrated with a bellows 75 so that the refrigerant 74 does not leak. Further, the lower part of the sapphire support cylinder 70 and the disc-shaped sample holder 62 are airtightly integrated with an adhesive. The cylindrical sapphire support cylinder 70 is desirably provided with an introduction port so that the coolant 74 enters the inside thereof to cool the examination cell tissue 63 better.

円盤型試料ホルダー６２は回転シャフト７６で回転制御される。円盤型試料ホルダー
６２と回転シャフト７６は接着剤等で気密的に一体化されている。回転シャフト７６は支持台７７上を移動可能な支持移動体７８内の磁気ノイズの少ない例えば超音波モータ（図示せず）で回転制御されている。また、上下移動体７２は、円盤型試料ホルダー６２と伴周りし、しかも回転シャフト７６を芯軸として上下移動機構７１により上下に昇降制御される。それぞれの制御は、電気演算制御装置７９から信号線８０を通じて操作される。 The disk type sample holder 62 is controlled to rotate by a rotating shaft 76. The disc-shaped sample holder 62 and the rotating shaft 76 are airtightly integrated with an adhesive or the like. The rotation shaft 76 is rotationally controlled by, for example, an ultrasonic motor (not shown) with little magnetic noise in the support moving body 78 that can move on the support base 77. Further, the vertical moving body 72 is moved up and down by the vertical moving mechanism 71 around the disk type sample holder 62 and with the rotary shaft 76 as a core axis. Each control is operated from the electric calculation control device 79 through the signal line 80.

円盤型試料ホルダー６２の回転位置検出を行うために、円盤型試料ホルダー６２の周辺部につけられたマーカー（図示せず）に位置検知装置８１からレーザー光を照射し、その反射光を位置検知装置内の光学センサーで読み取り、その情報を信号線８２で電気演算制御装置７９に送信する。   In order to detect the rotational position of the disk-shaped sample holder 62, a marker (not shown) attached to the periphery of the disk-shaped sample holder 62 is irradiated with laser light from the position detecting device 81, and the reflected light is reflected on the position detecting device. The information is read by the optical sensor, and the information is transmitted to the electric calculation control device 79 through the signal line 82.

また、ＳＱＵＩＤ６１の周囲は検査環境の磁気的ノイズを遮蔽するために、パーマロイ製等の外磁気シールド壁８３ａ，内磁気シールド壁８３ｂの二重の磁気シールド８３で囲われており、一部は円盤型試料ホルダー６２が出入りできるように開放されている。磁気シールド８３の外には、検査細胞組織３の端面部を切削する目的で、回転するセラミック等の素材で製作された鋭利な非磁性のカッター刃８４を有する等の切削手段である回転カッター８５が設けられている。回転カッター８５はモーター８６，上下昇降機構８７に支持された軸８８で、その回転数，位置を支持アーム８９を通じて電気演算制御装置７９からの信号線８０を通じて操作される。   Further, the periphery of the SQUID 61 is surrounded by a double magnetic shield 83 of an outer magnetic shield wall 83a and an inner magnetic shield wall 83b made of permalloy or the like in order to shield magnetic noise in the inspection environment, and part of the disk is a disk. The mold sample holder 62 is opened so that it can enter and exit. A rotary cutter 85, which is a cutting means such as a sharp nonmagnetic cutter blade 84 made of a material such as a rotating ceramic, is provided outside the magnetic shield 83 for the purpose of cutting the end face of the test cell tissue 3. Is provided. The rotary cutter 85 is a shaft 88 supported by a motor 86 and a vertical lift mechanism 87, and its rotational speed and position are operated through a support arm 89 through a signal line 80 from an electric arithmetic control device 79.

回転カッター８５の端部域には、カッター刃に付いた検査細胞組織６３の切削片を例えば空気吹き付け吸引機構等を有して除去し回収するクリーナ９０が、支持アーム９１回して支持アーム８９に設けられている。そして、その運転は電気演算制御装置７９からの信号線８０を通じて操作される。また、円盤型試料ホルダー６２の上部カバー９２に切削時に落ちた検査細胞組織６３の切削片は、例えば空気吹き付け吸引機構等を有して除去し回収するクリーナ９３で同様に除去される。そしてその運転は信号線９４を介して電気演算制御装置７９で操作される。   In the end region of the rotary cutter 85, a cleaner 90 that removes and collects a cut piece of the test cell tissue 63 attached to the cutter blade by using, for example, an air blowing suction mechanism or the like, and rotates the support arm 91 to the support arm 89. Is provided. The operation is operated through a signal line 80 from the electric arithmetic control device 79. In addition, the cut pieces of the test cell tissue 63 that have fallen on the upper cover 92 of the disk-type sample holder 62 during the cutting are similarly removed by a cleaner 93 that is removed and collected by, for example, an air blowing suction mechanism. The operation is operated by the electric arithmetic control device 79 via the signal line 94.

このようにして、円盤型試料ホルダー６２上に固形化された検査細胞組織６３は、カッター刃８４でその端面をスライス除去され回転方向に平行な面を露出する。検査細胞組織６３の端面を所定の厚さ例えば０.５mm 削りとられた後は、その端面を所定の円盤型試料ホルダー６２の回転位置で光学的な顕微鏡９５で撮影し、その画像データは例えばデジタルカメラ９６で信号化され、信号線９７を通じて電気演算制御装置７９に伝送されて電子的画像データとして保存される。検査細胞組織６３の端面部は、発光ダイオード等で構成された照明９８で撮影に必要な適切な照度が確保され、その制御は信号線９９を介して電気演算制御装置７９で操作される。こうして、端面を光学顕微鏡で撮影されて例えばデジタル化された第一画像データを取得する。   In this way, the test cell tissue 63 solidified on the disc-shaped sample holder 62 is sliced off by the cutter blade 84 to expose a surface parallel to the rotation direction. After the end surface of the test cell tissue 63 is cut to a predetermined thickness, for example, 0.5 mm, the end surface is photographed with an optical microscope 95 at a predetermined rotational position of the disc-shaped sample holder 62, and the image data is, for example, The signal is converted into a signal by the digital camera 96, transmitted to the electric arithmetic control device 79 through the signal line 97, and stored as electronic image data. The end surface portion of the test cell tissue 63 has an appropriate illuminance necessary for photographing with illumination 98 constituted by a light emitting diode or the like, and the control is operated by the electric arithmetic control device 79 via the signal line 99. In this way, the end face is photographed with an optical microscope, and for example, digitized first image data is acquired.

検査細胞組織６３内に含まれる微量な磁性薬剤を構成する微磁性粒子を磁化するための磁化用の永久磁石１００は、上限昇降機構１０１に支持された軸１０２に取り付けられ、信号線１０３を介してその昇降位置は電気演算制御装置７９で制御操作される。ここで、検査細胞組織６３内に含まれる微量１０の移動により、永久磁石１００円盤型試料ホルダー６２側に移動され、かつ円盤型試料ホルダーが回転して検査細胞組織６３の切削端面部を永久磁石の直下に移動させる。このようにして検査細胞組織６３内に含まれる微量な磁性薬剤を構成する微磁性粒子を磁化させる。   A permanent magnet for magnetization 100 for magnetizing fine magnetic particles constituting a small amount of magnetic drug contained in the test cell tissue 63 is attached to a shaft 102 supported by an upper limit elevating mechanism 101 and is connected via a signal line 103. The raising / lowering position of the lever is controlled by the electric calculation control device 79. Here, the movement of the trace amount 10 contained in the test cell tissue 63 is moved to the permanent magnet 100 disc sample holder 62 side, and the disc type sample holder rotates so that the cut end surface portion of the test cell tissue 63 is moved to the permanent magnet. Move it directly below. In this way, the fine magnetic particles constituting the minute amount of magnetic drug contained in the test cell tissue 63 are magnetized.

