TWI637722B - Magnetic detecting device and method for detecting using magnetic detecting device - Google Patents
Magnetic detecting device and method for detecting using magnetic detecting device Download PDFInfo
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Abstract
本發明揭露一種磁性檢測裝置及使用其檢測的方法，該磁性檢測裝置係包括：產生激發信號的激發單元；感測線圈組，其包含由該激發信號激發產生具有施加場強度的激發磁場之激發線圈；耦合線圈；容納含有磁物質之檢測標的之容器，該檢測標的具有磁團簇，該耦合線圈感應該磁團簇受該激發磁場磁化而產生額外的交流電磁化係數所造成的電磁場，該交流電磁化係數具有相關H的時間振動磁化強度(M(t))；磁偵測裝置，係具有輸入線圈及磁偵測器，該輸入線圈感測M，且該磁偵測器測定時間相依相延遲(θ(t))；以及分析θ以導出時間相依反應遲緩時間(teff)的計算單元。The invention discloses a magnetic detecting device and a method for detecting the same, the magnetic detecting device comprising: an exciting unit for generating an excitation signal; and a sensing coil group including excitation by the excitation signal to generate an excitation magnetic field having an applied field strength a coil; a coupling coil; a container containing a detection target of a magnetic substance, the detection target having a magnetic cluster, the coupling coil sensing an electromagnetic field caused by the magnetic field of the magnetic cluster being generated by the excitation magnetic field to generate an additional alternating electromagnetic coefficient The alternating electromagnetic coefficient has a time-magnetized magnetization (M(t)) associated with H; the magnetic detecting device has an input coil and a magnetic detector, the input coil senses M, and the magnetic detector measures time dependent Phase delay (θ(t)); and a calculation unit that analyzes θ to derive a time-dependent response lag time (teff).
Description
本發明係一種磁性檢測裝置及使用其檢測的方法，特別是指一種測定時間相依相延遲且據此導出時間相依反應遲緩時間而得到檢測標的之濃度的磁性檢測裝置及使用其檢測的方法。The present invention relates to a magnetic detecting device and a method for detecting the same, and more particularly to a magnetic detecting device that measures a time-dependent phase delay and derives a time-dependent reaction delay time to obtain a target concentration, and a method of detecting the same.
導量子干涉裝置(SQUIDs)係磁通量最靈敏之偵測器，且已被應用於偵測微弱生物磁信號，即心磁描記術及腦磁圖，磁免疫檢測係利用磁奈米粒子作為標記之新診斷工具，在磁免疫檢測中，使用由生物功能化磁奈米粒子(BMNs)組成的試劑以作為生物標的之探針，當由BMNs組成的試劑與生物標的混合時，將變更BMNs與生物標的結合之後的試劑之磁特性，而磁特性之改變係藉著偵測及分析之後得知，以免疫檢測未知之生物分子的量。此外，磁特性亦可使用傳統感測器偵測，即磁通閘磁力計、巨磁阻感測器及Hall感測器。而為了改進偵測靈敏度，目前已發展基於超導量子干涉裝置的磁偵測系統，其偵測機制係基於例如：飽和磁化強度、剩餘磁化強度、Néel弛緩、Brownian弛緩及交流電磁化係數降低等方法，其已展示以2aM濃度之IgE抗原及以10 pg/mL濃度之血管內皮生長係數偵測生物標的之高-T c超導量子干涉裝置。 Guided quantum interference devices (SQUIDs) are the most sensitive detectors for magnetic flux and have been used to detect weak biomagnetic signals, namely magnetocardiography and magnetoencephalography. Magnetic immunoassays use magnetic nanoparticles as markers. A new diagnostic tool that uses magnetically-immunized magnetic nanoparticles (BMNs) as a biomarker for magnetic immunoassays. When a reagent consisting of BMNs is mixed with a biological standard, BMNs and organisms will be altered. The magnetic properties of the reagents after labeling, and the changes in magnetic properties are known by detection and analysis to immunodetect the amount of unknown biomolecules. In addition, the magnetic characteristics can also be detected using conventional sensors, namely a fluxgate magnetometer, a giant magnetoresistive sensor, and a Hall sensor. In order to improve the detection sensitivity, a magnetic detection system based on a superconducting quantum interference device has been developed, and the detection mechanism is based on, for example, saturation magnetization, residual magnetization, Néel relaxation, Brownian relaxation, and AC electromagnetic coefficient reduction. Methods, which have demonstrated a high-T c superconducting quantum interference device with a 2 aM concentration of IgE antigen and a vascular endothelial growth factor at a concentration of 10 pg/mL.
然而，在診斷輕微認知損害及阿茲海默症的生醫應用中所混合基於高-T c超導量子干涉裝置與頻率交流磁化率計的技術需使用兩種激發信號f 1與f 2，其係施加於輸入線圈且當BMNs與生物標的結合時偵測到f 1+ 2f 2的時間相依強度。接著，將分析交流磁化係數降低以測定生物標的的量。然而小於1 pg/mL之濃度的偵測靈敏性則需使用其它技術展現。 However, techniques based on high-T c superconducting quantum interference devices and frequency alternating magnetic susceptibility meters in the biomedical applications for diagnosing mild cognitive impairment and Alzheimer's disease require the use of two excitation signals f 1 and f 2 , It is applied to the input coil and the time dependent intensity of f 1 + 2f 2 is detected when the BMNs are combined with the biomarker. Next, the analytical AC magnetization coefficient is lowered to determine the amount of the biological target. However, the detection sensitivity of concentrations less than 1 pg/mL is demonstrated using other techniques.
因此，如何讓使用超導量子干涉裝置(SQUIDs)之偵測器得到更佳的濃度偵測靈敏性係本領域之重要課題。Therefore, how to obtain better concentration detection sensitivity using detectors of superconducting quantum interference devices (SQUIDs) is an important issue in the field.
