FR3088531A1 - MICROSONIC FOR NUCLEAR MAGNETIC RESONANCE ANALYSIS - Google Patents

Abstract

The invention relates to a microprobe (10) of submillimetric size comprising a capillary (1), said capillary comprising a distal end (2) and a proximal end (3), an expandable microballoon (4) integral with the proximal end of the capillary. and in fluid communication with the capillary (1) and a magnetic resonance circuit (5), in particular in expandable form, integral with the expandable microballoon (4), in particular by fixing points (6), said balloon having a deflated position, or swollen after injection of a liquid or gas into the capillary (1) through its distal end (2). The microprobe (10) according to the invention can be included in a hollow microneedle (8), to form an insertion kit (20) allowing the placement of the microprobe (10) in a sample to be analyzed. The invention thus also relates to a magnetic resonance imaging or spectroscopy device comprising a microprobe as well as a method for metabolic analysis or imaging of a biological sample using the microprobe.

Description

Microprobe for nuclear magnetic resonance analysis

TECHNICAL AREA

The present invention relates to the field of nuclear magnetic resonance (NMR). The invention relates, more specifically, to the field of microprobes which can be implemented in a device for spectroscopic analysis by NMR (SRM) or imaging by NMR (MRI), in particular for the analysis of a biological sample.

TECHNOLOGICAL BACKGROUND

NMR is a spectroscopic method of analyzing matter, based on the magnetic properties of certain atomic nuclei. Despite its widespread use and its varied applications, notably in the medical field, the techniques which arise from NMR such as magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) are intrinsically insensitive techniques compared to techniques fluorescence analysis, mass spectrometry or nuclear imaging. NMR sensitivity is assessed by measuring the signal-to-noise ratio (SNR) of acquisitions in the time or frequency domain. This ratio depends, among other things, on the sample size, the concentration of the nuclei, the Larmor frequency and the efficiency Bi / i of the NMR probe, where B1 is the oscillating magnetic field generated by the probe NMR and i is the intensity of the current applied in the probe. The Bi / i ratio is inversely proportional to the size of the NMR probe. For this reason, the size of the NMR probes is, almost systematically, adapted to the volume of the sample, of the tissue or of the organ analyzed or imaged by NMR. The sensitivity of the NMR analysis is thus linked to the size of the NMR probe.

At present, implantable NMR probes are centimeter or millimeter in size and are in the form of rigid planar or solenoid structures. The rigidity of their structure allows the implantation of the NMR probe in soft tissues (such as the brain or the peritoneal cavity) and the planar geometry of the probe ensures optimal detection sensitivity on the tissues opposite. probe screw.

The main problem posed by this type of structure is related to their invasive and destructive aspect with respect to the tissues. Also, the dimensions of this type of NMR probe are constrained by the need to preserve the tissues at the time of insertion, along the path and at the final position of implantation of the NMR probe. It is for this reason that current NMR probes are generally implanted in the lumen of organs (stomach, esophagus, etc.) in order to avoid destruction of the surrounding tissue. Thus, the NMR probes are not implanted directly in the tissue to be analyzed, but only in the immediate vicinity.

The current compromise between safety and performance (sensitivity) of the NMR probe, does not allow the use of NMR probes directly in the tissues or organs to be imaged or analyzed, since their implantation within the tissue of interest would destroy the surrounding tissues .

There is therefore a need for NMR probes which can be used for the analysis or imaging of biological samples, which allow precise analysis without damaging tissue destruction.

SUMMARY OF THE INVENTION

The present invention therefore aims to remedy the drawbacks of current NMR probes, by proposing an extensible NMR microprobe of submillimetric size, advantageously flexible. The invention allows minimally invasive microprobe implantation, while ensuring biocompatibility and NMR detection sensitivity suitable for MRS / MRI studies in vivo.

These implantable NMR microprobes according to the invention can advantageously be used to carry out SRM or MRI analyzes with high detection sensitivity, in particular on small biological samples. The sensitivity of the probes according to the invention makes it possible to envisage profiling (detection, quantification) of biological chemical species (for example metabolites, neurotransmitters or small molecules), of nuclei (for example 23Na, 31P or 13C) present in weak quantities in the samples analyzed, in particular in quantities lower than the nanomole, or else to produce images with high spatial resolution of biological samples.

