Interface and method for preparing and transferring material to a mass spectrometer - Patent Application 20070122999

Abstract

The present invention relates to an interface for preparing biological material and transferring the biological material to a mass spectrometer. The interface includes a pathway for the biological material in aerosol form, a venturi system with two inlets and one outlet, a cartridge heater, a corona discharge needle for ionizing the biological material in aerosol form, a nebulizer for generating a mist, and a transfer tube connected to the outlet of the venturi system. The interface is configured such that the cartridge heater is disposed around the transfer tube, the corona discharge needle is disposed at the outlet of the transfer tube, and the venturi system is connected by two inlets to the pathway for the biological material and the nebulizer, so as to solvate the biological material in aerosol form with the mist in the venturi system.

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates to the field of mass spectrometer interfaces, and more particularly to interfaces and methods for preparing and transferring biological material to a mass spectrometer. [Background technology]

[0002] In all fields of biology and medicine, the identification of analytes, whether they are physiologically normal or pathological, is of paramount importance, particularly in relation to the diagnosis, prognosis, and treatment of disease.

[0003] For example, cancer is diagnosed based on information collected by imaging diagnostic methods. Although these imaging diagnostic methods (e.g., CT scan, MRI, etc.) can provide high-resolution images, these high-resolution methods cannot provide sufficient information, particularly regarding the identification of malignant growths. In contrast, other methods with lower image resolution (e.g., nuclear medicine imaging techniques, etc.) can instead provide information related to the growth of the disease. Generally, one or a combination of these imaging diagnostic methods must be utilized to identify and localize cancer.

[0004] Generally, an accurate diagnosis of pathological or abnormal tissue is obtained by histology, the branch of biology that involves the study of biological tissues, or cytology, the branch of biology that involves the study of cells.

[0005] These imaging and analytical methods allow for efficient diagnosis of pathological or abnormal tissue, but they do not provide information regarding the location of malignant tissue during surgical intervention.

[0006] One way to circumvent this problem is to perform histopathological examination of the excised tissue during surgery. This involves making an immediate diagnosis and observing whether the boundaries of the malignant tissue are sufficiently clear in the collected tissue. This method is very widespread, despite various drawbacks, such as the time required to keep the patient in the operating room (typically 20-50 minutes, depending on the case and the facility). Other methods, such as ultrasound and fluoroscopic imaging, are also used. Although these methods provide useful results, they are not sensitive enough to identify the presence of only a limited number of malignant cells.

[0007] Malignant tissue (i.e., tumors) can be distinguished from healthy tissue in several ways. Indeed, tumors have highly diverse molecular compositions, ranging from the distribution of minor metabolic components and lipids to the expression of various proteins. These molecular characteristics can be exploited to visualize tumors by various imaging techniques, including molecular imaging of tissues by infrared spectroscopy or mass spectrometry. Among these methods, mass spectrometry can serve as the basis for in situ and in vivo tissue identification tools by analyzing the diverse molecular compositions of different tissues.

[0008] Mass spectrometry ionization methods were initially developed for the analysis of gaseous or volatile materials. One of the drawbacks of these ionization methods is their inability to analyze non-volatile compounds, which account for approximately 90% of the molecules in pathological tissues.

[0009] Since the 1940s, new methods for ion production have been developed that allow for the production of gas-phase ions directly from solid samples. Most of these methods require a desorption / ionization process. Desorption ionization methods use an analytical beam to promote desorption and ionization. This analytical beam, consisting of entities of various compositions (atoms, molecules, atomic or molecular ions, photons, etc.), is directed at the surface of the sample and transmitted at variable energy levels.

[0010] For example, in fast atom bombardment (FAB) desorption / ionization, energetic inert gas atoms are used to bombard the sample to be analyzed, thereby pulverizing and ionizing the sample. Secondary ion mass spectrometry (SIMS) bombards the surface of the sample to be analyzed with a highly accelerated ion beam. The sample is then pulverized, and a portion of the powdered material is ionized. However, these techniques have the disadvantage of requiring high vacuum conditions. Therefore, these samples are inserted into the high-vacuum enclosure of the mass spectrometer, which imposes significant restrictions on the composition and shape of the sample and also requires a specialized system for inserting the sample.

[0011] The need for desorption ionization methods performed under atmospheric conditions has been called into question. Atmospheric pressure, and more specifically under atmospheric conditions (atmospheric pressure ionization mass spectrometry (AIMS)), offers the advantages of being a faster and more flexible analytical method, and of not requiring sample pretreatment, such as extraction of the compounds of interest. Furthermore, biological systems, including living organisms, can be investigated in vivo and in situ. All of this makes it possible to use these methods (AIMS) for in situ tissue identification.