本發明提供一種磁性檢測裝置，其包括：產生激發信號的激發單元；包含激發線圈、耦合線圈及容器的感測線圈組，其中：該激發線圈係與該激發單元耦接，以由該激發信號激發產生具有施加場強度(H)的激發磁場；該耦合線圈係對應該激發線圈而設置；且該容器係可容納含有或不含有磁物質之檢測標的，且對應該耦合線圈而設置，而含有該磁物質之檢測標的具有磁團簇，該耦合線圈感應該磁團簇受該激發磁場磁化而產生額外的交流電磁化係數所造成的電磁場，該交流電磁化係數具有相關該施加場強度的時間振動磁化強度(M(t))；具有對應設置之輸入線圈及磁偵測器的磁偵測裝置，該輸入線圈與該耦合線圈耦接以感測該時間振動磁化強度，且該磁偵測器測定相關於該施加場強度及該時間振動磁化強度的時間相依相延遲(θ(t))；以及與該磁偵測裝置耦接的計算單元，用以分析該時間相依相延遲以導出時間相依反應遲緩時間(t eff)，進而得到該檢測標的之濃度。 The invention provides a magnetic detecting device, comprising: an excitation unit for generating an excitation signal; a sensing coil group including an excitation coil, a coupling coil and a container, wherein: the excitation coil is coupled to the excitation unit to be excited by the excitation signal Excitation generates an excitation magnetic field having an applied field strength (H); the coupling coil is disposed corresponding to the excitation coil; and the container is capable of accommodating a detection target with or without a magnetic substance, and is disposed corresponding to the coupling coil, and contains The detection target of the magnetic substance has a magnetic cluster, and the coupling coil senses that the magnetic cluster is magnetized by the excitation magnetic field to generate an electromagnetic field caused by an additional alternating electromagnetic coefficient, and the alternating electromagnetic coefficient has a time related to the applied field strength. a vibration magnetization (M(t)); a magnetic detecting device having a corresponding input coil and a magnetic detector, the input coil being coupled to the coupling coil to sense the time vibration magnetization, and the magnetic detection Measuring a time dependent phase delay (θ(t)) associated with the applied field strength and the time vibration magnetization; and coupled to the magnetic detecting device A calculation unit is configured to analyze the time dependent phase delay to derive a time dependent response delay time (t eff ), thereby obtaining a concentration of the detection target.
本發明之該磁偵測器係為高-T c超導量子干涉裝置。 The magnetic detector of the present invention is a high-T c superconducting quantum interference device.
本發明之該感測線圈組更包括補償線圈，係分別與該激發單元及該激發線圈耦接，以平衡該耦合線圈。The sensing coil assembly of the present invention further includes a compensation coil coupled to the excitation unit and the excitation coil, respectively, to balance the coupling coil.
本發明之該感測線圈組更包括屏蔽件，係包覆該感測線圈組。The sensing coil set of the present invention further includes a shield covering the sensing coil set.
本發明之磁性檢測裝置更包括轉換單元，係耦接於該磁偵測裝置與該耦合線圈之間。The magnetic detecting device of the present invention further includes a conversion unit coupled between the magnetic detecting device and the coupling coil.
本發明之磁性檢測裝置，其中，該轉換單元耦合該耦合線圈至該磁偵測器。The magnetic detecting device of the present invention, wherein the converting unit couples the coupling coil to the magnetic detector.
本發明之磁性檢測裝置更包括鎖相放大器，該鎖相放大器係耦接於該磁偵測裝置與該計算單元之間。The magnetic detecting device of the present invention further includes a lock-in amplifier coupled between the magnetic detecting device and the computing unit.
本發明之磁性檢測裝置，其中，該鎖相放大器偵測該交流電磁化係數之實數部分(Re[χ ac])及虛數部分([χ ac])，且該計算單元分析該交流電磁化係數的資料以得到相關該施加場強度及基礎要素之強度的該時間相依相延遲。 The magnetic detecting device of the present invention, wherein the lock-in amplifier detects a real part (Re[χ ac ]) and an imaginary part ([χ ac ]) of the alternating current electromagnetic coefficient, and the calculating unit analyzes the alternating electromagnetic coefficient The data is delayed by the time-dependent phase associated with the strength of the applied field and the strength of the underlying elements.
本發明之磁性檢測裝置，其中，該磁物質係以磁性粒子修飾或至少塗佈一部分的有機分子，且該檢測標的係該磁物質與另一有機分子之聯合物，從而產生該磁團簇。In the magnetic detecting device of the present invention, the magnetic substance is modified with magnetic particles or at least a part of organic molecules, and the detection target is a combination of the magnetic substance and another organic molecule, thereby generating the magnetic cluster.
本發明之磁性檢測裝置，其中，該計算單元分析該時間相依反應遲緩時間隨時間改變以得到該檢測標的量。In the magnetic detecting device of the present invention, the calculating unit analyzes the time dependent response delay time to change with time to obtain the detected target amount.
本發明另提供一種使用磁性檢測裝置檢測的方法，其包括：提供包含激發單元、感測線圈組、含有輸入線圈及磁偵測器的磁偵測裝置，以及計算單元的該磁性檢測裝置，且該感測線圈組含有激發線圈和容器及耦合線圈；該容器可容納含有或不含有磁物質之檢測標的，且令該激發單元產生激發信號而使該激發線圈產生具有施加場強度(H)的激發磁場，以使含有該磁物質之檢測標的產生之磁團簇感應該激發磁場而產生額外的交流電磁化係數，且該耦合線圈感應該交流電磁化係數造成之電磁場，該交流電磁化係數具有相關該施加場強度的時間振動磁化強度(M(t))；令該輸入線圈感測該時間振動磁化強度，且令該磁偵測器測定相關於該施加場強度及該時間振動磁化強度的時間相依相延遲(θ(t))；以及，令該計算單元分析該相依相延遲以導出時間相依反應遲緩時間(teff)，進而得到該檢測標的之濃度。The present invention further provides a method for detecting using a magnetic detecting device, comprising: providing a magnetic detecting device including an excitation unit, a sensing coil group, a magnetic detecting device including an input coil and a magnetic detector, and a calculating unit, and The sensing coil set includes an excitation coil and a container and a coupling coil; the container can accommodate a detection target with or without a magnetic substance, and the excitation unit generates an excitation signal to cause the excitation coil to have an applied field strength (H) Exciting a magnetic field such that the generated magnetic cluster containing the detection target of the magnetic substance induces the excitation magnetic field to generate an additional alternating electromagnetic coefficient, and the coupling coil senses an electromagnetic field caused by the alternating electromagnetic coefficient, and the alternating electromagnetic coefficient has Correlating the time-magnetized magnetization (M(t)) of the applied field strength; causing the input coil to sense the time-magnetized magnetization, and causing the magnetic detector to determine the applied field strength and the time-magnetized magnetization Time dependent phase delay (θ(t)); and, causing the calculation unit to analyze the dependent phase delay to derive a time dependent response delay time (teff), and then the concentration of the detection target is obtained.
