Implantable nuclear magnetic resonance spectrometer

[0001] [Technical field to which the invention belongs] The present invention relates to medical implants, in particular to medical implantable devices comprising a nuclear magnetic resonance spectrometer array configuration capable of characterizing and monitoring the local flow velocity of a physiological fluid and its chemical composition. [0002] [Conventional technology] Nuclear magnetic resonance is based on the following known principles. That is, all nuclei with an odd atomic mass number or an odd atomic number (eg, hydrogen, etc.) have a unique nuclear magnetic moment. I won't go into details, but this moment is generated by the rotation of protons around the nucleus. Furthermore, when a nuclear magnetic resonance (NMR) active nucleus is placed in a static magnetic field, this moment takes two different orientation states. That is, this moment is either parallel to the magnetic field or oriented non-parallel to the magnetic field. Considering a group of hydrogen atoms placed in the same static magnetic field, the number of atoms having parallel orientation is slightly larger than the number of atoms having non-parallel orientation. The reason for this is that the parallel orientation is energetically relatively stable. Furthermore, this transition from the parallel state to the non-parallel state is caused by the absorption of electromagnetic energy at a constant frequency called the resonance frequency of atoms. This resonance frequency is determined by the strength of the nucleus and the static magnetic field. In general, nuclear magnetic resonance devices operate by analyzing the signals generated during the transition from these excited states (non-parallel orientation) to the equilibrium state (parallel orientation). In this case, after the nucleus is placed in a high-intensity static magnetic field, it is excited by an electromagnetic wave having a frequency corresponding to its resonance frequency. Further, when the state return or transition to the equilibrium state occurs, a signal having the same frequency as the excitation signal (resonance signal) is generated and can be measured via the antenna. [0003] Such resonance detection can be performed in the excited state by measuring the energy absorption by scanning in a certain frequency range, or can be performed when the atom returns to the equilibrium state. In the latter case, resonance detection is performed by measuring the electromagnetic signal generated by the transition of the magnetic moment when the atom returns to its equilibrium state. When atoms other than hydrogen atoms are present in the solution to be identified, the spin of those electrons creates a microscopic magnetic field. Therefore, the hydrogen atom is affected by the static magnetic field generated by the NMR apparatus in which the magnetic fields generated by these electrons are locally overlapped. Therefore, a change specific to the environment of the hydrogen atom in the solution to be identified is applied to its resonance frequency. Nuclear magnetic resonance spectroscopy is based on this principle and is mainly used in two different applications: biochemical analysis in experiments and magnetic resonance imaging spectroscopy. For experimental applications, nuclear magnetic resonance spectroscopy is generally performed at extremely high magnetic field strengths (> 10 Tesla) to study the atomic structure of each molecule. On the other hand, magnetic resonance imaging spectroscopy (MRIS) is performed by a standard MRI apparatus at a relatively low magnetic field strength (about 1.5 tesla) in order to investigate the composition of the tissue environment at the molecular level. [0004] Furthermore, it is also possible to collect information on the flow of liquid by analyzing the signal generated by the return from the excited state by resonance to the equilibrium state. That is, the characteristic of this signal is a constant decrease when the liquid is stationary, and a faster decrease when the liquid is moving. The reason for this is that the excited atoms move out of the detection space of the antenna and disappear. In addition, this technique is also used in magnetic resonance imaging spectrometers. [0005] Continuous monitoring of specific compounds in body fluids and gathering information about fluid flow rates in the human body are important processes in many areas of medicine, especially monitoring or bypassing of brain metabolites in injured patients. It is important for monitoring the flow velocity of cerebrospinal fluid in patients with hydrocephalus. Known techniques for monitoring the concentration of a particular compound in such a physiological fluid are generally techniques that require fluid sample collection (such as dialysis) or insertion of a probe into the fluid / tissue of interest. It is invasively performed by any of the treatments (microdialysis, blood gas analysis, etc.). These techniques include either a procedure of drilling each sample to be analyzed or a procedure of placing a catheter tube during the continuation of monitoring. In addition, the invasive catheter probe is O₂, CO₂, Glucose or lactose is the main target. [0006] [Problems to be Solved by the Invention] Other non-invasive techniques, such as magnetic resonance imaging spectroscopy, are costly and difficult to perform continuous monitoring. Furthermore, regarding flow velocity evaluation, there is currently no device that can perform these measurements in-sit. [0007] [Means for solving problems] An object of the present invention is to solve the above problems, which can be achieved by an implantable nuclear magnetic resonance spectrometer having the features described in claim 1 within the scope of the claims described herein. .. [0008] Another object of the present invention is to provide a method of using the above implantable nuclear magnetic resonance spectrometer in some medical applications. [0009] Yet another feature and other object of the invention is revealed by the following detailed description based on the accompanying drawings schematically and non-limitingly showing one