その後、一旦励磁用の永久磁石１００は、ＳＱＵＩＤ６１の磁気ノイズに成らない位置に円盤型試料ホルダー６２およびＳＱＵＩＤ６１側から離れるように移動させる。その後、円盤型試料ホルダー２を回転させて検査細胞組織３を磁気シールド２３で囲まれた
ＳＱＵＩＤ６１の直下に移動させる。ここで検査細胞組織６３端面部分をＳＱＵＩＤ６１直下で回転移動させ、ＳＱＵＩＤ６１をよぎる磁束変化量を精密に計測する。この際、測定精度を増すために、円盤型試料ホルダー６２をＳＱＵＩＤ６１の直下で複数回例えば
１０回、回転もしくは正逆運転による往復回転させて複数のデータを取得しデータを信号線１０４で電気演算制御装置７９に送信し、電気演算制御装置７９内でその平均値を算出して第一磁束量ａとしてそのデータを保存する。 Thereafter, the permanent magnet 100 for excitation is once moved away from the disk-shaped sample holder 62 and the SQUID 61 side to a position where the magnetic noise of the SQUID 61 does not occur. Thereafter, the disc-shaped sample holder 2 is rotated to move the test cell tissue 3 directly below the SQUID 61 surrounded by the magnetic shield 23. Here, the end surface portion of the test cell tissue 63 is rotated and moved directly below the SQUID 61, and the amount of magnetic flux change across the SQUID 61 is precisely measured. At this time, in order to increase the measurement accuracy, the disk-shaped sample holder 62 is rotated directly under the SQUID 61 a plurality of times, for example, 10 times, or reciprocally rotated by forward or reverse operation to obtain a plurality of data, and the data is electrically calculated by the signal line 104. The data is transmitted to the control device 79, the average value is calculated in the electric calculation control device 79, and the data is stored as the first magnetic flux amount a.

その後、円盤型試料ホルダー６２を回転させて検査細胞組織６３を磁気シールドの外に移動し、上下移動機構７１により上下移動体７２を所定の上昇量例えば０.５mm 上昇させ、上下ロッド７３によりサファイア支持筒７０内の検査細胞組織６３を０.５mm 上昇させる。その上昇分をカッター刃８４で切削して再び上下移動機構７１により上下移動体７２を切削前に上昇した量０.５mm 下降させ、上下ロッド７３によりサファイア支持筒７０内の検査細胞組織６３を０.５mm 下降させる。   Thereafter, the disc-shaped sample holder 62 is rotated to move the test cell tissue 63 to the outside of the magnetic shield, the vertical moving mechanism 71 is moved up by a predetermined rising amount, for example, 0.5 mm, and the vertical rod 73 is moved to sapphire. The test cell tissue 63 in the support tube 70 is raised by 0.5 mm. The ascending portion is cut by the cutter blade 84, and the vertical moving mechanism 71 lowers the vertical moving body 72 by 0.5 mm before the cutting, and the vertical rod 73 lowers the inspection cell tissue 63 in the sapphire support cylinder 70 to 0. Lower 5mm.

次に、今度は磁化させずにそのまま円盤型試料ホルダー６２を回転させて検査細胞組織６３を磁気シールドで囲まれたＳＱＵＩＤ６１の直下に移動させ、第一磁束量ａを取得した時と同様な操作で検査細胞組織６３端面部分の第一磁束量ｂのデータを取得する。   Next, the disc-shaped sample holder 62 is rotated as it is without being magnetized, and the test cell tissue 63 is moved directly below the SQUID 61 surrounded by the magnetic shield, and the same operation as that for obtaining the first magnetic flux amount a is performed. Thus, data of the first magnetic flux amount b of the end surface portion of the inspection cell tissue 63 is acquired.

次に、電気演算制御装置７９で第一磁束量ａから第一磁束量ｂを差し引いた第一の磁束差分量を求める。この操作により、第一磁束量ａから第一磁束量ｂの計測間に削除された第一の画像データが削除した検査細胞組織端面切片分の磁束量と計算される。   Next, a first magnetic flux difference amount obtained by subtracting the first magnetic flux amount b from the first magnetic flux amount a is obtained by the electric calculation control device 79. By this operation, the first image data deleted during the measurement of the first magnetic flux amount “a” to the first magnetic flux amount “b” is calculated as the magnetic flux amount of the test cell tissue end face section deleted.

第二の磁束量を計測するために、円盤型試料ホルダー６２を回転させて検査細胞組織
６３を磁気シールドの外に移動して上下移動機構７１により上下移動体７２を所定の上昇量０.５mm 上昇させる。 In order to measure the second magnetic flux amount, the disk-shaped sample holder 62 is rotated to move the test cell tissue 63 out of the magnetic shield, and the vertical moving mechanism 71 moves the vertical moving body 72 by a predetermined amount of 0.5 mm. Raise.

次に、カッター刃８４による切削操作は行わず、その端面を所定の円盤型試料ホルダー６２の回転位置で光学的な顕微鏡９５で撮影する。撮影された画像データは例えばデジタルカメラ９６で信号化され、信号線９７を通じて電気演算制御装置７９に伝送されて第二画像データとしてとして保存される。   Next, the cutting operation by the cutter blade 84 is not performed, and the end face is photographed with the optical microscope 95 at the rotation position of the predetermined disc-shaped sample holder 62. The photographed image data is converted into a signal by, for example, a digital camera 96, transmitted to the electric arithmetic control device 79 through the signal line 97, and stored as second image data.

次に、上限昇降機構１０１により永久磁石１００円盤型試料ホルダー６２側に移動して円盤型試料ホルダーが回転し、検査細胞組織６３の切削端面部を永久磁石の直下に移動して検査細胞組織６３内の微磁性粒子を磁化させる。   Next, the upper limit elevating mechanism 101 moves to the permanent magnet 100 disc type sample holder 62 side to rotate the disc type sample holder, and moves the cut end surface portion of the test cell tissue 63 directly below the permanent magnet to check the test cell tissue 63. The fine magnetic particles inside are magnetized.