本發明之使用磁性檢測裝置檢測的方法，其中，該磁偵測器係高-T c超導量子干涉裝置。 The method of the present invention uses a magnetic detecting device for detecting, wherein the magnetic detector is a high-T c superconducting quantum interference device.
本發明之使用磁性檢測裝置檢測的方法，該感測線圈組更包括補償線圈，係平衡該耦合線圈。In the method of the present invention for detecting using a magnetic detecting device, the sensing coil group further includes a compensation coil that balances the coupling coil.
本發明之使用磁性檢測裝置檢測的方法，該感測線圈組更包括屏蔽件，係包覆該感測線圈組。In the method of detecting a magnetic detecting device of the present invention, the sensing coil group further includes a shielding member that covers the sensing coil group.
本發明之使用磁性檢測裝置檢測的方法，該磁性檢測裝置更包括轉換單元，係耦接於該磁偵測裝置與該耦合線圈之間。The method of detecting a magnetic detecting device of the present invention further includes a converting unit coupled between the magnetic detecting device and the coupling coil.
本發明之使用磁性檢測裝置檢測的方法，其中，該轉換單元耦合該耦合線圈至該磁偵測器。The method of detecting a magnetic detecting device of the present invention, wherein the converting unit couples the coupling coil to the magnetic detector.
本發明之使用磁性檢測裝置檢測的方法，該磁性檢測裝置更包括鎖相放大器，該鎖相放大器係耦接於該磁偵測裝置與該計算單元之間。The method of detecting a magnetic detecting device of the present invention further includes a lock-in amplifier coupled between the magnetic detecting device and the computing unit.
本發明之使用磁性檢測裝置檢測的方法，其中，該鎖相放大器偵測該交流電磁化係數之實數部分(Re[χ ac])及虛數部分([χ ac])，且該計算單元分析該交流電磁化係數的資料以得到相關該施加場強度及基礎要素之強度的該時間相依相延遲。 The method for detecting by using a magnetic detecting device of the present invention, wherein the lock-in amplifier detects a real part (Re[χ ac ]) and an imaginary part ([χ ac ]) of the alternating electromagnetic coefficient, and the calculating unit analyzes the The data of the alternating electromagnetic coefficient is obtained to obtain a time-dependent phase delay associated with the applied field strength and the strength of the underlying element.
本發明之使用磁性檢測裝置檢測的方法，其中，該磁物質係以磁性粒子修飾或至少塗佈一部分的有機分子，且該檢測標的係該磁物質與另一有機分子之聯合物，從而在該檢測標的感應該激發磁場之後產生該磁團簇。The method for detecting by using a magnetic detecting device of the present invention, wherein the magnetic substance is modified with magnetic particles or at least a part of organic molecules, and the detection target is a combination of the magnetic substance and another organic molecule, thereby The magnetic cluster is generated after the detection target senses the excitation magnetic field.
本發明之使用磁性檢測裝置檢測的方法，其中，該計算單元分析該時間相依反應遲緩時間隨時間改變以得到該檢測標的之量。The method of the present invention for detecting using a magnetic detecting device, wherein the calculating unit analyzes the time-dependent response delay time to change with time to obtain the amount of the detection target.
與先前技術相較，本發明可僅使用單一頻率之激發信號且由時間相依相延遲(θ(t))時間相依反應遲緩時間(t eff)之順序得到檢測標的之濃度，且能建立Dt eff與F AFP之間的關係，並得到更佳的靈敏度。 Compared with the prior art, the present invention can use only a single frequency excitation signal and obtain the concentration of the detection target by the time dependent phase delay (θ(t)) time dependent reaction lag time (t eff ), and can establish Dt eff Relationship with F AFP and better sensitivity.
為充份瞭解本發明之目的、特徵及功效，茲藉由下述具體之實施例，並配合所附之圖式，對本發明作一詳細說明，說明如後：In order to fully understand the objects, features and advantages of the present invention, the present invention will be described in detail by the accompanying drawings
本發明提供一種磁性檢測裝置1，其包括如圖1所示的激發單元12、感測線圈組11、磁偵測裝置13及計算單元16。特定而言，磁性檢測裝置1可使用單一頻率以作為與 H相關之 M的相延遲之探針。 The present invention provides a magnetic detecting device 1 comprising an excitation unit 12, a sensing coil group 11, a magnetic detecting device 13, and a computing unit 16, as shown in FIG. In particular, the magnetic detecting device 1 can use a single frequency as a probe for the phase delay of M associated with H.
如上所述之激發單元12係產生激發信號，特定而言，該激發信號可為9-kHz交流電信號。The excitation unit 12 as described above generates an excitation signal, and in particular, the excitation signal can be a 9-kHz alternating current signal.