The present invention relates particularly to an implantable microprobe for imaging or spectroscopy by magnetic resonance comprising:

a capillary comprising a distal end and a proximal end, said capillary having an external diameter of between 50 and 300 micrometers,

at least one expandable microballoon integral with the proximal end of the capillary, said microballoon being in fluid communication with said capillary, and said microballoon having a diameter between 50 and 300 micrometers in the deflated position and a diameter between 500 and 1000 micrometers in inflated position; and

- At least one expandable magnetic resonance circuit secured to the microballoon, said magnetic resonance circuit having a perimeter between 300 and 500 micrometers.

Preferably, the expandable magnetic resonance circuit is fixed on the internal surface and / or the external surface of the microballoon, the at least one expandable magnetic resonance circuit being preferably arranged so as to cover the entire internal surface and / or external of at least one microballoon.

Advantageously, the expandable magnetic resonance circuit is in pleated form.

Advantageously, the expandable magnetic resonance circuit comprises at least one copper microfilter, having a diameter between 10 and 70 micrometers, preferably between 20 and 60 micrometers, more preferably between 30 and 50 micrometers.

In one embodiment, the microprobe comprises at least two expandable magnetic resonance circuits, preferably arranged without overlap between them when the microballoon is in the inflated position.

In a particular embodiment, the microprobe comprises two expandable microballoons arranged one inside the other so as to form an internal microballoon and an external microballoon, and at least one expandable magnetic resonance circuit fixed on the internal microballoon and / or external.

Advantageously, the microballoon consists of an extensible silicone polymer, preferably of the polydimethylsiloxane elastomer type.

In one embodiment, the detection volume of the microprobe is between 100 and 500 nanoliters, preferably between 200 and 300 nanoliters.

The invention also relates to a kit for inserting a microprobe comprising a hollow microneedle and a microprobe according to the invention.

Preferably, the microneedle has an external diameter between 300 and 500 micrometers and / or an internal diameter between 100 and 300 micrometers.

In a particular embodiment, the insertion kit for a microprobe further comprises therapeutic molecules.

The invention also relates to the use of a microprobe insertion kit for the metabolic analysis of a biological sample.

The invention also relates to a magnetic resonance imaging or spectroscopy device comprising a microprobe according to the invention, said magnetic resonance imaging or spectroscopy device further comprising a tuning-adaptation circuit disposed remotely of the magnetic resonance circuit of the microprobe.

The invention also relates to a method for metabolic analysis of a biological sample, said method comprising:

the insertion of a microprobe according to the invention, preferably by a hollow microneedle comprising said microprobe, in a biological sample;

- the expansion of the microballoon by the introduction of a liquid or a gas introduced at the distal end of the capillary; and

- metabolic analysis of the biological sample, preferably using a magnetic resonance spectroscopy system.

The invention finally relates to a magnetic resonance imaging method, said method comprising:

the insertion of the microprobe according to the invention, preferably by a hollow microneedle comprising said microprobe, in a biological sample;

- the extension of the microballoon by the introduction of a liquid or a gas introduced at the distal end of the capillary; and

- taking the image of the biological sample by magnetic resonance, preferably using a magnetic resonance imaging system.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to an implantable microprobe for imaging or spectrometry by magnetic resonance comprising a capillary comprising a proximal end and a distal end, at least one expandable microballoon integral with the proximal end of the capillary, said microballoon being in fluid communication with said capillary, and at least one expandable magnetic resonance circuit secured to the microballoon.

"Nuclear magnetic resonance microprobe" means the part of an apparatus for nuclear magnetic resonance analysis intended to generate a radiofrequency magnetic field to excite the nuclear spins of a sample and / or to detect a magnetic field. Such a microprobe generally comprises an LC-type resonant circuit (RLC circuit) which provides coupling with an external radiofrequency magnetic field, as well as an impedance matching circuit.

By "implantable" is meant that the microprobe can be inserted into a sample, in particular into a biological sample such as a tissue, possibly within an organ.