その後、励磁用の永久磁石１００はＳＱＵＩＤ１の磁気ノイズにならない位置に、円盤型試料ホルダー６２およびＳＱＵＩＤ６１側から離れるように移動させる。移動後、円盤型試料ホルダー６２を回転させて検査細胞組織６３を磁気シールド８３で囲まれたSQUID
６１の直下に移動させる。その後、検査細胞組織６３端面部分をＳＱＵＩＤ６１直下で回転移動させ、円盤型試料ホルダー６２をＳＱＵＩＤ６１の直下で１０回、回転もしくは正逆運転による往復回転させて複数のデータを取得しデータを信号線１０４で電気演算制御装置７９に送信し、電気演算制御装置７９内でその平均値を算出し、第二磁束量ａとしてそのデータを保存する。 Thereafter, the permanent magnet 100 for excitation is moved away from the disk-shaped sample holder 62 and the SQUID 61 side to a position where the magnetic noise of the SQUID 1 is not generated. After the movement, the disc-shaped sample holder 62 is rotated so that the test cell tissue 63 is surrounded by the magnetic shield 83.
Move to just below 61. Thereafter, the end surface portion of the test cell tissue 63 is rotated and moved directly below the SQUID 61, and the disk-shaped sample holder 62 is rotated 10 times immediately below the SQUID 61, and reciprocally rotated by forward or reverse operation to obtain a plurality of data. Is transmitted to the electric calculation control device 79, the average value is calculated in the electric calculation control device 79, and the data is stored as the second magnetic flux amount a.

その後、円盤型試料ホルダー６２を回転させて検査細胞組織６３を磁気シールドの外に移動し、上下移動機構７１により上下移動体７２を所定の上昇量例えば０.５mm 上昇させ、上下ロッド７３により、サファイア支持筒７０内の検査細胞組織６３を０.５mm 上昇させ、その上昇分をカッター刃８４で切削し、再び、上下移動機構７１により上下移動体
７２を切削前に上昇した量０.５mm 下降させ、上下ロッド７３により、サファイア支持筒７０内の検査細胞組織６３を０.５mm 下降させる。 Thereafter, the disc-shaped sample holder 62 is rotated to move the test cell tissue 63 out of the magnetic shield, the vertical moving mechanism 71 is moved up by a predetermined rising amount, for example, 0.5 mm, and the vertical rod 73 is moved up and down. The test cell tissue 63 in the sapphire support cylinder 70 is raised by 0.5 mm, the rise is cut by the cutter blade 84, and the vertical movement mechanism 71 is again raised by the vertical movement mechanism 71 by 0.5 mm. The test cell tissue 63 in the sapphire support cylinder 70 is lowered by 0.5 mm by the upper and lower rods 73.

次に、今度は磁化させずにそのまま円盤型試料ホルダー６２を回転させて検査細胞組織３を磁気シールドで囲まれたＳＱＵＩＤ６１の直下に移動させ、第二磁束量ａを取得した時と同様な操作で検査細胞組織６３端面部分の第二磁束量ｂのデータを取得する。   Next, the same operation as when the second magnetic flux amount a is acquired by rotating the disc-shaped sample holder 62 as it is without being magnetized and moving the test cell tissue 3 directly below the SQUID 61 surrounded by the magnetic shield. Thus, data of the second magnetic flux amount b of the end surface portion of the test cell tissue 63 is acquired.

次に、電気演算制御装置７９で第二磁束量ａから第二磁束量ｂを差し引いた第二の磁束差分量を求める。この操作により、第二磁束量ａから第二磁束量ｂの計測間に削除された第二の画像データの検査細胞組織端面切片分の磁束量と計算される。次に、第三の磁束量を計測するために、円盤型試料ホルダー６２を回転させて検査細胞組織６３を磁気シールドの外に移動し、上下移動機構７１により上下移動体７２を所定の上昇量０.５mm 上昇させる。   Next, a second magnetic flux difference amount obtained by subtracting the second magnetic flux amount b from the second magnetic flux amount a is obtained by the electric calculation control device 79. By this operation, it is calculated as the magnetic flux amount corresponding to the test cell tissue end face section of the second image data deleted during the measurement of the second magnetic flux amount a to the second magnetic flux amount b. Next, in order to measure the third magnetic flux amount, the disk-shaped sample holder 62 is rotated to move the test cell tissue 63 out of the magnetic shield, and the vertical moving mechanism 71 moves the vertical moving body 72 to a predetermined ascending amount. Raise 0.5mm.

この作業を繰り返して各層のデータを所得し、電気演算制御装置７９に保存した各層毎のデータをデジタル処理し、画像データから検査細胞組織全体の立体画像化する。さらに、各層の磁束量データから同装置を使用して別途実験的に求めた微量磁性薬剤単体量と、測定磁束量の校正データから各切削層の磁束量から微量磁性薬剤量を計算により求め、検査細胞組織６３内の微量磁性薬剤量の分布から濃度分布を画像化し、光学的３Ｄ映像と重なるように微量磁性薬剤量の濃度分布を画像化することができる。画像化した画像は、モニター１０５に写しだされる。   By repeating this operation, the data of each layer is obtained, the data for each layer stored in the electric calculation control device 79 is digitally processed, and a three-dimensional image of the entire examination cell tissue is formed from the image data. Furthermore, the amount of the magnetic drug alone obtained experimentally separately from the magnetic flux amount data of each layer and the amount of the magnetic magnetic agent calculated from the magnetic flux amount of each cutting layer from the calibration data of the measured magnetic flux amount are obtained by calculation, The concentration distribution can be imaged from the distribution of the trace magnetic drug amount in the examination cell tissue 63, and the concentration distribution of the trace magnetic drug amount can be imaged so as to overlap the optical 3D image. The imaged image is displayed on the monitor 105.

また、検査装置は低温下で操作されるので大気中の水分が結露する。したがって、これを防止するために装置をカバーで覆い、除湿装置１０６で湿度を下げた空気をダクト107でカバー１０５ａ内に送風し、カバー１０５ａ内を僅かにカバー外の大気の圧力より高めに維持し、結露を防止するようにしている。   Further, since the inspection apparatus is operated at a low temperature, moisture in the atmosphere is condensed. Therefore, in order to prevent this, the device is covered with a cover, and air whose humidity has been reduced by the dehumidifying device 106 is blown into the cover 105a through the duct 107, and the inside of the cover 105a is kept slightly higher than the atmospheric pressure outside the cover. In order to prevent condensation.

以上、本実施例では、細胞組織試料の位置制御及び連続計測を容易操作でき、細胞組織試料を冷却固形化し、細胞組織試料を順次スライスし、その切片毎の画像撮影するともに、磁束量を切削前後の磁束量の差分値により求め、その磁性質量を精密に、かつ正確に計測できるので、細胞組織試料の厚さ方向の濃度分布を正確に効率良く計測することができ、細胞組織試料に含まれる磁性薬剤の総量と濃度分布を３次元的に画像データとともに計測し、その濃度分布を細胞組織試料の３次元画像とともにモニター１０５に表示し、可視化することができる効果がある。   As described above, in this embodiment, the position control and continuous measurement of the cell tissue sample can be easily operated, the cell tissue sample is cooled and solidified, the cell tissue sample is sequentially sliced, and images of each section are taken, and the amount of magnetic flux is cut. Since the magnetic mass can be accurately and accurately measured based on the difference between the amount of magnetic flux before and after, the concentration distribution in the thickness direction of the tissue sample can be accurately and efficiently measured. The total amount and concentration distribution of the magnetic drug to be measured are three-dimensionally measured together with the image data, and the concentration distribution can be displayed on the monitor 105 together with the three-dimensional image of the cell tissue sample and visualized.