如上所述之感測線圈組11可包含激發線圈111、耦合線圈112及容器114；激發線圈111係與激發單元12耦接，以由該激發信號激發產生具有施加場強度( H)的激發磁場；而耦合線圈112可對應激發線圈111而設置，即耦合線圈112對應激發線圈111之設置方式可依磁性檢測裝置1之工作效果而設計，且耦合線圈112之外形可為漸變形式；容器114可容納含有或不含有磁物質之檢測標的且對應耦合線圈112而設置，含有該磁物質之檢測標的具有磁團簇，而該耦合線圈112感應該磁團簇受該激發磁場磁化而產生額外的交流電磁化係數所造成的電磁場，該交流電磁化係數具有相關該施加場強度的時間振動磁化強度( M(t))，其隨時間變化。舉例而言，容器114可為封閉之容器或腔體，或者可為至少具有一開口的容器、腔體或管道，且容器114可置於耦合線圈112中。再舉例而言，該磁物質可為以磁性粒子修飾或至少塗佈一部分的有機分子，且該檢測標的係該磁物質與另一有機分子之聯合物，從而產生該磁團簇；其中，修飾可指以磁性粒子或其上之某些分子或元素取代有機分子中的某部分分子或元素，又或修飾可指以磁性粒子或其上之某些分子或元素接合於該有機分子；該交流電磁化係數具有實數部分(Re[χ ac])及虛數部分([χ ac])。 The sensing coil group 11 as described above may include an excitation coil 111, a coupling coil 112, and a container 114; the excitation coil 111 is coupled to the excitation unit 12 to be excited by the excitation signal to generate an excitation magnetic field having an applied field strength ( H) . The coupling coil 112 can be disposed corresponding to the excitation coil 111, that is, the manner in which the coupling coil 112 is corresponding to the excitation coil 111 can be designed according to the working effect of the magnetic detecting device 1, and the outer shape of the coupling coil 112 can be a gradual form; the container 114 can be Having a detection target with or without a magnetic substance and corresponding to the coupling coil 112, the detection target containing the magnetic substance has a magnetic cluster, and the coupling coil 112 senses that the magnetic cluster is magnetized by the excitation magnetic field to generate additional communication. An electromagnetic field caused by an electromagnetization coefficient having a time-magnetized magnetization ( M (t)) associated with the applied field strength, which varies with time. For example, the container 114 can be a closed container or cavity, or can be a container, cavity or tube having at least one opening, and the container 114 can be placed in the coupling coil 112. For another example, the magnetic substance may be an organic molecule modified or at least partially coated with magnetic particles, and the detection target is a combination of the magnetic substance and another organic molecule, thereby generating the magnetic cluster; wherein, the modification May refer to the replacement of a portion of a molecule or element in an organic molecule with a magnetic particle or a molecule or element thereon, or a modification may refer to the attachment of a magnetic particle or a molecule or element thereof to the organic molecule; The electromagnetic coefficient has a real part (Re[χ ac ]) and an imaginary part ([χ ac ]).
如上所述之感測線圈組11可更包括補償線圈113，係分別與激發單元12及激發線圈111耦接，以平衡耦合線圈112，進而達到每兆分之30的平衡。The sensing coil group 11 as described above may further include a compensation coil 113 coupled to the excitation unit 12 and the excitation coil 111, respectively, to balance the coupling coil 112 to achieve a balance of 30 per megabit.
如上所述之感測線圈組11可更包括包覆感測線圈組11的屏蔽件115。The sensing coil group 11 as described above may further include a shield 115 that covers the sensing coil group 11.
如上所述之磁偵測裝置13可具有對應設置之輸入線圈131及磁偵測器132，輸入線圈131可與耦合線圈112耦接以感測該時間振動磁化強度，且磁偵測器132係測定相關於該施加場強度及該時間振動磁化強度的時間相依相延遲(θ(t))。舉例而言，磁偵測器132可為高-T c超導量子干涉裝置，而磁偵測器132可置於足以讓高-T c超導量子干涉裝置工作的介質中。 The magnetic detecting device 13 as described above may have a corresponding input coil 131 and a magnetic detector 132. The input coil 131 may be coupled to the coupling coil 112 to sense the time vibration magnetization, and the magnetic detector 132 is A time dependent phase delay (θ(t)) associated with the applied field strength and the time vibration magnetization is determined. For example, the magnetic detector 132 can be a high-T c superconducting quantum interference device, and the magnetic detector 132 can be placed in a medium sufficient for the high-T c superconducting quantum interference device to operate.
如上所述之計算單元16可與磁偵測裝置13耦接，以分析該時間相依相延遲以導出時間相依反應遲緩時間(t eff)，進而得到該檢測標的之濃度。具體而言，計算單元16分析該時間相依反應遲緩時間隨時間之改變以得到該檢測標的之量；計算單元16可為單一晶片或晶片組、機械或電子之計算機或電腦、彼此連接之電腦或運算系統、伺服器、微處理器、雲計算或其組合。 The computing unit 16 as described above can be coupled to the magnetic detecting device 13 to analyze the time dependent phase delay to derive a time dependent response time (t eff ), thereby obtaining the concentration of the detected target. Specifically, the computing unit 16 analyzes the time dependent response delay time to change with time to obtain the amount of the detection target; the computing unit 16 can be a single wafer or chipset, a mechanical or electronic computer or computer, a computer connected to each other or Computing system, server, microprocessor, cloud computing, or a combination thereof.
另外，本發明之磁性檢測裝置1可更包括耦接於磁偵測裝置13與耦合線圈112之間的轉換單元14，具體而言，轉換單元14可為一磁通量轉換器，且將耦合線圈112耦合至磁偵測器132，特定而言，係將交流電激發信號耦合至高-T c超導量子干涉裝置，從而使增強之磁性檢測裝置1能藉由通過該磁通量轉換器將耦合線圈112耦合至高-T c超導量子干涉裝置而偵測低濃度的檢測標的。而本發明之磁性檢測裝置1可更包括耦接於磁偵測器132與計算單元16之間的鎖相放大器15，從而使鎖相放大器15偵測該交流電磁化係數之實數部分(Re[χ ac])及虛數部分([χ ac])，且計算單元16分析該交流電磁化係數的資料以得到相關該施加場強度及基礎要素之強度的該時間相依相延遲，另外，本發明之磁性檢測裝置1可更包括耦接於磁偵測器132與鎖相放大器15之間的濾波器17，而濾波器17與磁偵測器132之間可以例如PCI100的匯流排18電性連接。 In addition, the magnetic detecting device 1 of the present invention may further include a converting unit 14 coupled between the magnetic detecting device 13 and the coupling coil 112. Specifically, the converting unit 14 may be a magnetic flux converter and the coupling coil 112 Coupled to the magnetic detector 132, in particular, the AC excitation signal is coupled to the high-T c superconducting quantum interference device such that the enhanced magnetic detection device 1 can couple the coupling coil 112 to the high through the magnetic flux converter -T c superconducting quantum interference device to detect low concentration detection targets. The magnetic detecting device 1 of the present invention may further include a lock-in amplifier 15 coupled between the magnetic detector 132 and the computing unit 16, so that the lock-in amplifier 15 detects the real part of the alternating current electromagnetic coefficient (Re[ Ac ac ]) and an imaginary part ([χ ac ]), and the calculation unit 16 analyzes the data of the alternating electromagnetic coefficient to obtain the time-dependent phase delay associated with the applied field strength and the strength of the basic element, and further, the present invention The magnetic detecting device 1 can further include a filter 17 coupled between the magnetic detector 132 and the lock-in amplifier 15. The filter 17 and the magnetic detector 132 can be electrically connected to each other, for example, the busbar 18 of the PCI 100.
