Interface and method for preparing material to transfer it into mass spectrometer

Abstract

The present disclosure relates to an interface for preparing a biological material to transfer it into a mass spectrometer. The interface comprises a guide tube for the biological material in the form of an aerosol, a Venturi system having two inlets and one outlet, a cartridge heater, a corona discharge needle for ionizing the biological material in the form of an aerosol, an atomizer for generating a mist, and a transfer tube connected to the outlet of the Venturi system. The interface is arranged such that the cartridge heater is located around the transfer tube, the corona discharge needle is located at the outlet of the transfer tube, and the venturi system is connected to the biomaterial guide tube and the atomizer through the two inlets, resulting in solvation of the biomaterial in the form of aerosol by the mist within the venturi system.

Description

Technical Field

[0001] This disclosure relates to the field of mass spectrometer interfaces. More specifically, it relates to an interface and method for preparing biological materials for transfer into a mass spectrometer. Background Technology

[0002] In any field of biology and medicine, identifying samples in physiological or pathological states is of paramount importance, particularly in the diagnosis, prognosis, and treatment of diseases.

[0003] For example, cancer is diagnosed based on information gathered through imaging methods. These methods (such as CT scans and MRI) provide high-resolution images, but they cannot obtain sufficient information, particularly regarding the identification of malignant proliferation. Conversely, other methods (such as nuclear imaging techniques) provide lower image resolution but can offer information related to disease proliferation. Typically, one or more of these imaging methods must be used in combination to identify and locate cancer.

[0004] Accurate diagnoses of pathological or abnormal tissues are usually obtained through histology (a branch of biology that involves the study of biological tissues) or cytology (a branch of biology that involves the study of cells).

[0005] These imaging and analysis methods can effectively diagnose pathological tissues or tissues with abnormalities. However, these methods cannot obtain location information of malignant tissues during surgical intervention.

[0006] One approach to this problem is to perform histopathological examination of the removed tissue during surgery. This involves making an immediate diagnosis and observing whether the boundaries of malignant tissue are clearly defined within the collected tissue. Despite various drawbacks, such as the time required (typically 20 to 50 minutes depending on the case and facility) and the need to keep the patient in the operating room, this method remains very common. Other methods used include ultrasound and X-ray fluoroscopy. While the results are useful, these methods are not sensitive enough to identify the presence of a limited number of malignant cells.

[0007] Malignant tissue (i.e., tumors) can be distinguished from healthy tissue in several ways. In fact, tumors have a very different molecular composition, ranging from small metabolic components and lipid distribution to the expression of various proteins. These molecular characteristics can be used to visualize tumors using various imaging techniques, including molecular imaging of tissues via infrared spectrophotometry or mass spectrometry. Among these methods, mass spectrometry serves as the basis for in situ and in vivo tissue identification tools by analyzing the diverse molecular composition of different tissues.

[0008] Mass spectrometry ionization methods were originally developed for the analysis of gaseous or volatile materials. One of the drawbacks of these ionization methods is that they cannot analyze non-volatile compounds, which account for approximately 90% of the molecules relevant to pathological tissue analysis.

[0009] Beginning in the 1940s, new ion generation methods were developed, making it possible to generate gaseous ions directly from solid samples. Most of these methods rely on desorption / ionization processes. Desorption-ionization methods use an analytical beam to facilitate desorption and ionization. The analytical beam contains various constituent entities (atoms, molecules, atomic or molecular ions, photons, etc.) that are directed to the sample surface and emitted at variable energy levels.

[0010] For example, accelerated atom bombardment desorption / ionization (FAB) uses high-energy inert gas atoms to bombard the sample to be analyzed, pulverizing and ionizing it; secondary ion mass spectrometry (SIMS) involves bombarding the surface of the sample to be analyzed with a highly accelerated ion beam. The sample is then pulverized, and a portion of the pulverized material is ionized. However, a drawback of these techniques is the requirement for high vacuum conditions. Therefore, the sample is inserted into the high-vacuum enclosure of the mass spectrometer, which involves significant restrictions on the composition and geometry of the sample, and its insertion also requires a specialized system.