[0012] Among these methods under atmospheric conditions, the following may be mentioned as examples: Rapid Evaporative Ionization Mass Spectrometry (REIMS) uses a heated impact surface to generate ions from an aerosol; Extractive Atmospheric Pressure Photoionization (EAPPI) uses an ultrasonic nebulization system to atomize and vaporize samples, which are then mixed with gaseous dopants and interact with photons and the surrounding medium, allowing for gas-phase ionization of analytes; Simple ionization by ultrasonic powdering under atmospheric conditions (Easy Ambient Sonic Spray Ionization (EASI)) uses a spray solvent stream directed at a surface where the solvent interacts with and carries away the analytes by evaporation, during which the analytes are ionized and released into the gas phase. Droplet Assisted Inlet Ionization (DAII) brings aqueous droplets and particles suspended in air into contact at the inlet to a mass spectrometer where they are heated and rapidly vaporize, resulting in the formation of molecular ions.

[0013] More recently, desorption electrospray ionization (DESI) has been developed, which uses charged solvent droplets as the analytical beam. DESI meets all the requirements associated with atmospheric pressure ionization, thus opening up the analytical scope of mass spectrometry to a wide variety of objects in terms of molecular composition, size, and shape.

[0014] The study of tissues by mass spectrometry has been pursued in two fundamentally different ways. The first approach aimed at the characterization (long-term, but also as comprehensive as possible) of the molecules present in the tissues by a strategy based on the extraction of specific compound families (metabolites, lipids, proteins, etc.) and the combination of mass spectrometry with separation methods (e.g. gas or liquid chromatography). On the other hand, the second approach emphasizes rapid analysis without extraction or separation, as well as rapid and direct molecular fingerprinting.

[0015] The first group of methods generally begins with homogenization and lysis of a certain amount of tissue, followed by selective extraction of compounds of interest. These compounds are separated by electrophoresis or chromatography and then analyzed by mass spectrometry. While these methods cannot be used for immediate tissue identification, they provide precise information about the molecular markers that characterize each tissue type, the variations in their relative abundance, and the signaling pathways in which these molecules are involved.

[0016] Rapid molecular printing of tissues by mass spectrometry is obtained by the above methods in general, and by desorption / ionization methods (SIMS, MALDI) and AIMS in particular.

[0017] Desorption and ionization of condensed-phase nonvolatile samples using lasers has been studied since the late 1960s. Most laser desorption methods result in the formation of molecular aggregates of various sizes and primarily neutral nature; therefore, these methods are often associated with post-ionization techniques. Traditionally, post-ionization was performed by electron impact (EI) or chemical ionization (CI). More recently, approaches utilizing laser ablation of the sample followed by electrospray ionization (ESI) of the resulting gaseous species have been introduced (laser ablation electrospray ionization (LAESI)). However, these methods suffer from the drawbacks of either being unable to completely destroy the molecular aggregates or failing to provide the ionization yields needed to further improve the sensitivity and depth of signals analyzable by mass spectrometry. Summary of the Invention [Problem to be solved by the invention]

[0018] Therefore, there remains a need to provide a suitable interface that serves to break down molecular aggregates and improve the ionization of the sample molecules (i.e., post-ionization) by preparing the sample to be analyzed after collection and before transfer to a mass spectrometer (particularly the mass analysis portion).

[0019] The purpose of this disclosure is to provide a solution to this situation. [Means for solving the problem]

[0020] According to a first aspect, there is provided an interface for preparing aerosolized material (neutral or partially ionized), in particular biological material, and transferring this material to a mass spectrometer, the interface comprising: a venturi system having two inlets and one outlet; A heater and a corona discharge needle for ionizing the material in aerosol form; This interface comprises: a sprayer for generating mist; a transfer tube connected to the outlet of the venturi system; and a heater configured to heat the transfer tube; a corona discharge needle positioned at the outlet of the transfer tube; a venturi system configured to receive the material in aerosol form through one of said inlets and connected to a nebulizer through the other of said inlets, thereby solvating the material in aerosol form by a mist within the venturi system; It is characterized by:

[0021] This interface according to the first aspect of the present invention serves to break down molecular aggregates of material from the sample collection site into an aerosol form and ionize or improve the ionization yield of the material. In a Venturi system connected to the nebulizer and pathway tube, the material is solvated into mist droplets and desolvated as it passes through a transfer tube surrounded by a cartridge heater. This solvation-desolvation process dissociates the material molecules and improves the ionization achieved by corona discharge. This ionization is achieved by a corona discharge needle positioned downstream of the transfer tube. This improvement in ionization means an increased rate of conversion of neutral material molecules to charged molecules, which serves to improve the sensitivity of the analysis performed by the mass spectrometer.