なお、本実施例では細胞組織試料を固形化するのに、ドライアイスで冷却した冷媒を使用したが、ドライアイスの代わりに液体窒素や液体空気を使用しても同様な効果が生じる。   In the present embodiment, a refrigerant cooled with dry ice is used to solidify the cell tissue sample, but the same effect can be obtained by using liquid nitrogen or liquid air instead of dry ice.

図４は他の実施例を示す装置の概略構成図である。
図３の実施例では、検査細胞組織６３を氷結固形化するのに、ドライアイスで冷却した冷媒を使用したが、図４の実施例ではドライアイスの代わりにペルチェ素子等を用い、電磁ノイズが少ない電子冷凍装置１０８で冷却する構成としたものである。これにより、電子冷凍装置１０８への電力供給は電気演算制御装置７９に結線された配線１０９を介して行われる。 FIG. 4 is a schematic configuration diagram of an apparatus showing another embodiment.
In the embodiment of FIG. 3, a refrigerant cooled with dry ice is used to freeze and solidify the test cell tissue 63, but in the embodiment of FIG. 4, a Peltier element or the like is used instead of dry ice, and electromagnetic noise is generated. In this configuration, cooling is performed with a small number of electronic refrigeration apparatuses 108. As a result, power is supplied to the electronic refrigeration apparatus 108 through the wiring 109 connected to the electric arithmetic control apparatus 79.

本実施例によれば、ドライアイスを供給しなくても冷媒７４を冷却できるので、ドライアイス等の冷却源を購入冷凍保存する必要が無く、さらに運転操作がより容易となる新たな効果が生じる。   According to the present embodiment, since the refrigerant 74 can be cooled without supplying dry ice, there is no need to purchase and store a cooling source such as dry ice, and a new effect that makes the operation easier becomes possible. .

図５は他の実施例を示す装置の概略構成図である。
図４の実施例では、検査細胞組織６３を氷結固形化するのに、ドライアイスで冷却した液体冷媒を使用したが、図５の実施例では液体冷媒の代わりに電子冷凍装置１０８で検査運転前に事前に時間をかけて冷却できるアルミニュームや銅のような蓄熱効果のある非磁性の蓄熱体１１１を配置する構成としたものである。このとき、蓋１１０は容器全体を断熱的に覆い、円盤型試料ホルダー６２は断熱性に優れた材料で構成する。サファイア支持筒７０と蓄熱体１１１は接着剤等で熱的に一体化されている。 FIG. 5 is a schematic configuration diagram of an apparatus showing another embodiment.
In the embodiment of FIG. 4, a liquid refrigerant cooled with dry ice is used to freeze and solidify the test cell tissue 63. However, in the embodiment of FIG. In addition, a non-magnetic heat storage body 111 having a heat storage effect, such as aluminum or copper that can be cooled over time, is arranged. At this time, the lid 110 covers the entire container in a heat-insulating manner, and the disc-shaped sample holder 62 is made of a material having excellent heat insulating properties. The sapphire support cylinder 70 and the heat storage body 111 are thermally integrated with an adhesive or the like.

本実施例によれば、液体冷媒を供給，補給しなくてもサファイア支持筒７０を冷却できるので運転操作がより容易となる効果が生じる。   According to the present embodiment, since the sapphire support cylinder 70 can be cooled without supplying and replenishing the liquid refrigerant, there is an effect that the operation operation becomes easier.

図６は他の実施例を示す装置の概略構成図である。
本実施例が図５の実施例と異なる点は、検査細胞組織６３を氷結固形化するのに、サファイア支持筒７０を電子冷凍装置１０８で直接冷却する構成とした点である。サファイア支持筒７０と電子冷凍装置１０８は接着剤等で熱的に一体化されている。 FIG. 6 is a schematic configuration diagram of an apparatus showing another embodiment.
This embodiment is different from the embodiment of FIG. 5 in that the sapphire support cylinder 70 is directly cooled by the electronic refrigeration apparatus 108 in order to freeze and solidify the test cell tissue 63. The sapphire support cylinder 70 and the electronic refrigeration apparatus 108 are thermally integrated with an adhesive or the like.

本実施例によれば、液体冷媒や蓄熱体を必要としないので装置構成が簡単となり装置がさらに軽量化できる新たな効果が生じる。   According to the present embodiment, since a liquid refrigerant or a heat storage body is not required, the apparatus configuration is simplified, and a new effect that the apparatus can be further reduced in weight is produced.

また、以上の実施例では、ＳＱＵＩＤ６１で測定する範囲を、円盤型試料ホルダー６２を支持台７７の一点の位置で、円盤型試料ホルダー６２を回転させて検査細胞組織６３がＳＱＵＩＤ６１直下をよぎる際の磁場変化量で磁束量を計測していたが、円盤型試料ホルダー６２をＳＱＵＩＤ６１直下で小刻みに移動させることにより、検査細胞組織６３端面の移動円周平面内の小領域間の磁束変化を測定することで、検査細胞組織６３端面内の回転方向の円周方向磁束量分布も測定可能となる。この場合、支持移動台を円盤型試料ホルダー６２の回転半径方向に移動制御し、同様な計測を実施することにより、検査細胞組織６３端面内の回転方向の半径方向磁束量分布も測定可能となる効果が生じる。   In the above embodiment, the range measured by the SQUID 61 is the same as that when the test cell tissue 63 crosses directly under the SQUID 61 by rotating the disc type sample holder 62 with the disc type sample holder 62 at one point of the support base 77. The amount of magnetic flux was measured by the amount of change in the magnetic field, but the change in magnetic flux between the small regions in the moving circumferential plane of the end surface of the test cell tissue 63 is measured by moving the disc-shaped sample holder 62 in small increments immediately below the SQUID 61. Thus, the circumferential magnetic flux distribution in the rotation direction within the end surface of the test cell tissue 63 can also be measured. In this case, it is possible to measure the radial magnetic flux distribution in the rotational direction in the end surface of the test cell tissue 63 by controlling the movement of the support moving table in the rotational radial direction of the disk-shaped sample holder 62 and performing the same measurement. An effect is produced.

なお、本発明では検査細胞組織６３を寒天等の常温固形剤で固形化すれば、冷却源および結露防止構造は不要となり、さらに運転効率よく細胞組織試料に含まれる磁性薬剤の総量と濃度分布を３次元的に画像データとともに計測し、その濃度分布を作成できる。   In the present invention, if the test cell tissue 63 is solidified with a normal temperature solid agent such as agar, a cooling source and a dew condensation prevention structure are not required, and the total amount and concentration distribution of the magnetic drug contained in the cell tissue sample can be obtained more efficiently. It is possible to measure three-dimensionally together with image data and create a density distribution.