By “biological sample” is meant a set of cells grouped into clusters, networks or bundles. In one embodiment, the biological sample is an organ or a portion of an organ. In particular, the biological sample can be a tissue sample obtained for example by biopsy, part of an organ, cancerous tissue, etc. In a particular embodiment, the biological sample is a liquid, preferably contained in a tissue or bone cavity, such as cerebrospinal fluid, pleural fluid, peritoneal fluid, heart fluid or blood. The biological sample can be of animal, human or plant origin. The biological sample can be analyzed or imaged in vivo or ex vivo / in vitro.

Advantageously, the capillary has a cylindrical tubular shape. Advantageously, the capillary is made of biocompatible material, preferably glass.

In one embodiment, the capillary has an external diameter between 50 and 300 micrometers, between 75 and 250 micrometers, between 100 and 300 micrometers or between 90 and 290 micrometers. Preferably, the capillary has an external diameter between 90 and 290 micrometers.

By "proximal end" is meant the portion of the capillary closest to the microballoon and / or the implantable area. Conversely, by “distal end” is meant the portion of the capillary furthest from the microballoon and / or from the implantable area.

By "expandable" is meant the possibility of development in volume and / or on the surface of the microprobe, the microballoon and / or the RLC circuit. In particular, the expansion of the NMR probe is linked to the expansion of the microballoon and the RLC circuit. When the microballoon is inflated, the circuit deploys to the surface of the microballoon. To ensure the expansion of the microballoon, a gas or a liquid under pressure (a few hundred mbar) can be injected inside the capillary by its distal end, which allows the deployment of the microballoon and the RLC circuit.

Advantageously, the RLC circuit is expandable. Preferably, the RLC circuit is produced in a pleated form to allow its deployment. By "pleated" means that the circuit is folded in accordion, the folds can be regular or irregular both by their size and by their arrangement. The RLC circuit can have a pleated shape when the microballoon is in the deflated and / or inflated position. Alternatively, the RLC circuit can have a wavy or curved shape to perfectly match the surface of the microballoon when the latter is in the inflated position. Of course, it is possible that the circuit has a pleated, wavy or curved shape only when the microballoon is in the deflated position.

In one embodiment, the RLC circuit is fixedly attached to the surface of the microballoon, preferably by fixing points, in particular points of biocompatible adhesive.

Alternatively, the circuit can be fixed over its entire length to the surface of the microballoon, in particular by taking the mass of the circuit in the microballoon, for example during the drying of the elastomer which composes the microballoon, or by any other suitable process. . Preferably, the circuit is fixed irreversibly on the surface of the microballoon. Alternatively, the circuit can be fixed reversibly on the surface of the microballoon.

In one embodiment, at least one expandable magnetic resonance circuit is attached to the inner surface and / or the outer surface of the microballoon.

In one embodiment, at least one expandable magnetic resonance circuit is fixed on the internal surface and on the external surface of the microballoon.

Of course, it is possible that at least one expandable magnetic resonance circuit is fixed only on the internal surface of the microballoon, so as to be completely covered by the microballoon. Alternatively, it is also possible that at least one expandable magnetic resonance circuit is only fixed on the external surface of the microballoon, so as to be directly exposed to the environment in which the microprobe will be implanted.

In one embodiment, the expandable magnetic resonance circuit is arranged so as to cover the entire internal and / or external surface of the microballoon. Alternatively, the RLC circuit can cover at least 50% or at least 75% of the internal and / or external surface of the microballoon. Alternatively, the RLC circuit can cover less than 75% or less than 50% of the internal and / or external surface of the microballoon

In a particular embodiment, the expandable magnetic resonance circuit has a perimeter between 300 and 800 micrometers, between 300 and 700 micrometers, between 300 and 600 micrometers or between 300 and 500 micrometers. Preferably, the expandable magnetic resonance circuit has a perimeter of between 300 and 500 micrometers. The perimeter of the circuit represents the distance traveled by the RLC circuit to the surface of the microballoon.

The expandable magnetic resonance circuit can be produced using procedures for producing micro-electro-mechanical systems (Micro-Electro-Mechanical Systems or MEMS) by micro-etching of an electrical circuit (copper alloy) on a Parylene C substrate. (PaC), a biocompatible and flexible polymer. In particular, the magnetic resonance circuit is made of a metal and / or a conductive ink. Preferably, the magnetic resonance circuit comprises a copper microfilm.