[0022] According to a second aspect, a method is proposed for preparing material, in particular biological material, and transferring this material to a mass spectrometer, the method comprising: Delivering the material in aerosol form towards the venturi system The method includes: injecting a mist containing solvent droplets into a venturi system; solvating a material in aerosol form into a mist of solvent droplets in a Venturi system; heating the solvated material in the solvent droplets of the mist passing through a transfer tube connected to the outlet of the Venturi system; ionizing the material by corona discharge delivered at the outlet of the transfer tube; The present invention is characterized in that it further comprises:

[0023] Other features, details, and advantages will become apparent upon reading the following detailed description and examining the accompanying drawings. [Brief explanation of the drawings]

[0024] [Figure 1] FIG. 1 is a schematic diagram of an interface according to a first embodiment of the present invention, in which the inlet flow of material and the outlet flow from the venturi system are collinear. [Figure 2] 1 is a schematic partial cross-sectional view of a venturi system and atomizer according to a first embodiment of the present invention; [Figure 3] FIG. 1 is a schematic diagram of an interface according to a first embodiment of the present invention, in which the mist flow and the discharge flow from the venturi system are collinear. [Figure 4] FIG. 2 is a schematic diagram of a method according to a second aspect of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0025] Interface 1 Please refer to Figures 1 and 2 below.

[0026] According to a first aspect, the invention proposes an interface 1 for preparing a material, in particular a biological material, and transferring this material to a mass spectrometer, said material being in aerosol form, said interface comprising: a venturi system 2 having two inlets 21, 22 and one outlet 23; Heater 3 and a corona discharge needle 4 for ionizing the material in aerosol form; and this interface 1 comprises: a sprayer 5 for generating mist; a transfer tube 6 connected to the outlet of the Venturi system 2; and a heater 3 configured to heat the transfer tube 6; A corona discharge needle 4 is positioned at the outlet of the transfer tube 6; The venturi system 2 is configured to receive the material in aerosol form through one of its inlets 21, 22 and is connected to the atomizer 5 through the other of its inlets 21, 22, thereby causing solvation of the material in aerosol form by the mist within the venturi system 2. It is characterized by:

[0027] The material ionized at interface 1 is in the form of particles, in particular particles of agglomerated, ablated, or detached biological tissue. Ablation or detachment may be performed, in particular, by laser. The biological tissue from which the biological material is collected may be any type of tissue of biological origin, with or without transformation, such as plant tissue (including cellulosic materials), animal tissue, including human tissue (e.g., nervous, muscular, epithelial, or connective tissue), or even microorganisms (e.g., bacteria, viruses, yeast). This biological material therefore mainly consists of aggregates of biomolecules (proteins, metabolites, lipids, etc.). These biological materials are generally substantially excipient-free. Non-biological materials may include the following: pharmaceuticals, xenobiotics, inorganic materials, and metallic, organometallic, or plastic compounds. The following description will be made with reference to biological materials. However, the description also encompasses non-biological materials.

[0028] During ablation or desorption, a certain amount of material is released into the gas phase, so that when the samples to be analyzed are collected, they are in the form of an aerosol containing solid particles, in particular molecular agglomerates of biological material, in a gaseous medium, which may in particular be a mixture of gas, which may be air, nitrogen, carbon dioxide, helium or other noble gases, and water vapor.

[0029] The interface 1 according to the first embodiment comprises a sprayer 5 capable of generating a mist.

[0030] The atomizer 5 is a unit that transforms a liquid into a cloud of very fine particles. With it, solutions and / or suspensions can be broken down into aerosols containing droplets of the solution and / or suspension. These aerosols are also called mist, and this term will be used hereafter.

[0031] The atomizer 5 is a means for suspending a liquid in a gas. The atomizer 5 can be selected from a compressor atomizer, a mesh atomizer, a jet atomizer, a saturated steam atomizer, and an ultrasonic atomizer. A compressor atomizer uses a compressed gas flow to extract free droplets from a liquid and form a mist. A mesh atomizer uses a vibrating membrane perforated with small openings, and generates mist by forcing a liquid through the membrane. A jet atomizer generates mist by forcing a liquid under pressure through very small openings. A saturated steam atomizer is an atomizer in which gas is passed through a heated liquid or a liquid at ambient temperature. The gas becomes filled with vapor and droplets of the liquid in the form of a mist, which is then conveyed to the outlet. An ultrasonic atomizer applies ultrasonic waves to the liquid, causing high-frequency vibrations to generate droplets of the liquid and form a mist.

[0032] The atomizer 5 may also be a nanoelectro atomizer or a microelectro atomizer. Preferably, the atomizer 5 is a nanoelectro atomizer.

[0033] The following discussion will be focused on compressor atomizers, but the same applies to other types of atomizers. Compressor atomizers are the most commonly used type of atomizer. Compressor atomizers are also known as atomizers. A compressor atomizer is typically a means for delivering a high-velocity compressed gas stream that is directed around a needle through which the liquid to be atomized is expelled. The passage of the gas results in the atomization of the liquid, forming a mist.

[0034] The compressor sprayer 5 may include an emitter 51 for generating mist, a solvent path pipe 52, and a gas path pipe 53. The solvent path pipe 52 and the gas path pipe 53 are connected to a socket 55 at their first sides, and the emitter 51 extends from the other side of the socket 55 opposite the first side.