以上、本発明によれば、細胞組織試料の位置制御及び連続計測を容易操作でき、細胞組織試料を冷却固形化し、細胞組織試料を順次スライスし、その切片毎の画像撮影するともに、磁束量を切削前後の磁束量の差分値により求め、その磁性質量を精密に、かつ正確に計測できるので、細胞組織試料の厚さ方向，平面方向の濃度分布を正確に効率良く計測することができ、細胞組織試料に含まれる磁性薬剤の総量と濃度分布を３次元的に画像データとともに計測し、その濃度分布を細胞組織試料の３次元画像とともにモニター１０５に表示し、可視化することができる効果がある。   As described above, according to the present invention, the position control and continuous measurement of the cell tissue sample can be easily performed, the cell tissue sample is cooled and solidified, the cell tissue sample is sequentially sliced, and the image of each section is taken, and the amount of magnetic flux is reduced. Since the magnetic mass can be accurately and accurately measured based on the difference value of the magnetic flux before and after cutting, the concentration distribution in the thickness direction and plane direction of the cell tissue sample can be accurately and efficiently measured. The total amount and concentration distribution of the magnetic drug contained in the tissue sample can be measured three-dimensionally together with the image data, and the concentration distribution can be displayed on the monitor 105 together with the three-dimensional image of the cell tissue sample for visualization.

以上のごとく本発明は、検査細胞組織内に３次元的に分布した微量な磁気微粒子に外部磁場を印加する手段として磁石又は磁場発生コイルが磁気シールドの外部に配置され、微量な磁気微粒子から発生する磁場を検出する磁気センサーが磁気シールドの内部に配置される。微量な磁気微粒子を含有する検査細胞組織を収納する円盤型試料ホルダーは、非磁性体から構成される円盤型試料ホルダーの円周上に保持される。   As described above, in the present invention, a magnet or a magnetic field generating coil is disposed outside a magnetic shield as a means for applying an external magnetic field to a minute amount of magnetic fine particles distributed three-dimensionally in a test cell tissue, and is generated from the minute amount of magnetic fine particles. A magnetic sensor for detecting a magnetic field is disposed inside the magnetic shield. A disk-type sample holder for storing a test cell tissue containing a minute amount of magnetic fine particles is held on the circumference of a disk-type sample holder made of a non-magnetic material.

非磁性の円盤型試料ホルダーは、複数の円盤型試料ホルダーを円周上に固定する機構を具備する。円盤型試料ホルダーは、超音波モーターから構成される回転機構により回転可能である。ＳＱＵＩＤ磁気センサーは、磁気シールド装置の内部に配置される。円盤型試料ホルダーを磁気シールド装置内に挿入するための移動機構及び位置調整機構が設けられる。   The non-magnetic disc type sample holder includes a mechanism for fixing a plurality of disc type sample holders on the circumference. The disc-shaped sample holder can be rotated by a rotation mechanism composed of an ultrasonic motor. The SQUID magnetic sensor is disposed inside the magnetic shield device. A moving mechanism and a position adjusting mechanism for inserting the disk-shaped sample holder into the magnetic shield device are provided.

円盤型試料ホルダーの回転位置検出を行うために、円盤型試料ホルダーの周辺部につけられたマーカーにレーザー光を照射し、その反射光を光学センサーで読み取ることによって位置検出を行う機構が設けられる。円盤型ホルダーの一部が磁気シールドの外部に露出するように、磁気シールドの一部には円盤型ホルダー及び上記の回転機構を通すための穴が空けられており、ある位置の円盤型試料ホルダーに設置された試料中の微量な磁気微粒子から発生する磁場の計測中も上記の磁石又は磁場発生コイルにより、上記のある位置と異なる位置の円盤型試料ホルダーの試料中の微量な磁気微粒子を磁化させることが可能なように構成される。   In order to detect the rotational position of the disk-shaped sample holder, a mechanism is provided that detects the position by irradiating a marker attached to the periphery of the disk-shaped sample holder with laser light and reading the reflected light with an optical sensor. A part of the magnetic shield has a hole for passing the disk type holder and the above rotating mechanism so that a part of the disk type holder is exposed to the outside of the magnetic shield. During the measurement of the magnetic field generated from a minute amount of magnetic fine particles in a sample placed on the magnet, the minute amount of magnetic fine particles in the sample of the disk-shaped sample holder at a position different from the above position is magnetized by the magnet or the magnetic field generating coil. It is configured to be able to be made.

一方、資料容器に固定された検査細胞組織は、磁気シールドの外部で回転するセラミック等の素材で製作された鋭利な非磁性のカッター刃等の切削手段でその端面を厚さ１μｍ以上の所定の厚さで削りとられ、その端面を所定の円盤型試料ホルダーの回転位置で光学的な顕微鏡で撮影し、その画像データはパーソナルコンピュータ等の電子的画像保存され、加工装置及びカッティング，回転駆動制御は、電気的制御装置でコントロールされることが可能なように構成される。ここで、検査細胞組織を冷凍装置等の固形化手段で例えば氷結させ固相状態を維持させることが可能なように構成される。   On the other hand, the test cell tissue fixed to the data container is formed with a predetermined non-cutting thickness of 1 μm or more by a cutting means such as a sharp non-magnetic cutter blade made of a material such as ceramic rotating outside the magnetic shield. The thickness is cut off, and the end face is photographed with an optical microscope at the rotation position of a predetermined disc-shaped sample holder. The image data is stored in an electronic image such as a personal computer, and the processing device, cutting, and rotation drive control are performed. Is configured to be controlled by an electrical control device. Here, it is configured such that the test cell tissue can be frozen, for example, by solidification means such as a refrigeration apparatus and the solid phase state can be maintained.

このようにして、円盤型試料ホルダー上に固形化された検査細胞組織は、切削手段でその端面をスライス除去され回転方向に平行な面を露出し、円盤型試料ホルダーを回転させて検査細胞組織を光学顕微鏡直下に移動させ、まずその端面を光学顕微鏡で撮影されて例えばデジタル化された第一の画像データを取得する。なお、切削手段のカーター部は切削作業後、ふき取り容器内に移動し刃先部の切削片を十分に除去される。その後、励磁用の永久磁石を円盤型試料ホルダー側に移動させ、かつ、円盤型試料ホルダーを回転させて検査細胞組織を永久磁石直下に移動させ磁化させ、その後、一旦、励磁用の永久磁石を円盤型試料ホルダー側から離れるように移動させる。その後、円盤型試料ホルダーを回転させて検査細胞組織を磁気シールドで囲まれたＳＱＵＩＤ素子の直下に移動させ、検査細胞組織端面部分の第一磁束量ａのデータを取得する。   In this way, the test cell tissue solidified on the disk type sample holder is sliced by the cutting means to expose a surface parallel to the rotation direction, and the test sample tissue is rotated by rotating the disk type sample holder. Is moved directly under the optical microscope, and first, the end face is photographed with the optical microscope to obtain, for example, digitized first image data. In addition, the carter part of the cutting means is moved into the wiping container after the cutting operation, and the cutting pieces on the blade edge part are sufficiently removed. After that, the permanent magnet for excitation is moved to the disk-type sample holder side, and the disk-type sample holder is rotated to move the test cell tissue directly under the permanent magnet to be magnetized. Move away from the disk-shaped sample holder. Thereafter, the disc-shaped sample holder is rotated to move the test cell tissue directly below the SQUID element surrounded by the magnetic shield, and data on the first magnetic flux amount a at the end surface portion of the test cell tissue is acquired.