[0011] The need for desorption ionization methods operating under atmospheric pressure has been questioned. Operating at atmospheric pressure, and more specifically under ambient conditions (Ambient Ionization Mass Spectrometry, AIMS), offers particular advantages: the analytical methods are faster and more flexible, and do not require sample pretreatment (such as extraction of target compounds). Furthermore, biological systems, including living organisms, can be studied in vivo and in situ. All of this allows for in situ tissue identification using these methods (AIMS).

[0012] Among the methods used under these environmental conditions, the following methods can be cited: Rapid Evaporation Ionization Mass Spectrometry (REIMS), which uses heated collision surfaces to generate ions from aerosols; Extractive Atmospheric Pressure Photoionization (EAPPI), which uses an ultrasonic nebulizer system to atomize and vaporize the sample, then mixes it with a gaseous dopant and interacts with photons and the ambient medium to achieve gas-phase ionization of the analyte; Easy Ambient Sonic Spray Ionization (EASI), which uses a surface-directed atomized solvent stream, where the solvent interacts with the analyte and carries it away by evaporation, during which the analyte is ionized and released into the gas phase; and Droplet Assisted Inlet Ionization (DAII), which contacts aqueous droplets and particles suspended in the air at the mass spectrometer inlet, where the droplets are heated and their rapid evaporation leads to the formation of molecular ions.

[0013] Recently, desorption electrospray ionization (DESI) has been developed. This method uses charged solvent droplets as the analytical beam. DESI fulfills all the expectations associated with ambient ionization methods, thereby extending the range of mass spectrometry analysis to objects with different molecular compositions, sizes, and geometries.

[0014] Mass spectrometry is used to study tissues in two fundamentally different ways. The first approach aims to characterize the molecules present in tissues in a lengthy but as detailed a manner as possible by combining a strategy based on the extraction of specific families of compounds (metabolites, lipids, proteins, etc.) with mass spectrometry and separation methods (such as gas or liquid chromatography). The second approach focuses on rapid analysis without the need for extraction or separation, similar to obtaining rapid and direct molecular fingerprints.

[0015] Methods belonging to the first group typically begin with the homogenization and lysis of a certain amount of tissue, followed by selective extraction of the target compound group. The compounds are separated by electrophoresis or chromatography and then analyzed by mass spectrometry. Although these methods cannot be used for transient tissue identification, they provide precise information about molecular markers characterizing specific tissue types, variations in their relative abundance, and the signaling pathways involved in these molecules.

[0016] Rapid molecular imprinting of tissues using mass spectrometry is typically achieved through the methods described above, particularly desorption / ionization methods (SIMS, MALDI) and AIMS.

[0017] Since the late 1960s, there has been a search for the use of lasers to desorb and ionize condensed-phase nonvolatile samples. Most laser desorption methods result in the formation of molecular aggregates of variable size and predominantly neutral composition; therefore, these methods are often associated with post-ionization techniques. Post-ionization has traditionally been accomplished via electron bombardment (EI) or chemical ionization (CI). Recently, a method using electrospray ionization (ESI) of gaseous material generated by laser ablation of the sample (laser ablation electrospray ionization, LAESI) has been introduced. However, these methods have drawbacks, such as the inability to successfully and completely break down molecular aggregates, or insufficient ionization yields to achieve better sensitivity and analyzable signal depth for mass spectrometry.

[0018] Therefore, there is still a need to provide a suitable interface for preparing the sample to be analyzed after sample acquisition and before transfer to the mass spectrometer (especially the mass analyzer) to break up molecular aggregates and improve the ionization of sample molecules (i.e., post-ionization). Invention Overview

[0020] This disclosure aims to provide a solution to the above-mentioned situation.

[0021] According to the first aspect, an interface for preparing materials (particularly biomaterials) for transfer to a mass spectrometer is proposed, wherein the materials are in aerosol form (neutral or partially ionized), the interface comprising:

[0022] - The Venturi system has two inlets and one outlet.