[0035] The emitter 51 may include a tube 511 terminating in a tip and a hollow needle 512. The tube 511 and the hollow needle 512 are coaxial. The tip of the hollow needle 512 extends beyond the tip of the tube 511. The solvent path tube 52 is fluidly connected to the interior of the hollow needle 512, and the gas path tube 53 is fluidly connected to the space between the tube 511 and the hollow needle 512. The tip of the tube 511 and the tip of the hollow needle 512 form the tip of the sprayer 5 for generating mist. The smaller the inner diameter of the hollow needle 512, the smaller the droplet size of the mist. The needle typically has an inner diameter between 50 μm and 200 μm. The emitter 51 is configured so that the flow rate of the mist generated at the outlet of the sprayer 5 is between 100 nL / min and 2 mL / min. In some cases, the flow rate may be between 100 nL / min and 500 nL / min, and in other cases, the flow rate may be between 100 μL / min and 2 mL / min.

[0036] The solvent path pipe 52 serves to deliver the solvent to the atomizer 5, and the gas path pipe 53 serves to deliver a gas to the atomizer 5. The gas serves to atomize the solvent into fine droplets to form a mist. The mist is therefore in the form of an aerosol of fine solvent droplets contained in the gas delivered by the gas path pipe 53.

[0037] The interface 1 may further comprise a spray connector 54 in which the sprayer 5 is disposed. The spray connector 54 comprises an outlet 541 connected to the venturi system 2.

[0038] The spray connector 54 partially receives the sprayer 5 and serves to fluidly connect the sprayer 5 to the venturi system 2. Preferably, the spray connector 54 has a shape optimized for effectively transporting mist inside the venturi system 2, for example, its shape is conical (particularly its inner surface), with the smallest cross-sectional end of the cone located near the entrance to the venturi system 2. Furthermore, the spray connector 54 accommodates the tube 511 and hollow needle 512 of the sprayer 5 inside the spray connector 54, and serves to concentrate the mist flow inside the venturi system 2. The spray connector 54 extends from the bottom of the socket 55 of the sprayer 5 beyond the tip of the sprayer 5, thus forming a spray chamber 56 between the tip and the end.

[0039] The distance between the inlets 21, 22 of the venturi system 2 and the tip of the sprayer 5 may be between 1 and 50 mm, preferably between 2 and 10 mm, and more preferably between 3 and 5 mm.

[0040] The interface 1 according to the first embodiment comprises a venturi system 2. The venturi system 2 comprises two inlets 21, 22 and one outlet 23. The two inlets 21, 22 are connected to a passage tube 7 for biological material and to a sprayer 5. If the interface 1 comprises a spray connector 54, the spray connector 54 is connected to the inlets 21, 22 of the venturi system 2, but not to the sprayer 5.

[0041] The mist generated by the atomizer 5 is sent to the venturi system 2. This mist flow serves to prime the venturi system 2. A reduced pressure is generated within the venturi system 2, which serves to draw the biological material into the interior of the venturi system 2 in the form of an aerosol. Furthermore, the mist serves to break down aggregates of the biological material in order to isolate various biological material molecules, which are solvated in the mist droplets.

[0042] The solvent delivered by the solvent pathway tube 52 is selected to effectively separate the biological material aggregates and further solvate the biological material molecules in the solvent droplets. The solvent may be neutral to the biological material molecules. Because the primary role of the solvent is to solvate the biological material molecules, the solvent must be gentle on the biological material molecules so as not to alter subsequent analysis performed by the mass spectrometer. However, molecular alterations may be desirable. Thus, the solvent may be selected to alter the biological material molecules and improve the observation of specific species. The solvent may be selected from organic solvents, volatile compounds, polar molecules, nonpolar molecules, water, one or more alcohols (methanol, ethanol, isopropanol, propanol, butanol, pentanol), acetone, acetonitrile, tetrahydrofuran, ethyl acetate, ethylene glycol, dimethyl sulfoxide or dimethylformamide, methyl tert-butyl ether, aldehydes, ketones, hexane, and chloroform. In some embodiments, the solvent may include a supercharger, a lock mass (a mass measurement compound), or a calibration compound.

[0043] The compressed gas delivered by the gas path tube 53 is selected to have no effect on the biological material. Because solvation occurs between the biological material molecules and the solvent droplets, the compressed gas must be neutral with respect to the biological material molecules so as not to alter the biological material molecules and, therefore, the mass spectrometry analysis results.

[0044] However, in some cases it is desirable for the gas to interact with the biological material molecules and / or the solvent, for example ammonia to enhance proton transfer.

[0045] This gas may be selected from molecular nitrogen and compressed air, preferably molecular nitrogen.

[0046] The venturi system 2 may comprise an inlet connector making it possible to receive a passage tube 7, in particular for biological material in aerosol form. This passage tube 7 may be located within the interface. Alternatively, the passage tube is part of the laser sample collection device.