In one embodiment, the copper microfilter has a diameter of less than 150 micrometers or less than 100 micrometers, preferably less than 70 micrometers, 60 micrometers, 50 micrometers, 40 micrometers, 30 micrometers or 20 micrometers . Preferably, the copper microfilm has a diameter less than or equal to 50 micrometers. Alternatively, the copper microfilm has a diameter between 10 and 70 micrometers, between 20 and 60 micrometers or between 30 and 50 micrometers. Preferably, the copper microfilm has a diameter between 30 and 50 micrometers.

In a particular embodiment, the microprobe comprises a plurality of expandable magnetic resonance circuits. Preferably, the microprobe comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 RLC circuits. Preferably, the microprobe comprises 2, 3, 4, 5, 6, 7, 8, 9 or 10 RLC circuits. Preferably, said RLC circuits are arranged without overlap between them on the surface of the microballoon when the latter is in the inflated position. By "without overlap" is understood that the circuits do not meet, do not overlap, nor overlap with each other on the surface of the microballoon when the latter is in the inflated position.

In one embodiment, the microballoon has an external diameter of between 100 and 400 micrometers, between 100 and 300 micrometers or between 100 and 200 micrometers in the deflated position. Preferably, the microballoon has an external diameter of between 100 and 300 micrometers in the deflated position.

In one embodiment, the microballoon has an external diameter of between 500 and 1000 micrometers, between 500 and 900 micrometers, between 500 and 800 micrometers, or between 500 and 700 micrometers in the inflated position. Preferably, the microballoon has a diameter of between 500 and 1000 micrometers in the inflated position. Preferably, the microballoon has an external diameter of less than 1 millimeter in the inflated position.

In a particular embodiment, the microprobe comprises at least two microballoons arranged one inside the other. Preferably, the microprobe comprises two expandable microballoon (s) arranged one inside the other. In this embodiment, a magnetic resonance circuit can be fixed on the internal and / or external surface of the first microballoon, and / or of the second microballoon.

Preferably, the microprobe according to the invention comprises two expandable microballoons arranged one inside the other so as to form an internal microballoon and an external microballoon, and at least one expandable magnetic resonance circuit fixed on the internal microballoon and / or external. In particular, the at least one magnetic resonance circuit is fixed on the internal and / or external surface of the internal microballoon and / or the external microballoon.

In one embodiment, the microprobe according to the invention comprises at least one expandable magnetic resonance circuit fixed on the internal surface of the internal microballoon.

In another embodiment, the microprobe according to the invention comprises at least one expandable magnetic resonance circuit fixed on the external surface of the internal microballoon.

In another embodiment, the microprobe according to the invention comprises at least one expandable magnetic resonance circuit fixed on the internal surface of the external microballoon.

In another embodiment, the microprobe according to the invention comprises at least one expandable magnetic resonance circuit fixed on the external surface of the external microballoon.

In another embodiment, the microprobe according to the invention comprises at least one expandable magnetic resonance circuit fixed on the internal surface of the internal microballoon and at least one expandable magnetic resonance circuit fixed on the internal surface of the external microballoon.

In another embodiment, the microprobe according to the invention comprises at least one expandable magnetic resonance circuit fixed on the external surface of the external microballoon.

In another embodiment, the microprobe according to the invention comprises at least one expandable magnetic resonance circuit fixed on the internal surface of the external microballoon.

In another embodiment, the microprobe according to the invention comprises at least one expandable magnetic resonance circuit fixed on the internal surface of the internal microballoon and at least one expandable magnetic resonance circuit fixed on the external surface of the external microballoon. In one embodiment, the microballoon is fixed integrally to the proximal end of the capillary so as to be in fluid communication with the capillary.

By "integral fixation" means a close connection between the microballoon and the capillary. Preferably, the microballoon is fixed irreversibly on the proximal end of the capillary. Alternatively, the microballoon is reversibly attached to the proximal end of the capillary.

By “fluid communication” is meant that the capillary and the microballoon are linked or connected together so as to be able to pass a fluid, for example a liquid or a gas, from the capillary to the microballoon and / or from the microballoon to the capillary. Preferably, this connection is sealed.