本發明亦提供一種使用磁性檢測裝置檢測的方法，其包括如圖2之以下步驟S21至S24。在步驟S21中，提供包含激發單元12、感測線圈組11、含有輸入線圈131及磁偵測器132的磁偵測裝置13、以及計算單元16的磁性檢測裝置1，且感測線圈組11含有激發線圈111和容器114及耦合線圈112。由於磁性檢測裝置1之各部分已於上文敘述，故不再贅述。The present invention also provides a method of detecting using a magnetic detecting device, which includes the following steps S21 to S24 as shown in FIG. In step S21, the magnetic detecting device 1 including the excitation unit 12, the sensing coil group 11, the magnetic detecting device 13 including the input coil 131 and the magnetic detector 132, and the calculating unit 16 is provided, and the coil group 11 is sensed. The excitation coil 111 and the container 114 and the coupling coil 112 are included. Since each part of the magnetic detecting device 1 has been described above, it will not be described again.
在步驟S22中，將含有或不含有磁物質之檢測標的容納進容器114，且令激發單元12產生激發信號而使激發線圈111產生具有施加場強度( H)的激發磁場，以使含有該磁物質之檢測標的產生之磁團簇感應該激發磁場而產生額外的交流電磁化係數，且該耦合線圈112感應該交流電磁化係數造成之電磁場，該交流電磁化係數具有相關該施加場強度的時間振動磁化強度( M(t))，需注意的是，將檢測標的容納進容器114及產生激發信號之順序並無限定，而檢測標的之內容已於上文敘述，故不再贅述。 In step S22, the detection target with or without the magnetic substance is accommodated in the container 114, and the excitation unit 12 is caused to generate an excitation signal to cause the excitation coil 111 to generate an excitation magnetic field having an applied field strength ( H) so as to contain the magnetic The magnetic cluster generated by the detection target of the substance induces the excitation magnetic field to generate an additional alternating electromagnetic coefficient, and the coupling coil 112 senses the electromagnetic field caused by the alternating electromagnetic coefficient, and the alternating electromagnetic coefficient has a time related to the applied field strength. Vibration magnetization ( M (t)), it should be noted that the order in which the detection target is accommodated in the container 114 and the excitation signal is generated is not limited, and the contents of the detection target are described above, and therefore will not be described again.
在步驟S23中，令輸入線圈131感測該時間振動磁化強度，且令磁偵測器132測定相關於該施加場強度及該時間振動磁化強度的時間相依相延遲(θ(t))。In step S23, the input coil 131 senses the temporal vibration magnetization, and causes the magnetic detector 132 to measure the time-dependent phase delay (θ(t)) associated with the applied field strength and the temporal vibration magnetization.
在步驟S24中，令計算單元16分析該相依相延遲以導出時間相依反應遲緩時間(t eff)，進而得到該檢測標的之濃度。 In step S24, the calculation unit 16 is caused to analyze the dependent phase delay to derive a time dependent response delay time (t eff ), thereby obtaining the concentration of the detection target.
需提及的是，磁偵測器132、補償線圈113、屏蔽件115、轉換單元14、鎖相放大器15及濾波器17之內容已於上文敘述，故不再贅述。It should be noted that the contents of the magnetic detector 132, the compensation coil 113, the shield 115, the conversion unit 14, the lock-in amplifier 15 and the filter 17 have been described above, and therefore will not be described again.
為了清楚說明本發明之機制，以下將搭配圖3至圖8以一特定但非限定之範例說明。In order to clearly illustrate the mechanism of the present invention, a specific but non-limiting example will be described below in conjunction with FIGS. 3 through 8.
使用於本發明之磁物質可例如為塗覆Fe 3O 4的葡萄聚糖(MF-DEX-0060，MagQu Co. Ltd.)。Fe 3O 4核之平均直徑可於檢測前以X-ray繞射(D-500，Siemens)量測為接近35 nm，但本發明不以此為限，用於合成由Fe 3O 4–反-CEA及Fe 3O 4–反-AFP構成的生物功能化磁奈米粒子(BMNs，即磁物質)之流程係相似用於Fe 3O 4-反CRP者。氧化塗覆有Fe 3O 4之具有四氧碘鈉(NaIO 4)的葡萄聚糖以產生醛群(–CHO)，其引起葡萄聚糖通過–CH=N–與反-AFP共價結合而與抗體反應，在磁分離引導未束縛之抗體從結合的BMNs分離之後，以通過動態雷射散射(Nanotrac 150, Microtrac)所偵測的BMNs之流體直徑的平均值係54.8 nm，而生物標的(即另一有機分子) 係反-AFP(ab40942；Abcam, Cambridge, MA)，與生物標的結合之BMNs的磁化強度可在檢測前以振動樣品磁量儀(Model Hystermag, MagQu Co., Ltd.)測定，且交流電磁化係數可使用磁化率計(即磁偵測器)測試。 The magnetic substance used in the present invention may be, for example, Fe 3 O 4 coated dextran (MF-DEX-0060, MagQu Co. Ltd.). The average diameter of the Fe 3 O 4 core can be measured by X-ray diffraction (D-500, Siemens) to be close to 35 nm before the detection, but the invention is not limited thereto and is used for the synthesis of Fe 3 O 4 - The process of bio-functionalized magnetic nanoparticles (BMNs, ie, magnetic substances) composed of anti-CEA and Fe 3 O 4 -trans-AFP is similar to that used for Fe 3 O 4 -anti-CRP. Oxidizing a galvanose with sodium thioate (NaIO 4 ) coated with Fe 3 O 4 to produce a aldehyde group (–CHO) which causes co-valent binding of glucomann to the anti-AFP via –CH=N– Reacting with the antibody, after the magnetic separation directs the separation of the unbound antibody from the bound BMNs, the average diameter of the fluids of the BMNs detected by dynamic laser scattering (Nanotrac 150, Microtrac) is 54.8 nm, and the biological target ( That is, another organic molecule) is anti-AFP (ab40942; Abcam, Cambridge, MA), and the magnetization of the BMNs combined with the biomarker can be measured by a vibrating sample magnetic meter (Model Hystermag, MagQu Co., Ltd.) before detection. The measurement and the AC susceptibility can be tested using a susceptibility meter (ie, a magnetic detector).