[0047] The pathway tube 7 may have a cylindrical section with a diameter between 1 and 12 mm, preferably between 1 and 8 mm, and even between 1 and 5 mm. Preferably, the pathway tube 7 is long and flexible enough to allow the surgeon to aspirate the ablated biological material regardless of the surgical zone and the difficulty of accessing the surgical zone, so that the interface 1 and the mass spectrometer are not located too close to the surgical zone. In some cases, the pathway tube 7 may be in contact with an incision during open surgery. In this case, the pathway tube 7 is made of a material that can be sterilized and used in the operating room. Preferably, the pathway tube 7 is made of a plastic or thermoplastic material selected from polycarbonate (PC), polypropylene (PP), polyethylene (PE), polyvinyl chloride (PVC), acrylonitrile butadiene styrene (ABS), or polytetrafluoroethylene (PTFE).

[0048] In particular, the venturi system 2 has a shape such that, in operation, the flow from the pathway 7 for biological material and the flow from the atomizer 5 cross each other, or even intersect at right angles.

[0049] The orthogonal relationship between the biological material flow and the mist flow allows for better solvation of the biological material, particularly by the mist. Indeed, the orthogonal flow increases the likelihood that aggregates of the biological material will collide with mist droplets, which serves to improve the separation of the aggregates of the biological material. The higher the proportion of biological material molecules solvated in the mist droplets, the higher the proportion of isolated biological material molecules.

[0050] The venturi system 2 may have a T-shape or alternatively a Y-shape.

[0051] This T-shape is characterized by two major axes. Thus, the venturi system 2 may comprise a through longitudinal channel 24 having an inlet and an outlet corresponding to the inlet 21 and outlet 23 of one of the venturi systems 2, respectively, and a second channel 25 connected to the through longitudinal channel 24, with one inlet corresponding to the other inlet 22 of the venturi system 2. Here, the through longitudinal channel 24 and the second channel 25 are perpendicular to each other.

[0052] Alternatively, the venturi system 2 has a shape such that, in operation, the flow from the pathway tube for the biological material intersects with the flow from the sprayer 5. The second channel may therefore intersect with the through longitudinal channel, in particular forming an angle with the through longitudinal channel of between 20° and 120°, preferably between 30° and 110°, more preferably between 80° and 100°, for example 90°.

[0053] The destinations of the inlets 21, 22 to the venturi system 2 are not fixed. Therefore, various incoming flows can be interchanged between the two inlets 21, 22. The inlet 21 corresponds to one end of a through longitudinal channel 24, and the inlet 22 corresponds to the end of a second channel 25.

[0054] The pathway tube 7 and sprayer 5 may be arranged such that in operation the flow exiting the venturi system 2 is collinear with the flow from the pathway tube 7 for the biological material.

[0055] In this configuration, the pathway tube 7 is connected to the inlet 21 and the atomizer 5 is connected to the inlet 22 by means of the atomizing connector 54 located specifically in this region. This configuration corresponds to the interface 1 shown in Figures 1 and 2. In this configuration, the flow from the pathway tube 7 is collinear with the through longitudinal channel 24 and the mist flow from the atomizer 5 is collinear with the second channel 25 of the Venturi system 2.

[0056] The pathway tube 7 and sprayer 5 may be arranged such that, in operation, the flow exiting the venturi system 2 is collinear with the flow from the sprayer 5. In this configuration, the biological material flow from the pathway tube 7 is collinear with the second channel 25 of the venturi system 2, and the flow from the sprayer 5 is collinear with the through longitudinal channel 24.

[0057] In this configuration, the sprayer 5 is connected to the inlet 21 via a spray connector 54 located specifically in this area, and the pathway tube 7 is connected to the inlet 22. This configuration corresponds to the interface 1 shown in FIG.

[0058] The through-flow longitudinal channel 24 may have a first circular cross-section at the inlet 21, a second circular cross-section at the channel outlet 23, and a third circular cross-section in an intermediate zone 241 between the inlet 21 and the outlet 23. The ratio of the third circular cross-section to the first circular cross-section may be between 0.25 and 0.75, preferably between 0.35 and 0.65, and more specifically 0.5. The ratio of the third circular cross-section to the second circular cross-section may be between 0.25 and 0.75, preferably between 0.35 and 0.65, and more specifically 0.5. The first and second cross-sections may be the same or different. In the latter case, the second cross-section may be smaller or larger than the first cross-section.

[0059] The intermediate zone 241 has a smaller circular cross section than the inlet 21 and outlet 23 of the through-flow longitudinal channel 24 of the Venturi system 2. This cross-sectional difference is the origin of the Venturi effect. This cross-sectional difference causes a pressure drop near the zone of smaller cross section. Because the passage tube 7 for the biological material is at atmospheric pressure at one end, this reduced pressure results in the suction of the biological material from the ablation zone. The smaller the ratio between the third circular cross section and the first or second circular cross section, the greater the pressure drop. In contrast, the flow velocity near the intermediate zone 241 of the through-flow longitudinal channel 24 is higher than the flow velocity at the inlet 21 and outlet 23 of the through-flow channel 24. This increased flow velocity favors a more turbulent flow regime than at the inlet 21 or outlet 23 of the Venturi system 2, thereby enabling improved separation of aggregates of biological material into isolated molecules of biological material and therefore improved solvation of these molecules.