The expansion of the microprobe according to the invention is carried out in particular by the expansion, that is to say the swelling, of the microballoon. Expansion of the microballoon can be achieved by the introduction of a fluid or gas at the distal end of the capillary. In a particular embodiment, the liquid is chosen from water, a proton-free fluid such as deuterated water and a perfluorocarbon of the perfluorodecaline type. In another particular embodiment, the gas is chosen from Pair, nitrogen and an inert gas such as helium.

The “inflated” / “expanded” and “deflated” / “unexpanded” positions of the microballoon also mean respectively the position for which the microballoon is stretched after inflation, in particular after it has been filled with a liquid or a gas, and the position in which the microballoon is empty, for example before or during the implantation of the microprobe, and before filling with a gas or a liquid.

Advantageously, the expandable microballoon has an ovoid shape in the unexpanded position and a spherical shape in the expanded position. Advantageously, the microballoon consists of a biocompatible material, preferably an extensible silicone polymer, preferably of the polydimethylsiloxane elastomer type.

In a particular embodiment, the production of the microballoon may follow the following procedure reported by Cao and colleagues (Biosens Bioelectron. 2014 Apr. 15; 54: 610-6):

- a drop of photoresist is deposited at the end of a capillary,

- the drop of photoresist is coated, with the exception of its top, with a layer of silicone (for example PDMS or PMMA). The whole is dried at high temperature and then the photoresist is eliminated by chemical dissolution (for example acetone, DMSO, etc.).

- the silicone layer is sealed at the top by adding silicone at the top to form the microballoon. The whole is dried at high temperature.

The subject of the invention is also a kit for inserting a microprobe comprising a hollow microneedle and a microprobe according to the invention. Preferably, the micro-needle has a beveled tip to facilitate its introduction into the biological sample. The positioning of NMR microprobes using a microneedle included in an insertion kit, followed by the deployment and expansion of these microprobes allows for example to access and explore by SRM / MRI the all tissues of a biological sample in a minimally invasive manner.

Preferably, a microprobe according to the invention can be mounted in translation in a microneedle. The kit can thus either include a ready-to-use micro-needle in which a microprobe is already housed in translation, or a micro-needle and a microprobe ready to be mounted in translation inside the micro-needle.

In one embodiment, the microneedle has an external diameter between 100 and 800 micrometers, between 200 and 700 micrometers, between 200 and 600 micrometers, between 300 and 500 micrometers or between 300 and 400 micrometers. Preferably, the micro-needle has an external diameter of between 300 and 500 micrometers.

In one embodiment, the microneedle has an internal diameter between 100 and 400 micrometers, between 100 and 300 micrometers or between 100 and 200 micrometers. Preferably, the micro-needle has an internal diameter of between 100 and 300 micrometers.

In general, the diameter of the microneedle is strictly greater than the external diameter of the microprobe, so that the microprobe can be mounted in translation inside the microneedle.

Preferably, the micro-needle is made of biocompatible material, preferably metal, in particular metal of the stainless steel type.

The insertion kit may also include therapeutic molecules. In one embodiment, the insertion kit includes therapeutic molecules for their administration to a subject. In the context of the invention, the term “subject” designates a mammal, and preferably a human, including an adult, a child or an infant. The term "subject" can also designate a non-human animal, in particular a non-human primate.

In the context of the invention, such administration of therapeutic molecules allows the analysis of the activity of therapeutic molecules administered by the NMR microprobe according to the invention. Thus, the subject of the invention is also the use of a microprobe insertion kit for the metabolic analysis of a biological sample. The biological sample can be analyzed in vivo or ex vivo, in particular after taking a sample, tissue or organ from a subject.

A subject of the invention is also a magnetic resonance imaging or spectroscopy device comprising the microprobe according to the invention, said magnetic resonance imaging or spectroscopy device further comprising a tuning-adaptation circuit disposed remotely of the magnetic resonance circuit of the microprobe.

In one embodiment, the microprobe is interfaced (via the amplification, digitization and signal processing chain) with the magnetic resonance imaging system for the production of images and spectra by magnetic resonance.

Advantageously, the magnetic resonance imaging device comprising the microprobe according to the invention makes it possible to obtain spectra of a biological sample with a spectral resolution of less than 5 Hz.