圖3顯示BMNs之激發場( H)及 M值的時間相依信號。相關 H之 M的相延遲係為θ，其具有對應之Re[χ ac]及Im[χ ac]，如方程式(1)所示： (1) 其中ω係 H之激發頻率，而t eff係BMNs之反應遲緩時間。 Figure 3 shows the time dependent signals of the excitation field ( H ) and M values of BMNs. The phase delay of the M of the relevant H is θ, which has the corresponding Re[χ ac ] and Im[χ ac ], as shown in equation (1): (1) where ω is the excitation frequency of H , and t eff is the response time of BMNs.
圖4顯示BMNs、生物標的、生物探針(BMNs用於與生物標的結合者)及磁團簇，其中，BMNs包括Fe 3O 4–反-AFP、AFP之生物標的及Fe 3O 4–反-AFP–AFP的磁團簇，而當AFP與包括Fe 3O 4–反-AFP之試劑混合時，Fe 3O 4–反-AFP–AFP的磁團簇係藉由與Fe 3O 4–反-AFP聯合之AFP而形成，而在BMNs與AFP聯合的期間，藉由使用磁化率計而監測試劑的θ，另外，測量已與AFP結合之試劑的磁滯迴圈以藉由使用振動樣品磁量儀(Model Hystermag, MagQu Co., Ltd.) 而了解磁團簇之 M的效應。 Figure 4 shows BMNs, biomarkers, bioprobes (BMNs for binding to biomarkers) and magnetic clusters, where BMNs include Fe 3 O 4 - anti-AFP, AFP biomarkers and Fe 3 O 4 - anti AFP-AFP-magnetic clusters, when AFP and comprises Fe 3 O 4 - anti-AFP when mixing the reagents, Fe 3 O 4 - anti-AFP-AFP-based cluster by the magnetic Fe 3 O 4 - The anti-AFP is combined with the AFP, and during the combination of the BMNs and the AFP, the θ of the reagent is monitored by using a susceptibility meter, and in addition, the hysteresis loop of the reagent that has been combined with the AFP is measured to use the vibrating sample. The magnetic meter (Model Hystermag, MagQu Co., Ltd.) understands the effect of the magnetic cluster M.
BMNs之交流磁化係數(c ac(w))可表示成如下之方程式(2)： c ac= χ' + ic'' = Re[c ac]+ i Im[ χ ac ] (2) 其中 χ' =且 c'' = i = (-1) 1/2，c''/c' = tanq = wt eff(t)；q係相關施加之交流電磁場( H(t))的時間振動磁化強度( M(t))的相延遲；且t eff係反應遲緩率，t eff將施加之直流場移除之後的保持磁化強度之能力特徵化，其反應磁團簇奈米粒子在Brownian及Néel弛緩上的影響，因此，可得到如下之方程式(3)： 1/t eff= 1/t B+ 1/t N(3) 其中1/t B係Brownian弛緩率，且1/t N係Néel弛緩率，時間相依q(t)係藉由使用磁化率計並通過鎖相偵測技術而測量，t eff(t)之值係通過tanq(t) = wt eff(t)之關係而估計，因此，本發明可藉由監測q(t)而了解t eff(t)之演進，且本發明可分析Dt eff= [t eff(t = 0) - t eff(t = ¥)]作為生物標示之濃度的函數以建立Dt eff與AFP(F AFP)濃度之間的關係，係提供用於生物標的之未知量的定量分析基礎。 The AC susceptibility (c ac (w)) of BMNs can be expressed as the following equation (2): c ac = χ' + ic'' = Re[c ac ]+ i Im[ χ ac ] (2) χ' = and c'' = i = (-1) 1/2 , c''/c' = tanq = wt eff (t); q is the time-dependent vibrational magnetization of the applied alternating electromagnetic field ( H (t)) ( M ( t)) phase delay; and t eff is the rate of reaction slowness, t eff characterizes the ability to maintain magnetization after removal of the applied DC field, and the effect of reactive magnetic cluster nanoparticles on Brownian and Néel relaxation Therefore, the following equation (3) can be obtained: 1/t eff = 1/t B + 1/t N (3) where 1/t B is the Brownian relaxation rate, and 1/t N is the Néel relaxation rate, time dependent q (t) by using lines and magnetic susceptibility meter measured by lock-in detection technique, t eff (t) by the value based tanq (t) = wt relationship eff (t) of the estimate, therefore, the present invention The evolution of t eff (t) can be understood by monitoring q(t), and the present invention can analyze Dt eff = [t eff (t = 0) - t eff (t = ¥) as a function of the concentration of the biomarker To establish the relationship between Dt eff and AFP (F AFP ) concentrations, the basis for quantitative analysis of unknown quantities for biomarkers is provided.
圖5(a)顯示F AFP(AFP之濃度)= 0 ppm時 M為 H的函數，且圖5(b)顯示F AFP= 10 ppm時 M為 H的函數，為了化驗F AFP= 0時的AFP，本發明可混合40μL Fe 3O 4–反-AFP (0.3 emu/g)與60μL緩衝溶液，為了化驗F AFP= 10 ppm時的AFP，本發明可混合40 μL Fe 3O 4–反-AFP (0.3 emu/g)與F AFP= 10 ppm，在BMNs與AFP結合後增強的 M(或χ = M/ H)係以 M– H曲線表現；包括Fe 3O 4–反-AFP之試劑的飽和磁化強度( M S)係0.13 emu/g，且當F AFP= 10 ppm時之 M S係增強至0.18 emu/g；而 M S之增強係起因於BMNs與AFP聯合後產生之磁團簇，BMNs與AFP之聯合對於試劑貢獻額外的磁化強度。 FIG 5 (a) M is displayed as a function of H, and FIG. 5 (b) is displayed F AFP = 10 ppm M as a function of H, when F. AFP (concentration of AFP's) = 0 ppm, to test F. AFP 0 = a AFP, the present invention can mix 40 μL Fe 3 O 4 -trans-AFP (0.3 emu/g) with 60 μL buffer solution. In order to test AFP at F AFP = 10 ppm, the present invention can mix 40 μL Fe 3 O 4 - anti- AFP (0.3 emu/g) and F AFP = 10 ppm, M (or χ = M / H ) enhanced after BMNs combined with AFP is expressed in M – H curve; reagents including Fe 3 O 4 – anti-AFP the saturation magnetization (M S) Department of 0.13 emu / g, and enhanced to 0.18 emu / g when M S based upon the F AFP = 10 ppm; and enhancement M S's due to the magnetic group generated after BMNs and AFP joint Clusters, the combination of BMNs and AFPs contribute additional magnetization to the reagents.