その後、円盤型試料ホルダーを回転させて検査細胞組織を磁気シールドの外に移動し、微量昇降手段で所定の距離分上昇させ、切削手段でその昇降分の端部をスライス除去する。次に、今度はそのまま円盤型試料ホルダーを回転させて検査細胞組織を磁気シールドで囲まれたＳＱＵＩＤ素子の直下に移動させ、検査細胞組織端面部分の第一磁束量ｂのデータを取得する。そして、電子演算手段で第一磁束量ａから第一磁束量ｂを差し引いた第一の磁束差分量が、第一磁束量ａから第一磁束量ｂの計測間に削除された第一の画像データの検査細胞組織端面部分の磁束量と計算される。この作業を繰り返して各層のデータを所得し、各層毎のデータを画像化することで、光学的３Ｄ映像と重なるように磁束量の濃度分布を画像化することができる。   Thereafter, the disk-shaped sample holder is rotated to move the test cell tissue out of the magnetic shield, raised by a predetermined distance by a minute lifting / lowering means, and sliced and removed by the cutting means. Next, this time, the disk-shaped sample holder is rotated as it is to move the examination cell tissue directly below the SQUID element surrounded by the magnetic shield, and data on the first magnetic flux amount b at the end portion of the examination cell tissue is acquired. The first image obtained by subtracting the first magnetic flux amount b from the first magnetic flux amount a by the electronic computing means is deleted during the measurement of the first magnetic flux amount b from the first magnetic flux amount a. Examination of data Calculated as the amount of magnetic flux at the end surface portion of the tissue. By repeating this operation, the data of each layer is obtained, and the data for each layer is imaged, whereby the concentration distribution of the magnetic flux amount can be imaged so as to overlap the optical 3D image.

本発明の微量磁性薬剤検出装置は、微量な磁気微粒子から発生する磁場を高感度に検出するＳＱＵＩＤ，ＳＱＵＩＤを冷却するクライオスタット，ＳＱＵＩＤを駆動する駆動回路を有し、ＳＱＵＩＤの出力を収集し、表示及び加算処理を行う装置を有する。また、
ＳＱＵＩＤをレーザー又はハロゲンランプの光源によって超電導転移温度以上に加熱して、磁気雑音の原因となる磁束トラップを除去するためのＳＱＵＩＤ昇温用光源を有する。この磁束トラップの除去は、磁場の計測に先立って実行される。 The trace magnetic drug detection device of the present invention has a SQUID that detects a magnetic field generated from a minute amount of magnetic fine particles with high sensitivity, a cryostat that cools the SQUID, and a drive circuit that drives the SQUID, and collects and displays the output of the SQUID. And a device for performing addition processing. Also,
A SQUID temperature increasing light source is provided for heating the SQUID to a superconducting transition temperature or higher by a laser or halogen lamp light source to remove magnetic flux traps that cause magnetic noise. The removal of the magnetic flux trap is executed prior to the measurement of the magnetic field.

なお、本発明の微量磁性薬剤検出装置では、磁気センサーの検出コイル面と検査細胞組織端面との距離をｄとした時、隣接する試料もしくは磁気を有する部品等をｄ√２以上の間隔を置いて配置して、即ち、隣接する試料もしくは磁気を有する部品等との間のギャップ距離をｄ√２以上として、隣接する部材から発する磁気信号の干渉を抑制している。また、ＳＱＵＩＤの磁気雑音の原因となる磁束トラップを短時間で除去するために、SQUID昇温用光源を設けている。円盤型試料ホルダーのための回転機構には磁気雑音の小さな超音波モーターを使用した。微量な磁気微粒子の磁気信号をより正確に計測するために、円盤型試料ホルダーを複数回回転させて、試料が回転している状態で、１回転毎に微量な磁気微粒子の磁気信号を計測し、加算平均を行えるようにしている。   In the trace magnetic drug detection device of the present invention, when the distance between the detection coil surface of the magnetic sensor and the end surface of the test cell tissue is d, an adjacent sample or a magnetic part is placed at an interval of d√2 or more. In other words, interference between magnetic signals emitted from adjacent members is suppressed by setting the gap distance between adjacent samples or magnetized parts to be d√2 or more. In addition, a SQUID temperature raising light source is provided in order to quickly remove magnetic flux traps that cause SQUID magnetic noise. An ultrasonic motor with low magnetic noise was used as the rotating mechanism for the disk-shaped sample holder. To more accurately measure the magnetic signal of a minute amount of magnetic particles, rotate the disk-shaped sample holder multiple times, and measure the magnetic signal of a minute amount of magnetic particles every rotation while the sample is rotating. , So that the averaging can be performed.

以上、本発明の微量磁性薬剤検出装置を要約すると、以下の通りである。細胞組織試料の位置制御及び連続計測を容易にするため、回転機構により回転制御可能な固形化手段を有する円盤型試料ホルダーを用いた。細胞組織試料を順次スライスし、その切片毎の磁束量を切削前後の磁束量の差分値により求める計測の検出方法を用いた。   The trace magnetic drug detection device of the present invention is summarized as follows. In order to facilitate the position control and continuous measurement of the cell tissue sample, a disk-type sample holder having a solidification means that can be rotationally controlled by a rotating mechanism was used. A detection method for measurement was used in which a cell tissue sample was sequentially sliced, and the amount of magnetic flux for each slice was determined from the difference value of the amount of magnetic flux before and after cutting.

以上のようにして、微量な磁気微粒子の計測において、細胞組織試料の厚さ方向の濃度分布を効率良く計測可能としている。   As described above, the concentration distribution in the thickness direction of the cell tissue sample can be efficiently measured in the measurement of a minute amount of magnetic fine particles.

微量な磁気微粒子を用いた磁性薬剤の構造を説明する図である。It is a figure explaining the structure of the magnetic chemical | medical agent using a trace amount magnetic particle. 従来の磁気微粒子をＳＱＵＩＤを用いてその磁束量を計測する装置の構造例を説明する図である。It is a figure explaining the structural example of the apparatus which measures the magnetic flux amount of the conventional magnetic fine particle using SQUID. 本発明の一実施例になる微量磁性薬剤検出装置の構成を説明する図である。It is a figure explaining the structure of the trace magnetic chemical | medical agent detection apparatus which becomes one Example of this invention. 本発明の他の実施例になる微量磁性薬剤検出装置の構成を説明する図である。It is a figure explaining the structure of the trace magnetic chemical | medical agent detection apparatus which becomes another Example of this invention. 本発明の他の実施例になる微量磁性薬剤検出装置の構成を説明する図である。It is a figure explaining the structure of the trace magnetic chemical | medical agent detection apparatus which becomes another Example of this invention. 本発明の他の実施例になる微量磁性薬剤検出装置の構成を説明する図である。It is a figure explaining the structure of the trace magnetic chemical | medical agent detection apparatus which becomes another Example of this invention.