embodiment of the implantable nuclear magnetic resonance spectrometer according to the invention described above. Become. [0010] BEST MODE FOR CARRYING OUT THE INVENTION FIG. 1 shows an embodiment of a portable device for a nuclear magnetic resonance spectrometer according to the present invention. In this embodiment, a static magnetic field is generated by a constant arrangement of permanent magnets. This static magnetic field must meet two criteria. First, this static magnetic field needs to be strong. That is, the strength of the nuclear magnetic resonance signal is directly proportional to the number of atoms involved in the resonance, and is also directly proportional to the strength of the magnetic field. Therefore, in order to generate an NMR signal that can be easily detected and analyzed, it is necessary to operate the device with a static magnetic field in the range of 1 Tesla or more. In addition, the second criterion that the above magnetic field must satisfy is related to its uniformity. That is, it is a very important condition that the sample to be analyzed is completely enclosed in the same static magnetic field. If this condition is not met, the deexcited frequency spectrum expands, making it difficult to measure and analyze. At present, the uniformity of this static magnetic field needs to be in the range of 1 ppm to 10 ppm. [0011] A static magnetic field that satisfies these requirements is generated by a constant arrangement of permanent magnets. Returning to FIG. 1, this permanent magnet array configuration includes a cylindrical external permanent magnet 1. In addition, this magnet array configuration includes two cylindrically shaped internal permanent magnets 2. These magnets 1 and 2 are polarized along their respective longitudinal axes. Further, although the magnetization directions of the internal magnet 2 are the same, they are opposite to the polarization direction of the external magnet 1. That is, when the north pole of the external magnet 1 is arranged above the external magnet 1 in FIG. 1, the north pole of the internal magnet 2 is arranged below it in FIG. Further, the above-mentioned magnet arrangement configuration includes magnetic concentrators 3 arranged on adjacent magnetic poles of each internal magnet 2. The function of these magnets is to improve the strength and uniformity of the static magnetic field in the region formed directly between the two internal magnets 2. In addition, the two ferrite caps 4 close this magnet array configuration, reducing the loss of magnetic field that occurs in this region. [0012] The external magnet 1 includes two central radial holes 5 for inserting the catheter 6 between the internal magnets 2 having two magnetic concentrators 3 at the ends. Therefore, the fluid to be analyzed flows into the catheter 6 at the center of the magnet array configuration. In addition, excitation / detection coils 7 are arranged around the catheter 6 in the center of the permanent magnet structure. The measured volume is determined by the volume of this coil 7, which needs to be reduced to optimize field uniformity in the vicinity of the sample to be analyzed. The simulation revealed that at a field strength of about 0.7 Tesla, a uniformity of 1 ppm was obtained for a sphere with a diameter of 100 μm at the center of the structure. [0013] The excitation / detection coil 7 described above is connected to an electron pretreatment circuit 8 which, in a preferred embodiment, is placed as close as possible to the coil 7 in order to increase the signal-to-noise ratio. ing. The preprocessing circuit 8 that detects, amplifies, and preprocesses this NMR signal is further connected to the main printed circuit board 9, which houses all the electronic components necessary to further process the signal. There is. These known components are not described in detail herein, but their functionality can be summarized as follows. That is, the main printed circuit board 9 is composed of components necessary for generating an excitation signal by nuclear magnetic resonance at the resonance frequency. Further, the circuit board 9 includes the components necessary for formatting the signal detected by the preprocessing circuit 8. In addition, the main circuit board 9 comprises electronic components used to transfer acquired and formatted data using telemetry technology. In such a configuration, the RF antenna 10 is located within the housing 11 of the implantable device. When using passive telemetry, the antenna 10 excites the printed circuit board by inductive coupling and acts to transfer the formatted measurement data to an external reader. An example of such a passive absorption modulation telemetry method is described in European Patent Publication No. EP0377695. [0014] In another embodiment, a power source such as a battery can be incorporated within the housing 11 of the implantable device described above. This is the case when the required energy exceeds the energy that can be transferred by telemetry. Active telemetry is widely used and known in the field of implantable medical devices. Devices and methods for telemetry of analog and digital data percutaneously between portable medical devices such as peacemakers and external receivers or readers are described in US Pat. No. 5,314,450. It can be performed to transfer data in two directions between an external receiver (not shown) and the portable device of the invention. [0015] The portable device of the present invention is encapsulated in a waterproof housing to protect electronic components. For example, the device can be completely encapsulated in a bioacceptable titanium housing, which provides a configuration suitable for long-term transplantation in the human body. In addition, a waterproof passage is provided in the housing at the height of the catheter 6 to allow the fluid to be analyzed to flow into the catheter 6 by diffusion, for example. [0016] In addition, other isolation techniques can be used, such as coating the implantable device with a bioacceptable polymer such as silicone or epoxy. [0017] The disclosed portable device of the present invention makes it possible to