圖6顯示與各種濃度AFP結合之BMNs的θ(t)，對於AFP濃度為零者，θ(t)係獨立於時間且為磁化率計之背景噪訊；對於AFP濃度為固定者(例如，F AFPs)，如於t = 0時F AFP= 1 ppm，θ = 4.2º且於t = 7200秒時θ增加至5.5º；對於各種F AFPs，發現θ(t)隨時間增加且當結合完全時呈現飽和，其因在BMNs與AFP聯合期間產生的磁團簇，對試劑貢獻額外的磁化強度且從而增進相延遲，於高濃度AFP中更多磁團簇結合，因此，在更多F AFPs與試劑混合之後增加了相延遲的改變；此表示為Dθ = θ(t = 7200 s) − θ(t = 0)。 Figure 6 shows θ(t) of BMNs combined with various concentrations of AFP. For AFP concentrations of zero, θ(t) is background noise independent of time and is a magnetic susceptibility meter; for AFP concentrations is fixed (for example, F AFPs ), such as F AFP = 1 ppm at t = 0, θ = 4.2o and θ increases to 5.5o at t = 7200 seconds; for various F AFPs , it is found that θ(t) increases with time and when the combination is complete At the time of saturation, due to the magnetic cluster generated during the combination of BMNs and AFP, it contributes additional magnetization to the reagent and thus increases the phase delay. More magnetic clusters are combined in the high concentration AFP, therefore, more F AFPs The change in phase delay is increased after mixing with the reagent; this is expressed as Dθ = θ(t = 7200 s) − θ(t = 0).
圖7顯示BMNs與AFP結合期間BMNs之時間相依t eff(t)，t eff(t)的值係從方程式t eff(t) = tanq(t)/ω計算；對於當F AFP= 1 ppm時含有BMNs的試劑而言，t eff=1.3 ms，且t = 0時t eff= 1.3 ms，而t = 7200秒時t eff= 1.75 ms，兩種遲緩係藉由BMNs呈現，該等遲緩名為Néel弛緩及Brownian弛緩其因磁團簇對BMNs貢獻額外磁化強度，而額外磁化強度降低Néel弛緩及Brownian弛緩，從而增進t eff。 Figure 7 shows BMNs and AFP bonding time BMNs DURING dependent t eff (t), the value t eff (t) lead from the equation t eff (t) = tanq ( t) / ω calculated; for when F AFP = 1 ppm reagent containing BMNs terms, t eff = 1.3 ms, at t = 0 and t eff = 1.3 ms, and the time t eff = 1.75 ms t = 7200 seconds, the two kinds of delay lines presented by BMNs, such slow named Néel relaxation and Brownian relaxation are due to magnetic clusters contributing additional magnetization to BMNs, while additional magnetization reduces Néel relaxation and Brownian relaxation, thereby increasing t eff .
圖8顯示Dt eff為F AFP之函數，其中Dt eff= [t eff(t = 0) - t eff(t = ¥)]。觀察結果揭示Dt eff隨F AFP增加，因此，Dt eff為F AFP之函數且可如以下指數函數，即方程式(4)表示： Dt eff=(A − B)/｛1+［(F AFP)/(F 0)］ g｝+B (4) 其中A及B係微秒單位且F 0與尺寸無關，實線係以參數A = −0.016 ms、B = 0.72 ms、Φ 0= 0.15 ppm及g = 0.52所擬合之曲線，指數行為係相似於各種生物樣本中所觀察到者，本發明可建立在Dt AFP與F AFP之間的關係，且F AFP之範圍係從1 ppb至1 ppm，該關係提供未知AFP量之定量分析的基礎。此外，本發明可從圖8所顯示結果測定偵測靈敏度，Dt eff之變化影響AFP之偵測濃度，本發明驗証對於F AFP= 0.001 ppm之資料的標準偏差且藉由使用指數函數對於AFP濃度估計Dt之最高值，且本發明對於報告的偵測極限得到0.0024 ppm的遷移濃度。 Figure 8 shows that Dt eff is a function of F AFP where Dt eff = [t eff (t = 0) - t eff (t = ¥)]. The observations reveal that Dt eff increases with F AFP , so Dt eff is a function of F AFP and can be expressed as the following exponential function, ie equation (4): Dt eff =(A − B)/{1+[(F AFP ) /(F 0 )] g }+B (4) where A and B are microsecond units and F 0 is independent of size, and the solid line is parameter A = −0.016 ms, B = 0.72 ms, Φ 0 = 0.15 ppm and g = 0.52 fitted curve, exponential behavior is similar to that observed in various biological samples, the present invention can establish a relationship between Dt AFP and F AFP , and F AFP ranges from 1 ppb to 1 ppm This relationship provides the basis for quantitative analysis of unknown AFP quantities. In addition, the present invention can determine the detection sensitivity from the results shown in FIG. 8, and the change in Dt eff affects the detection concentration of AFP. The present invention verifies the standard deviation of the data for F AFP = 0.001 ppm and uses the exponential function for the AFP concentration. The highest value of Dt is estimated, and the present invention achieves a migration concentration of 0.0024 ppm for the reported detection limit.
由於AFP係使用於偵測腫瘤之生物標示，高於500 ng/mL的程度可指出惡性腫瘤，例如肝癌細胞(HCC)或轉移性肝癌，如本發明之磁性檢測裝置中的磁偵測器可偵測低於2.4 ng/mL濃度之檢測標的，故該磁偵測器足夠靈敏以測定癌症治療的進程，其偵測靈敏性及基於Dt eff之增量的特性將應用在HCC病患的血液測試。 Since AFP is used to detect tumor biomarkers, a level higher than 500 ng/mL may indicate a malignant tumor, such as liver cancer cells (HCC) or metastatic liver cancer, such as a magnetic detector in the magnetic detecting device of the present invention. Detection of detection values below 2.4 ng/mL, so the magnetic detector is sensitive enough to measure the progress of cancer treatment, its detection sensitivity and the increase in Dt eff based characteristics will be applied to the blood of patients with HCC test.