[0060] The second channel may be connected to an intermediate zone of the through longitudinal channel.

[0061] The second channel of the Venturi system 2 may have a mist inlet system and an end portion for connection to the through-flow longitudinal channel. This inlet portion has a longitudinal axis that is not collinear with the longitudinal axis of the connecting portion. In the following description of the angle formed by the through-flow longitudinal channel and the second channel, the axis of the inlet portion is taken as the reference axis of the second channel. Preferably, the longitudinal axis of this connecting portion is configured such that the mist inlet flow F2 and the aerosol flow F3 form an acute angle, for example between 10 and 80°, preferably between 20 and 50°, more preferably between 25 and 40°, for example about 30°, with each other near the point where they intersect. Advantageously, this angle may correspond to the inclination of the passage between the first and third cross sections.

[0062] The venturi system 2 may further include a suction regulator 26 disposed within the through longitudinal channel near the outlet of the venturi system 2 .

[0063] The suction adjustment portion 26 may have a circular cross-sectional shape with an outer diameter sized to allow insertion into the Venturi system 2. The adjustment portion may have an annular protrusion 261 forming a collar on its outer surface, which prevents insertion of the suction adjustment portion 26 by contacting a corresponding edge of the outlet 23 of the Venturi system 2, causing the suction adjustment portion 26 to protrude outside the Venturi system 2. The suction adjustment portion 26 may have a fourth circular cross-section smaller than the second circular cross-section, which reduces the circular cross-section near the outlet of the through-longitudinal channel, thereby varying the underpressure generated by the Venturi system 2 to adjust the suction of biological material.

[0064] The ratio of the fourth circular cross section to the second circular cross section may be between 0.5 and 1.5, preferably between 0.5 and 0.89, more preferably between 0.6 and 0.8, and more specifically 0.7.

[0065] The venturi system 2 may be made, in whole or in part, from a material selected from metal (e.g., stainless steel, titanium, brass, aluminum, or alloys thereof) or plastic (polyetheretherketone (PEEK), polytetrafluoroethylene (PTFE), perfluoroalkoxy (PFA), fluorinated ethylene propylene (FEP), polylactic acid (PLA), acrylonitrile butadiene styrene (ABS), polyethylene terephthalate glycol (PETG), or mixtures thereof).

[0066] The interface 1 according to the first embodiment comprises a transfer tube 6 connected to the outlet 23 of the venturi system 2, a heater 3 configured to heat the transfer tube 6, and one or more corona discharge needles 4 (hereinafter the singular form will be used) for ionizing the biological material in aerosol form exiting the outlet of the transfer tube 6.

[0067] The transfer tube 6 serves to transport the biological material solvated in the solvent droplets on the outlet 23 from the venturi system 2 to the corona discharge needle 4. The transfer tube 6 is collinear with the through longitudinal channel of the venturi system 2.

[0068] The transfer tube 6 may have a circular cross section with a diameter between 2 and 8 mm, preferably between 2 and 5 mm, in particular 3 mm. The transfer tube 6 may be made from a material selected from metal (stainless steel, titanium, brass, aluminum), glass, or high-temperature resistant plastics, such as polyethylene ketone (PEEK) or polytetrafluoroethylene (PTFE).

[0069] Heater 3 may be a cartridge heater disposed around transfer tube 6 and serves to desolvate the biological material in solvated aerosol form by heating the biological material. Cartridge heater 3 may be configured to deliver heat between 40-500°C, preferably between 100-300°C, and more specifically 250°C.

[0070] Alternatively, the cartridge heater 3 may be replaced by other heating types, such as heating inside the transfer tube 6 (e.g., a grid heater), a microwave heater positioned around the transfer tube 3, or an ultrasonic disrupter.

[0071] At the outlet of the transfer tube 6, the corona discharge needle 4 serves to ionize the desolvated aerosolized biological material by delivering a corona discharge. This corona discharge needle 4 is positioned so that the flow of desolvated biological material at the outlet from the transfer tube 6 is cross or parallel to the direction of the corona discharge needle 4, for example, the angle formed by the flow of desolvated biological material and the plasma plume is between 0° and 90°, preferably between 20° and 60°, and more preferably between 40° and 50°. In this way, a corona discharge is delivered to the flow of desolvated biological material.

[0072] The corona discharge needle 4 may conventionally be constructed from tungsten, but may also be made from one or more of the pure metals silver, gold, platinum, iron, nickel, and lithium, or alloys thereof, for the purpose of interacting with the gas phase analyte, which may serve to improve the quality of analyte detection, particularly by improving detection sensitivity.