The subject of the invention is also a method of metabolic analysis of a biological sample, said method comprising:

the insertion of the microprobe according to the invention, preferably by a hollow microneedle comprising said microprobe, in a biological sample;

- the expansion of the microballoon by the introduction of a liquid or a gas introduced at the distal end of the capillary; and

- metabolic analysis of the biological sample, preferably using a magnetic resonance spectrometry system.

In one embodiment, the insertion of the microprobe into a biological sample and the metabolic analysis of this sample are carried out in vivo or ex vivo, preferably on a sample previously taken from the subject.

In particular, the microprobe according to the invention has a detection volume of the biological sample of between 100 and 400 nanoliters, between 100 and 300 nanoliters or between 100 and 200 nanoliters, preferably between 150 and 300 nanoliters, between 150 and 250 nanoliters , between 150 and 200 nanoliters or between 200 and 250 nanoliters. Preferably, the microprobe has a detection volume of the biological sample of around 200 nanoliters. By "detection volume" is meant the volume of the region of the biological sample in which the microprobe has the capacity to collect and transmit the NMR signal.

For example, the sensitivity of the microprobe according to the invention has been evaluated in vitro on lactate solutions as well as in situ implantation situation in grapes. Detection thresholds of 1 mM on lactate were obtained with acquisition times of the order of a second. These detection thresholds are compatible with the concentrations of many metabolites and molecules of interest present in vivo (NAA, lactate, creatine, glutamate, etc.), in particular in an animal or human body.

The subject of the invention is also a method of anatomical magnetic resonance imaging, said method comprising:

the insertion of the microprobe according to the invention, preferably by a hollow microneedle comprising said microprobe, in a biological sample;

- the extension of the microballoon by the introduction of a liquid or a gas introduced at the distal end of the capillary; and

- taking the image of the biological sample by magnetic resonance, preferably using a magnetic resonance imaging system.

In one embodiment, the insertion of the microprobe into a biological sample and the taking of images of this sample are carried out in vivo or ex vivo. Preferably, the biological sample is a tissue and / or an organ of a subject and the microprobe is inserted at an anatomical location of interest in a tissue and / or an organ of a subject. The use of such a probe is therefore similar to an in situ non-destructive biopsy method on living tissue.

In particular, the pathologies concerned by the use of implantable microprobes for imaging or NMR spectroscopy are:

- cancer, for example for the development of biomarkers, evaluation of the grade of the tumor, monitoring of the tumor, evaluation of therapeutic treatments. The type of cancer targeted can be glioma, breast cancer, liver cancer, lung cancer, or sarcomas,

- neurodegenerative diseases, for example for the quantification of neurotransmitters in Parkinson's disease, the development of biomarkers in Alzheimer's disease and multiple sclerosis,

- metabolic pathologies such as fatty liver or diabetes.

The invention will be better understood on reading the description which follows and on examining the figures which accompany it. These are presented as an indication and in no way limit the invention.

Figure 1: Schematic representation of an RLC circuit included in a microprobe according to an embodiment of the invention.

Figure 2A-2B: Schematic representation of the deployment of a microprobe according to an embodiment of the invention, in the deflated (A) and inflated (B) position.

Figure 3A-3C: Schematic representation of a method of using a micro probe insertion kit according to Figure 2.

FIG. 1 schematically shows one of the shapes envisaged here a wavy shape which an RLC circuit 5 can take on the surface of a microballoon according to the invention.

FIG. 2A schematically shows an embodiment of a microprobe 10 according to the invention comprising a capillary 1 comprising a distal end 2 and a proximal end 3, an expandable microballoon 4 secured to the proximal end and in fluid communication with the capillary 1 and a magnetic resonance circuit 5 secured by attachment points 6 to the expandable microballoon 4, the microballoon being in the deflated position. In this embodiment, the RLC circuit 5 is in pleated form when the microballoon is in the deflated position.

FIG. 2B schematically shows said microprobe 10 when the microballoon is in the inflated position, in particular following the introduction of a fluid or gas 7 through the distal end 2 of the capillary 1. In this embodiment, the RLC circuit 5 retains a pleated shape when the microballoon is in the inflated position.

FIG. 3 schematically shows an example of the use of an insertion kit 20 of a microprobe 10 according to the invention.

In a first step A, the microneedle 8, inside which the microprobe 10 is positioned, is inserted into the biological sample of interest (not shown);

In a second step B, the microneedle 8 is withdrawn and the NMR microprobe 10 left 10 implanted at the desired position.