因此由上述本發明之範例說明，本發明可僅使用單一頻率之激發信號且藉由磁偵測器量測到的時間相依相延遲(θ(t))而由計算單元分析該時間相依相延遲以導出時間相依反應遲緩時間(t eff)，進而得到該檢測標的之濃度，也就是在本發明之偵測方法中僅施加一種激發頻率給激發線圈，且可使用補償線圈以平衡輸出信號，因BMNs與AFP聯合，觀察到θ(t)值係隨時間增加，此外，Dt eff值隨F AFP增加，而這些結果歸因於當BMNs與AFP結合時產生的額外磁化強度，從而減少試劑的Néel遲緩及Brownian遲緩，本發明已建立Dt eff與F AFP之間的關係，因此提供用於AFP之未知量的定量分析之基礎。 Thus, as exemplified by the above described examples of the present invention, the present invention can analyze the time dependent phase delay by the calculation unit using only a single frequency excitation signal and by the time dependent phase delay (θ(t)) measured by the magnetic detector. Taking the time-dependent response delay time (t eff ), the concentration of the detection target is obtained, that is, only one excitation frequency is applied to the excitation coil in the detection method of the present invention, and the compensation coil can be used to balance the output signal. BMNs combined with AFP, observed that the θ(t) value increases with time. In addition, the Dt eff value increases with F AFP , and these results are attributed to the additional magnetization generated when BMNs bind to AFP, thereby reducing the reagent Néel. Slowness and Brownian sluggishness, the present invention has established a relationship between Dt eff and F AFP , thus providing a basis for quantitative analysis of unknown quantities of AFP.
本發明在上文中已以詳細說明揭露，然熟習本技術者應理解的是，該詳細說明僅用於描繪本發明，而不應解讀為限制本發明之範圍，應注意的是，舉凡與該詳細說明等效之變化與置換，均應設為涵蓋於本發明之範疇內。The invention has been described above in detail, and it should be understood by those skilled in the art that The equivalent changes and permutations are intended to be included within the scope of the present invention.
<TABLE border="1" borderColor="#000000" width="85%"><TBODY><tr><td> 1 </td><td> 磁性檢測裝置 </td></tr><tr><td> 11 </td><td> 感測線圈組 </td></tr><tr><td> 111 </td><td> 激發線圈 </td></tr><tr><td> 112 </td><td> 耦合線圈 </td></tr><tr><td> 113 </td><td> 補償線圈 </td></tr><tr><td> 114 </td><td> 容器 </td></tr><tr><td> 115 </td><td> 屏蔽件 </td></tr><tr><td> 12 </td><td> 激發單元 </td></tr><tr><td> 13 </td><td> 磁偵測裝置 </td></tr><tr><td> 131 </td><td> 輸入線圈 </td></tr><tr><td> 132 </td><td> 磁偵測器 </td></tr><tr><td> 14 </td><td> 轉換單元 </td></tr><tr><td> 15 </td><td> 鎖相放大器 </td></tr><tr><td> 16 </td><td> 計算單元 </td></tr><tr><td> 17 </td><td> 濾波器 </td></tr><tr><td> 18 </td><td> 匯流排 </td></tr><tr><td> S21至S24 </td><td> 步驟 </td></tr></TBODY></TABLE><TABLE border="1" borderColor="#000000" width="85%"><TBODY><tr><td> 1 </td><td> Magnetic detection device</td></tr><tr ><td> 11 </td><td> Sensing coil set</td></tr><tr><td> 111 </td><td> Excitation coil</td></tr><tr ><td> 112 </td><td> Coupling coil</td></tr><tr><td> 113 </td><td> Compensation coil</td></tr><tr>< Td> 114 </td><td> Container</td></tr><tr><td> 115 </td><td> Shield</td></tr><tr><td> 12 </td><td> excitation unit</td></tr><tr><td> 13 </td><td> magnetic detection device</td></tr><tr><td> 131 </td><td> Input coil</td></tr><tr><td> 132 </td><td> Magnetic detector</td></tr><tr><td> 14 </td><td> Conversion Unit</td></tr><tr><td> 15 </td><td> Lock-in Amplifier</td></tr><tr><td> 16 < /td><td> Computational Units</td></tr><tr><td> 17 </td><td> Filters</td></tr><tr><td> 18 </td ><td> Bus </td></tr><tr><td> S21 to S24 </td><td> Steps</td></tr></TBODY></TABLE>
圖1係基於高-T c超導量子干涉裝置之磁性檢測裝置的示意圖。 圖2係本發明使用磁性檢測裝置檢測的方法之流程圖。 圖3係時間相依激發場(H)及相關偵測到BMNs之磁化強度(M)。 圖4係顯示生物探針、生物標的、生物功能化磁奈米粒子及磁團簇的示意圖。 圖5(a)係當F AFP= 0 ppm時M作為H之函數的圖表，且第5(b)圖係顯示當F AFP= 10 ppm時M作為H之函數的圖表。 圖6係與各種AFPs濃度結合之BMNs的時間相依相延遲(θ)之圖表。 圖7係BMNs與AFPs結合期間BMNs之時間相依t eff的圖表。 圖8係Dt eff作為F AFP之函數的圖表。 1 is a schematic diagram of a magnetic detecting device based on a high-T c superconducting quantum interference device. 2 is a flow chart of a method of detecting using the magnetic detecting device of the present invention. Figure 3 is a time dependent excitation field (H) and associated magnetization (M) of detected BMNs. Figure 4 is a schematic diagram showing bioprobes, biomarkers, biofunctionalized magnetic nanoparticles, and magnetic clusters. Figure 5(a) is a graph of M as a function of H when F AFP = 0 ppm, and Figure 5(b) shows a graph of M as a function of H when F AFP = 10 ppm. Figure 6 is a graph of the time dependent phase delay ([theta]) of BMNs combined with various AFPs concentrations. Figure 7 is a graph of the time dependent t eff of BMNs during the binding of BMNs to AFPs. Figure 8 is a graph of Dt eff as a function of F AFP .
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| US20080024117A1 (en) * | 2005-11-16 | 2008-01-31 | Shieh-Yueh Yang | Ultra-sensitive magnetoreduction measurement system and ultra-sensitive, wash-free assay using the same |
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| TW200745554A (en) * | 2006-06-06 | 2007-12-16 | Chin-Yih Hong | Diagnostic methods using magnetic nanoparticles |
| US20130121879A1 (en) * | 2010-07-21 | 2013-05-16 | Hitachi, Ltd. | Magnetic-Field Measurement Device |
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