[0023] - Heater,

[0024] - A corona discharge needle for ionizing the material in aerosol form.

[0025] The interface is characterized in that it further includes:

[0026] - Atomizer, which is used to produce mist.

[0027] - A transfer tube, which is connected to the outlet of the Venturi system.

[0028] And it is characterized by:

[0029] The heater is configured to heat the transfer tube.

[0030] - The corona discharge needle is located at the outlet of the transfer tube, and

[0031] The Venturi system is configured to receive the material in aerosol form through one of its inlets and to be connected to the atomizer through the other inlet, causing the material in aerosol form to be solubilized by mist within the Venturi system.

[0032] According to a first aspect of this disclosure, an interface is used to break up aggregates of material molecules obtained from a sample collection point into aerosol form and to ionize or increase the ionization yield of the material. In a Venturi system connected to an nebulizer and a transfer tube, the material is solvated in droplets of mist and desolated as it passes through a guide tube surrounded by a cylindrical heater. This solvation-desolation process is used to depolymerize material molecules, thereby improving the ionization accomplished by corona discharge. The corona discharge is provided by a corona discharge needle located downstream of the transfer tube. This improvement in ionization, i.e., the increased conversion rate of neutral material molecules to charged molecules, contributes to improving the sensitivity of the mass spectrometer for analysis.

[0033] According to the second aspect, a method for preparing materials (especially biological materials) for transfer to a mass spectrometer is proposed, comprising:

[0034] -Guiding materials in aerosol form to the Venturi system

[0035] The method is characterized in that it further includes:

[0036] - Inject a mist containing solvent droplets into the Venturi system.

[0037] - In the Venturi system, the material in aerosol form is solvated into solvent droplets of mist.

[0038] -The material solvated in the solvent droplets of the mist is heated by a transfer tube connected to the outlet of the Venturi system, and

[0039] - The material is ionized by corona discharge delivered at the outlet of the transfer tube. Attached Figure Description

[0040] Other features, details, and advantages will become apparent upon reading the following detailed description and analyzing the accompanying drawings, in which:

[0041] Figure 1

[0042] Figure 1 A schematic diagram of the interface according to the first aspect of this disclosure is shown, wherein the guiding flow of material is collinear with the outlet flow of the Venturi system.

[0043] Figure 2

[0044] Figure 2 A partial cross-sectional view of the Venturi system and atomizer according to the first aspect of this disclosure is shown.

[0045] Figure 3

[0046] Figure 3 A schematic diagram of the interface according to the first aspect of this disclosure is shown, wherein the mist flow is collinear with the outlet flow of the Venturi system.

[0047] Figure 4

[0048] Figure 4 A schematic diagram of the method according to the second aspect of this disclosure is shown. Invention Details

[0050] Interface 1

[0051] Now for reference Figure 1 and Figure 2 .

[0052] According to a first aspect, the present invention provides an interface 1 for preparing materials (particularly biological materials) for transferring them into a mass spectrometer, wherein the material is in aerosol form, the interface comprising:

[0053] - Venturi system 2, which has two inlets 21, 22 and one outlet 23.

[0054] -Heater 3

[0055] - Corona discharge needle 4, which is used to ionize materials in the form of aerosols.

[0056] The interface is characterized in that it further includes:

[0057] - Atomizer 5, which is used to generate mist.

[0058] - Transfer tube 6, which is connected to the outlet of the Venturi system 2,

[0059] And it is characterized by:

[0060] The heater 3 is configured to heat the transfer tube 6.

[0061] - The corona discharge needle 4 is located at the outlet of the transfer tube 6, and

[0062] - The Venturi system 2 is configured to receive the material in aerosol form through one of its inlets 21, 22 and to be connected to the atomizer 5 through the other inlet 21, 22, causing the material in aerosol form to be solubilized by mist within the Venturi system 2.