Finally, in a third step C, the microballoon 4 is inflated by the injection of a gas or liquid at the distal end 2 of the capillary 1 to allow the deployment of the RLC circuit 5 of the microprobe 10 before NMR analysis / MRI.

It is the local deployment of the microprobe by the expansion of the microballoon which makes it possible to adapt its geometry to the area to be analyzed in SRM / MRI and to optimize the sensitivity by widening the detection area.

Claims (12)

1. Implantable magnetic resonance imaging or spectroscopic microprobe comprising: a capillary (1) comprising a distal end (2) and a proximal end (3), said capillary having an external diameter between 50 and 300 micrometers, - at least one expandable microballoon (4) integral with the proximal end (3) of the capillary (1), said microballoon (4) being in fluid communication with said capillary (1), and said microballoon (4) having a diameter included between 100 and 300 micrometers in the deflated position and a diameter between 500 and 1000 micrometers in the inflated position: and at least one expandable magnetic resonance circuit (5) integral with the microballoon (4), said magnetic resonance circuit (5) having a perimeter between 300 and 500 micrometers. 2. Microprobe (10) according to claim 1, comprising at least one expandable magnetic resonance circuit (5) fixed on the internal surface and / or the external surface of the at least one microballoon (4), the at least one resonance circuit expandable magnetic (5) being preferably arranged so as to cover the entire internal and / or external surface of the at least one microballoon (4). 3. Microprobe (10) according to claim 1 or 2, in which the expandable magnetic resonance circuit (5) is in pleated form, and / or in which the expandable magnetic resonance circuit (5) comprises at least one copper microfilament , having a diameter between 10 and 70 micrometers, preferably between 20 and 60 micrometers, more preferably between 30 and 50 micrometers. 4. Microprobe (10) according to any one of claims 1 to 3, comprising a plurality of expandable magnetic resonance circuits (5), preferably arranged without overlap between them when the microballoon is in the inflated position. 5. Microprobe (10) according to any one of claims 1 to 4, in which the microprobe comprises two expandable microballoons arranged one inside the other so as to form an internal microballoon and an external microballoon, and at least one circuit. of expandable magnetic resonance being fixed on the internal and / or external microballoon, and / or in which the microballoon (4) consists of an extensible silicone polymer, preferably of the polydimethylsiloxane elastomer type. 6. Microprobe (10) according to any one of claims 1 to 5, in which the detection volume of the microprobe is between 100 and 500 nanoliters, preferably between 200 and 300 nanoliters. 7. Kit for inserting (20) a microprobe (10) comprising a hollow microneedle (8) and a microprobe (10) according to any one of claims 1 to 6, said microneedle (8) having advantageously an external diameter between 300 and 500 micrometers and / or an internal diameter between 100 and 300 micrometers. 8. Kit for inserting (20) a microprobe (10) according to claim 7, further comprising therapeutic molecules. 9. Use of an insertion kit (20) of a microprobe (10) according to claim 7 or 8, for the in vitro / ex vivo metabolic analysis of a biological sample. 10. Magnetic resonance imaging or spectroscopy device comprising a microprobe (10) according to any one of claims 1 to 6, said magnetic resonance imaging or spectroscopy device further comprising a tuning-adaptation circuit. arranged at a distance from the magnetic resonance circuit of the microprobe. 11. Method for in vitro / ex vivo metabolic analysis of a biological sample, said method comprising - the insertion of a microprobe (10) according to any one of claims 1 to 6, preferably by a hollow microneedle (8) comprising said microprobe (10), in a biological sample; - the expansion of the microbalion (4) by the introduction of a liquid or a gas (7) introduced at the distal end (2) of the capillary; and - metabolic analysis of the biological sample, preferably using a magnetic resonance spectroscopy system. 12. In vitro / ex vivo magnetic resonance imaging method, said method comprising: - the insertion of the microprobe (10) according to any one of claims 1 to 6, preferably by a hollow microneedle (8) comprising said microprobe (10), in a biological sample; - the extension of the microballoon (4) by the introduction of a liquid or a gas (7) introduced at the distal end (2) of the capillary; and - taking the image of the biological sample by magnetic resonance, preferably using a magnetic resonance imaging system.