[0073] The interface 1 may further comprise a current source 41 for powering the corona discharge needle 4 to deliver a corona discharge, in particular at an absolute voltage between 2 kV and 10 kV.

[0074] Since the biological material molecules are previously separated from the biological material aggregates in the Venturi system 2, the biological material desolvated by the heat supplied by the heater 3 is mostly in the form of isolated molecules, which therefore serves to improve the ionization achieved by the corona discharge from the corona discharge needle 4.

[0075] After ionization, the ionized molecules of biological material can be transferred to a mass spectrometer for analysis. The improved ionization of biological material by the present interface serves to improve system performance, particularly by increasing the analytical signal from the mass spectrometer and thus improving the discrimination of the molecules being analyzed. Thus, the operator analyzing the signal can better distinguish the composition of the biological tissue and identify the presence or absence of pathological or abnormal elements.

[0076] method Please refer to Figure 4 below.

[0077] According to a second aspect, the invention proposes a method for preparing and transferring material, in particular biological material, to a mass spectrometer, comprising: (S1) delivering a material in aerosol form towards a venturi system; The method includes: Step (S2) of injecting a mist containing solvent droplets into the venturi system; solvating the material in aerosol form into solvent droplets from the mist in a Venturi system (S3); (S4) heating the mixture of solvated material in the solvent droplets from the mist by a heater disposed around a transfer tube connected to the outlet of the Venturi system, thereby desolvating the material; Step (S5) of ionizing the material by corona discharge delivered at the outlet of the transfer tube; The present invention is characterized in that it further comprises:

[0078] Step S1 Step S1 involves delivering a biological material in aerosol form.

[0079] The biological material exists in the form of molecular aggregates as described above.

[0080] The flow of biological material may have a flow rate between 0.5 L / min and 5 L / min, preferably 1 L / min.

[0081] The delivery of the biological material may be achieved by a pressure differential generated by a Venturi system.

[0082] Since the biological material in aerosol form is ablated or collected in a zone at atmospheric pressure, the pressure differential created by the venturi system serves to draw the biological material in aerosol form towards the venturi system.

[0083] Step S2 Step S2 includes injecting a mist containing solvent droplets into the venturi system.

[0084] A mist is injected into the venturi system, which serves to prime the venturi system by creating a low pressure, drawing and delivering biological material towards the venturi system.

[0085] The mist containing solvent droplets may be generated by a nebulizer, preferably a compressor nebulizer. A compressor nebulizer sprays an aerosol containing solvent droplets dispersed in a carrier gas. As described above, the carrier gas serves to generate the mist. The solvent may be selected from one or more organic solvents, one or more volatile compounds, one or more polar molecules, one or more non-polar molecules, water, and mixtures thereof. Examples of organic solvents include alcohols (methanol, ethanol, isopropanol, propanol, butanol, pentanol), acetone, acetonitrile, tetrahydrofuran, ethyl acetate, ethylene glycol, dimethyl sulfoxide, dimethylformamide, methyl tert-butyl ether, aldehydes, ketones, hexane, and chloroform. In some embodiments, the solvent may be acidic or basic, including superchargers, lock masses, or calibration compounds.

[0086] The mist may be emitted at a flow rate between 100 nL / min and 2 mL / min. In some cases, the flow rate may be between 100 nL / min and 500 nL / min. In other examples, the flow rate may be between 100 μL / min and 2 mL / min.

[0087] This production rate serves to regulate the underpressure generated within the venturi system to modify the delivery rate of the biological material in aerosol form.

[0088] Step S3 Step S3 involves solvating the biological material in aerosol form in the solvent droplets of the mist within the venturi system.

[0089] The stream of biological material in aerosol form and the stream of mist meet within the Venturi system. As previously mentioned, the collision of these two streams serves to break up aggregates of the biological material and isolate various molecules of the biological material. These isolated molecules are then solvated within the solvent droplets.

[0090] Step S3 may be performed so that the flow of biological material and the flow of mist are mutually orthogonal. Preferably, the mist inlet flow F2 and the aerosol flow F3 form an acute angle near their intersection, for example between 10° and 80°, preferably between 20° and 50°, more preferably between 25° and 40°, for example about 30°. Advantageously, this angle may correspond to the gradient of the passage between the first and third cross sections.

[0091] As mentioned above, the orthogonal orientation of these two flows serves to improve the separation of biological material aggregates into isolated biological material molecules, thereby improving the conversion of biological material aggregates into solvated biological material molecules.

[0092] Step S4 Step S4 includes heating the solvated biological material in the solvent droplets from the mist by a heater configured to heat a transfer tube connected to the outlet of the Venturi system, thereby resulting in desolvation of the biological material.