continuously monitor the composition and / or concentration of a particular compound in a physiological fluid. After transplanting this device, it will also be possible to monitor the flow of fluid. One of the main advantages of such a technique is that it requires a single transplantation process and telemetry techniques send a non-invasive response command to the transplantation device at any time and for the required time. Is what you can do. Many uses can be expected for this portable device. Therefore, some usage methods of the present invention will be described below. [0018] Diabetics may need to test their blood glucose several times a day. The device proposed by the present invention can accurately monitor the blood glucose level by non-invasively sending a response command by a telemetry method after transplantation. This data can then be used to determine the optimal amount of insulin to inject or inject. In addition, the transplant device can be used to automatically control the injection rate of the transplanted insulin infusion pump. [0019] Another application relates to the measurement of effective flow rates from transplanted drug feeders, as there are currently no commercially available implantable flow sensors. For example, knowing the effective flow velocity in the bypass portion of a bypassed hydrocephalus patient is important for proper management of hydrocephalus. Therefore, by transplanting the device proposed by the present invention along the bypass portion, it becomes possible to confirm the proper operation of the bypass, and it becomes possible to optimize the bypass setting. [0020] In addition, the implantable device described above can also be used, especially for long-term continuous monitoring of certain compounds in the body fluids of injured patients. The measurable analyte in this case includes metabolites such as amino acids, glucose, glutamate, lactose and dissolved gas. [0021] [0021] In addition, the implantable device described above constitutes a feedback loop that allows control of another implantable device, such as a pacemaker or transplanted drug feeder, depending on the results of parameters measured by the transplanted device. It is also possible to do. [0022] Embodiments of the present invention are as follows.<u style="single">(A) A housing (11) crossed by a fluid-permeable catheter (6) and a permanent magnet (1,2,3,) that generates a uniform magnetic field of constant intensity near the catheter (6). 4) Arrangement configuration, electronic circuit (8,9) array configuration for exciting and detecting the nuclear magnetic resonance signal, and formatting the measured signal, and nuclear magnetic resonance by exposing the fluid sample to the excitation signal. An implantable nuclear magnetic resonance spectrometer for measuring the chemical composition of a fluid or the flow velocity of a fluid consisting of at least one excitation coil (7) for collecting signals.</u> (1) Furthermore, it consists of an antenna (10) and an electronic circuit required to transmit the data measured by telemetry to an external reader.<u style="single">Embodiment (A)</u>The implantable nuclear magnetic resonance spectrometer described in. (2) The arrangement of the permanent magnets is composed of an external cylindrical magnet (1) and two internal cylindrical magnets (2) arranged inside the magnet (1). The magnets are magnetized along their respective axes of symmetry, and the magnetization direction of the outer magnet (1) is opposite to the magnetization direction of the inner magnet (2).<u style="single">Embodiment (A)</u>Alternatively, the implantable nuclear magnetic resonance spectrometer according to embodiment (1). (3) The arrangement of the permanent magnets (1, 2) further closes the cylindrical external permanent magnet (1), and the proximity of the two ferrite caps (4) and the internal permanent magnet (2). The implantable nuclear magnetic resonance spectrometer according to embodiment (2), which comprises two magnetic concentrators (3) arranged at the ends. (4) The excitation coil (7) is arranged around a catheter (6) that traverses the arrangement of the permanent magnets (1,2,3,4) to detect and preprocess the nuclear magnetic resonance signal. The implantable nuclear magnetic resonance spectrometer according to embodiment (3), wherein the pretreatment circuit (8) for is located very close to the excitation coil (7). (5) Further, it consists of a battery for supplying electric power to the electronic circuit (8, 9).<u style="single">Embodiment (A)</u>And the implantable nuclear magnetic resonance spectrometer according to any one of embodiments (1) to (4). (6) Inclusive with bioacceptable material<u style="single">Embodiment (A)</u>And the implantable nuclear magnetic resonance spectrometer according to any one of embodiments (1) to (5).<u style="single"> (B) A device for measuring the chemical composition or flow velocity of a physiological fluid consisting of an implantable nuclear magnetic resonance spectrometer and an external reader communicable to the implantable device by telemetry. ..</u> (7) In the body passage by catheter<u style="single">Embodiment (A)</u>The step of transplanting the device, the step of exciting and activating the transplantable device by an external reader that is inductively connected to the transplantable device, and the data transmitted by the portable device. A method for measuring the chemical composition of a physiological fluid and / or the flow velocity of the fluid, which comprises the steps of collecting and analyzing the fluid. [0023] [Effect of the invention] Accordingly, according to the present invention, an implantable nuclear magnetic resonance spectrometer for measuring the chemical composition of a fluid and / or the flow velocity of a fluid can be provided. [Simple explanation of drawings] FIG. 1 is a schematic partial cross-sectional view of an implantable nuclear magnetic resonance spectrometer according to the present invention. [Explanation of symbols] 1 External magnet 2 Internal magnet 3 Magnetic concentrator 4 Ferrite cap 5 Central radial hole 6 catheter 7 Excitation / detection coil