符号の説明Explanation of symbols

４ 回転機構
６１ 高温超電導ＳＱＵＩＤ
６２ 円盤型試料ホルダー
６３ 検査細胞組織
６４ 液体窒素
６５ 銅ロッド
６６ サファイアロッド
６７ 真空断熱容器
６８ サファイアウインドウ
７０ サファイア支持筒
７１ 上下移動機構
７２ 上下移動体
７３ 上下ロッド
７４ 冷媒
７６ 回転シャフト
７９ 電気演算制御装置
８３，８３ａ，８３ｂ 磁気シールド
８４ カッター刃
８７ 上下昇降機構
９０ クリーナ
９５ 顕微鏡
９６ デジタルカメラ
１００ 永久磁石
１０１ 上限昇降機構
１０５ モニター
１０５ａ カバー
１０６ 除湿装置
１０８ 電子冷凍装置
１０９ 配線
１１１ 蓄熱体 4 Rotating mechanism 61 High-temperature superconducting SQUID
62 Disk type sample holder 63 Test cell tissue 64 Liquid nitrogen 65 Copper rod 66 Sapphire rod 67 Vacuum heat insulating container 68 Sapphire window 70 Sapphire support cylinder 71 Vertical moving mechanism 72 Vertical moving body 73 Vertical rod 74 Refrigerant 76 Rotating shaft 79 Electric calculation control device 83, 83a, 83b Magnetic shield 84 Cutter blade 87 Vertical elevating mechanism 90 Cleaner 95 Microscope 96 Digital camera 100 Permanent magnet 101 Upper limit elevating mechanism 105 Monitor 105a Cover 106 Dehumidifying device 108 Electronic refrigerating device 109 Wiring 111 Heat storage body

Claims (13)