[0093] After solvation of the biological material molecules, the solvated biological material in the solvent droplets from the mist passes through a transfer tube. This transfer tube is heated by a heater that serves to heat the solvated biological material molecules. The selection of the heating temperature influences the proportion of the biological material molecules that are desolvated. Step S4 may be performed at a temperature between 40 and 500°C, preferably between 100 and 300°C.

[0094] More generally, the flow and temperature inside the transfer tube may be selected to achieve a heat transfer between 50 and 300°C, preferably 250°C.

[0095] This temperature range serves to maximize the proportion of biological material that is desolvated during step S4. The proportion of desolvated material at the end of step S4 may be between 60-100%, preferably between 90-100%.

[0096] Step S5 Step S5 involves ionizing the biological material by a corona discharge delivered at the outlet of the transfer tube.

[0097] Following desolvation of the biological material molecules in step S4, the biological material molecules are ionized by a corona discharge delivered by a corona discharge needle at the outlet of the transfer tube. The voltage at which the corona discharge is delivered affects the proportion of ionized molecules among the desolvated biological material molecules. The delivered corona discharge may have an absolute value between 2 kV and 8 kV, preferably 5 kV.

[0098] The corona discharge delivered at this voltage serves to maximize the proportion of biological material molecules that are ionized during step S5.

[0099] As a result of step S5, the biological material molecules are ionized and ready to be transferred to a mass spectrometer for analysis. The method according to the second aspect of the invention serves to improve the ionization of the biological material molecules, which in turn serves to improve the amount of signal that can be analyzed by the mass spectrometer and therefore the quality of the analysis. [Explanation of symbols]

[0100] 1. Interface 2. Venturi System 3 Cartridge heater 4 Corona discharge needle 5 Sprayer 6 Transfer Tube 7. Pathway 21 Entrance 22 Entrance 23 Exit 24 through longitudinal channels 25 Second Channel 26 Suction adjustment section 41 Current source 51 Emitter 52 Solvent path tube 53 Gas pipeline 54 Spray Connector 55 sockets 56 Spray chamber 241 Intermediate Zone 261 Annular protrusion 511 Tube 512 Hollow Needle 541 Exit

Claims

1. An interface (1) for preparing a material in aerosol form, in particular a biological material, and transferring said material to a mass spectrometer, comprising: a venturi system (2) having two inlets (21, 22) and one outlet (23); A heater (3), a corona discharge needle (4) for ionizing said material in aerosol form; The interface (1) comprises: The interface (1) a sprayer (5) for generating mist; a transfer tube (6) connected to the outlet of the venturi system; Furthermore, the heater is configured to heat the transfer tube; the corona discharge needle is disposed at the outlet of the transfer tube; The venturi system is configured to receive the material in aerosol form through one of the inlets and is connected to the sprayer through the other inlet, thereby solvating the material in aerosol form with the mist in the venturi system.

2. 2. The interface of claim 1, further comprising a passage tube (7) for the biological material in aerosol form, the passage tube being connected to the inlet of the Venturi system that receives the passage tube.

3. 3. The interface according to claim 1 or 2, wherein the sprayer is a compressor sprayer, and the compressor sprayer further comprises an emitter (51) that generates the mist, a solvent path pipe (52), and a gas path pipe (53).

4. 4. The interface of claim 1, further comprising a spray connector (54) in which the sprayer is disposed, the spray connector having an outlet coupled to the venturi system.

5. 5. An interface according to claim 1, wherein in operation the flow from the pathway tube for the biological material and the flow from the sprayer are orthogonal or intersecting with each other.

6. 6. The interface of claim 1, wherein in operation, the flow exiting the venturi system is collinear with the flow from the atomizer.

7. An interface according to any one of claims 1 to 6, further comprising a current source (41) for supplying the corona discharge needle with a potential difference, in particular between 2 kV and 8 kV.

8. An interface according to any one of claims 1 to 7, wherein the cartridge heater is configured to deliver heat at a temperature of between 40°C and 500°C, preferably between 100°C and 300°C.

9. 1. A method for preparing a material, in particular a biological material, and transferring said material to a mass spectrometer, said method comprising a step (S1) of delivering said material in aerosol form towards a venturi system, The method comprises: Injecting a mist containing solvent droplets into the venturi system (S2); solvating the material in aerosol form into solvent droplets from the mist in the Venturi system (S3); heating (S4) the mixture of material solvated in the solvent droplets from the mist by a heater disposed around a transfer tube connected to the outlet of the Venturi system, thereby desolvating the material; ionizing the material by corona discharge delivered at the outlet of the transfer tube (S5); The method further comprising:

10. 10. The method of claim 9, wherein the mist is emitted from the nebulizer at a flow rate of 100 nL / min to 2 mL / min, or 100 μL / min to 2 mL / min.

11. The method according to claim 9 or 10, wherein step (S4) is carried out at a temperature between 40°C and 500°C, preferably between 100°C and 300°C.

12. 12. The method according to any one of claims 9 to 11, wherein the delivered corona discharge is between 2 kV and 10 kV, preferably 5 kV.

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