非磁性物質と結合した微少な磁気微粒子を含有する微量磁性薬剤を含む細胞組織の検体を収納する試料ホルダーを円周上に保持する円盤型試料ホルダーと、前記円盤型試料ホルダーをその中心軸の回りに回転させる回転手段と、前記検体を前記円盤型試料ホルダー上で昇降させる昇降手段と、前記検体の一部を切削除去する切削手段と、前記検体の一部を切削除去した部分を拡大撮影する画像取得手段と、前記検体を磁化する磁化手段と、磁化された標識化検体から発生する磁場を検出する磁気センサーと、前記磁気センサーを囲む磁気シールドとを有し、
前記複数の円盤型試料ホルダーは前記円盤型試料ホルダーの回転により順次前記磁気シールドの外部から内部に挿入されるよう構成され、前記磁化手段は前記標識化検体を前記磁気シールドの外部で磁化し、前記磁気センサーは磁化された前記標識化検体から発生する磁場を前記磁気シールドの内部で検出し、前記磁場の検出と前記磁化とが並行して実行され、前記検体を連続的に切削し、切削前後に前記磁気センサーで磁化された前記標識化検体から発生する磁場を計測するよう構成するとともに、
前記磁場を検出する際に、前記切削工程前後に計測された結果から、その差分を演算するよう構成したことを特徴とする微量磁性薬剤検出装置。 A sample holder for holding a sample holder for storing a specimen of a cellular tissue containing a minute amount of magnetic drug containing minute magnetic fine particles combined with a non-magnetic substance on the circumference, and the disk-type sample holder on the center axis Rotating means for rotating around, lifting / lowering means for moving the specimen up and down on the disc-shaped sample holder, cutting means for cutting and removing a part of the specimen, and enlarged photographing of a part where the specimen is cut and removed Image acquisition means, magnetizing means for magnetizing the specimen, a magnetic sensor for detecting a magnetic field generated from the magnetized labeled specimen , and a magnetic shield surrounding the magnetic sensor,
The plurality of disk-type sample holders are configured to be sequentially inserted from the outside of the magnetic shield by the rotation of the disk-type sample holder, and the magnetizing means magnetizes the labeled specimen outside the magnetic shield, The magnetic sensor detects a magnetic field generated from the magnetized labeled specimen inside the magnetic shield, the detection of the magnetic field and the magnetization are performed in parallel, and the specimen is continuously cut and cut. While configured to measure the magnetic field generated from the labeled specimen magnetized by the magnetic sensor before and after ,
When detecting the said magnetic field, it comprised so that the difference might be calculated from the result measured before and after the said cutting process, The trace magnetic chemical | medical agent detection apparatus characterized by the above-mentioned. 非磁性物質と結合した微少な磁気微粒子を含有する微量磁性薬剤を含む細胞組織の検体を収納する試料ホルダーを円周上に保持する円盤型試料ホルダーと、前記円盤型試料ホルダーをその中心軸の回りに回転させる回転手段と、前記検体を前記円盤型試料ホルダー上で昇降させる昇降手段と、前記検体の一部を切削除去する切削手段と、前記検体の一部を切削除去した部分を拡大撮影する画像取得手段と、前記検体を磁化する磁化手段と、磁化された標識化検体から発生する磁場を検出する磁気センサーと、前記磁気センサーを囲む磁気シールドとを有し、A sample holder for holding a sample holder for storing a specimen of a cellular tissue containing a minute amount of magnetic drug containing minute magnetic fine particles combined with a non-magnetic substance on the circumference, and the disk-type sample holder on the center axis Rotating means for rotating around, lifting / lowering means for moving the specimen up and down on the disc-shaped sample holder, cutting means for cutting and removing a part of the specimen, and enlarged photographing of a part where the specimen is cut and removed Image acquisition means, magnetizing means for magnetizing the specimen, a magnetic sensor for detecting a magnetic field generated from the magnetized labeled specimen, and a magnetic shield surrounding the magnetic sensor,
前記複数の円盤型試料ホルダーは前記円盤型試料ホルダーの回転により順次前記磁気シールドの外部から内部に挿入されるよう構成され、前記磁化手段は前記標識化検体を前記磁気シールドの外部で磁化し、前記磁気センサーは磁化された前記標識化検体から発生する磁場を前記磁気シールドの内部で検出し、前記磁場の検出と前記磁化とが並行して実行され、前記検体を連続的に切削し、切削前後に前記磁気センサーで磁化された前記標識化検体から発生する磁場を計測するよう構成するとともに、  The plurality of disk-type sample holders are configured to be sequentially inserted from the outside of the magnetic shield by the rotation of the disk-type sample holder, and the magnetizing means magnetizes the labeled specimen outside the magnetic shield, The magnetic sensor detects a magnetic field generated from the magnetized labeled specimen inside the magnetic shield, the detection of the magnetic field and the magnetization are performed in parallel, and the specimen is continuously cut and cut. While configured to measure the magnetic field generated from the labeled specimen magnetized by the magnetic sensor before and after,
前記切削工程前後に前記磁場を計測する際に、検体を上昇させた後に切削を実行し、その後計測する前に検体を降下させて、検体を切削前の位置に戻して切削後の計測を実行し、その後再度検体を切削後の位置に上昇させ、前記切削後の検体を磁化する構成としたことを特徴とする微量磁性薬剤検出装置。  When measuring the magnetic field before and after the cutting process, perform cutting after raising the specimen, then lower the specimen before measuring, and return the specimen to the position before cutting to perform measurement after cutting The specimen is then raised again to the position after cutting, and the specimen after cutting is magnetized. 請求項１または２に記載の微量磁性薬剤検出装置において、
前記細胞組織の検体を氷結固形化する冷却手段を前記円盤型試料ホルダーに具備することを特徴とする微量磁性薬剤検出装置。 In the trace magnetic chemical | medical agent detection apparatus of Claim 1 or 2 ,
An apparatus for detecting a minute amount of magnetic drug, comprising a cooling means for freezing and solidifying the specimen of the cell tissue in the disk-type sample holder. 請求項３に記載の微量磁性薬剤検出装置において、
前記冷却手段を液体冷媒で構成されることを特徴とする微量磁性薬剤検出装置。 In the trace magnetic chemical | medical agent detection apparatus of Claim 3 ,
A trace magnetic drug detection device, wherein the cooling means is composed of a liquid refrigerant. 請求項３に記載の微量磁性薬剤検出装置において、
前記冷却手段をドライアイスで冷却される液体冷媒で構成されることを特徴とする微量磁性薬剤検出装置。 In the trace magnetic chemical | medical agent detection apparatus of Claim 3 ,
An apparatus for detecting a minute amount of magnetic drug, wherein the cooling means is composed of a liquid refrigerant cooled by dry ice. 請求項３に記載の微量磁性薬剤検出装置において、
前記冷却手段を電子冷却手段で冷却される液体冷媒で構成されることを特徴とする微量磁性薬剤検出装置。 In the trace magnetic chemical | medical agent detection apparatus of Claim 3 ,
An apparatus for detecting a minute amount of magnetic drug, wherein the cooling means is composed of a liquid refrigerant cooled by an electronic cooling means. 請求項３に記載の微量磁性薬剤検出装置において、
前記冷却手段を電子冷却手段で冷却される非磁性蓄熱物質で構成されることを特徴とする微量磁性薬剤検出装置。 In the trace magnetic chemical | medical agent detection apparatus of Claim 3 ,
An apparatus for detecting a minute amount of magnetic drug, wherein the cooling means is composed of a non-magnetic heat storage material cooled by an electronic cooling means. 請求項３に記載の微量磁性薬剤検出装置において、
前記冷却手段を電子冷却手段で冷却される非磁性ホルダーで構成されることを特徴とする微量磁性薬剤検出装置。 In the trace magnetic chemical | medical agent detection apparatus of Claim 3 ,
An apparatus for detecting a minute amount of magnetic drug, wherein the cooling means is composed of a non-magnetic holder cooled by an electronic cooling means. 請求項１または２に記載の微量磁性薬剤検出装置において、
前記切削手段で切削後発生する切片を除去，回収する清掃手段を具備することを特徴とする微量磁性薬剤検出装置。 In the trace magnetic chemical | medical agent detection apparatus of Claim 1 or 2 ,
A trace magnetic drug detection device comprising a cleaning means for removing and collecting a section generated after cutting by the cutting means. 非磁性物質と結合した微少な磁気微粒子を含有する微量磁性薬剤を含む細胞組織の検体を収納する試料ホルダーを円周上に保持する円盤型試料ホルダーと、前記円盤型試料ホルダーをその中心軸の回りに回転させる回転工程と、前記検体を前記円盤型試料ホルダー上で昇降させる昇降工程と、前記検体の一部を切削除去する切削工程と、前記検体の一部を切削除去した部分を拡大撮影する画像取得工程と、前記検体を磁化する磁化工程と、磁化された標識化検体から発生する磁場を検出する工程とが連続的もしくはプログラム化されて実行されることを特徴とする磁性薬剤検出方法であって、
前記磁場を検出する工程で、切削工程前後に計測された結果から、その差分を演算する演算工程がなされることを特徴とする磁性薬剤検出方法。 A sample holder for holding a sample holder for storing a specimen of a cellular tissue containing a minute amount of magnetic drug containing minute magnetic fine particles combined with a non-magnetic substance on the circumference, and the disk-type sample holder on the center axis A rotating step for rotating the sample around, a lifting step for moving the sample up and down on the disc-shaped sample holder, a cutting step for cutting and removing a part of the sample, and a magnified image of a portion obtained by cutting and removing a part of the sample A magnetic drug detection method comprising: performing an image acquisition step, a magnetization step of magnetizing the specimen, and a step of detecting a magnetic field generated from the magnetized labeled specimen, continuously or programmed. Because
A magnetic drug detection method comprising a step of calculating a difference from results measured before and after the cutting step in the step of detecting the magnetic field. 非磁性物質と結合した微少な磁気微粒子を含有する微量磁性薬剤を含む細胞組織の検体を収納する試料ホルダーを円周上に保持する円盤型試料ホルダーと、前記円盤型試料ホルダーをその中心軸の回りに回転させる回転工程と、前記検体を前記円盤型試料ホルダー上で昇降させる昇降工程と、前記検体の一部を切削除去する切削工程と、前記検体の一部を切削除去した部分を拡大撮影する画像取得工程と、前記検体を磁化する磁化工程と、磁化された標識化検体から発生する磁場を検出する工程とが連続的もしくはプログラム化されて実行されることを特徴とする磁性薬剤検出方法であって、
切削工程前後に計測される工程で、検体を上昇させる工程後に切削工程が実行され、その後計測される工程前に検体を降下させる工程を実行させ、検体を切削前の位置に戻して切削後の計測される工程を実行し、その後再度検体を切削後の位置に上昇させる工程が実施され、前記切削後の検体を磁化する磁化工程を実施する工程を有することを特徴とする磁性薬剤検出方法。 A sample holder for holding a sample holder for storing a specimen of a cellular tissue containing a minute amount of magnetic drug containing minute magnetic fine particles combined with a non-magnetic substance on the circumference, and the disk-type sample holder on the center axis A rotating step for rotating the sample around, a lifting step for moving the sample up and down on the disc-shaped sample holder, a cutting step for cutting and removing a part of the sample, and a magnified image of a portion obtained by cutting and removing a part of the sample A magnetic drug detection method comprising: performing an image acquisition step, a magnetization step of magnetizing the specimen, and a step of detecting a magnetic field generated from the magnetized labeled specimen, continuously or programmed. Because
In the process that is measured before and after the cutting process, the cutting process is executed after the process of raising the specimen, and the process of lowering the specimen is executed before the process to be measured thereafter, and the specimen is returned to the position before cutting and after the cutting. A method of detecting a magnetic drug, comprising performing a step of measuring, then performing a step of raising the specimen again to a position after cutting, and performing a magnetization step of magnetizing the specimen after cutting. 請求項１０または１１に記載の磁性薬剤検出方法において、
前記円盤型試料ホルダーをその中心軸の回りに回転させる回転工程とその回転の半径方向に移送する半径方向移動工程を組み合わせる工程が必要に応じてなされることを特徴とする磁性薬剤検出方法。 The magnetic drug detection method according to claim 10 or 11 ,
A magnetic drug detection method comprising a step of combining a rotating step of rotating the disc-shaped sample holder about its central axis and a radial moving step of transferring the disc-shaped sample holder in the radial direction of the rotation as necessary. 請求項１０または１１に記載の磁性薬剤検出方法において、
前記円盤型試料ホルダーをその中心軸の回りに回転させる回転工程と正逆方向の切り返し回転工程が必要に応じてなされることを特徴とする磁性薬剤検出方法。 The magnetic drug detection method according to claim 10 or 11 ,
A magnetic drug detection method comprising: a rotating step of rotating the disk-shaped sample holder about its central axis and a turning-back rotating step in the forward and reverse directions as necessary.
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