[0063] In Interface 1, the ionized material exists in particulate form, particularly aggregated, ablated, or desorbed biological tissue particles. Ablation or desorption can be accomplished, in particular, by laser. The biological tissue from which the biomaterial is collected can be any type of biologically derived tissue, whether or not it has been transformed, such as plant tissue (including cellulose-based materials), animal tissue, including human tissue (e.g., nerve, muscle, epithelial, or connective tissue), or even microorganisms (e.g., bacteria, viruses, yeast). Thus, biomaterials are primarily composed of aggregates of biomolecules (proteins, metabolites, lipids, etc.). They typically contain very little filler. As for non-biological materials, the following can be cited: pharmaceuticals, exogenous substances, inorganic materials, and metal, organometallic, or plastic compounds. The following description will concern biomaterials. However, the description also covers the case of non-biological materials.

[0064] During ablation or desorption, a certain volume of material is ejected in the gas phase. Therefore, when the samples to be analyzed are collected, they are found to be in aerosol form within a gaseous medium containing aggregates of solid particles (particularly molecules of biological material). This gaseous medium can, in particular, be a mixture of gases, such as air, nitrogen, carbon dioxide, helium or other rare gases, and water vapor.

[0065] According to the first aspect, interface 1 includes an atomizer 5, which allows the generation of mist.

[0066] The atomizer 5 is a unit that converts a liquid into a cloud of extremely fine particles. It can be used to break down solutions and / or suspensions into aerosols containing droplets of said solution and / or suspension. This aerosol is also referred to as fog; this term will be used below.

[0067] Atomizer 5 is a device that suspends a liquid in a gas. Atomizer 5 can be selected from compressor atomizers, mesh atomizers, jet atomizers, saturated vapor atomizers, and ultrasonic atomizers. A compressor atomizer is an atomizer that uses a compressed airflow to draw free droplets from a liquid and form a mist. A mesh atomizer is an atomizer that uses a perforated membrane with small holes that vibrates, where a mist is generated by forcing liquid through the membrane. A jet atomizer is an atomizer in which liquid is forced under pressure through a very small opening to produce a mist. A saturated vapor atomizer is an atomizer in which gas passes through a liquid heated to or at ambient temperature, where the gas is loaded with droplets of the liquid in the form of vapor and mist, and then carried to an outlet. An ultrasonic atomizer is an atomizer in which ultrasonic waves are applied to a liquid, causing it to vibrate at a high frequency, thereby generating droplets of the liquid and forming a mist.

[0068] The atomizer 5 can also be a nano-electro-atomizer or a micro-electro-atomizer. Preferably, the ionization device 2 is a nano-electro-atomizer.

[0069] The following description focuses on compressor atomizers, but also applies to other types of atomizers. Compressor atomizers are the most common type of atomizer. They are also known by the name "sprayer." They typically include a device for directing a high-speed compressed airflow around a needle from which the liquid to be atomized flows. The passage of gas causes the liquid to break up, forming a mist.

[0070] The compressor atomizer 5 may include an emitter 51 for generating mist, a solvent guide tube 52, and a gas guide tube 53. The solvent guide tube 52 and the gas guide tube 53 are connected to a socket 55 on their first side, and the emitter 51 extends from the socket 55 from the opposite side to the first side.

[0071] The emitter 51 may include a tube 511 with a pointed end 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. A solvent guide tube 52 is fluidly connected to the interior of the hollow needle 512, while a gas guide tube 53 is fluidly connected to the space between the tube 511 and the hollow needle 512. The tips of the tube 511 and the hollow needle 512 form the tip of the atomizer 5, thereby 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 of 50 to 200 μm. The emitter 51 is configured such that the flow rate of the mist generated at the outlet of the atomizer 5 is from 100 nL / min to 2 mL / min. In some cases, the flow rate may be from 100 nL / min to 500 nL / min. In other cases, the flow rate may be from 100 μL / min to 2 mL / min.

[0072] Solvent guide tube 52 is used to guide solvent to atomizer 5, and gas guide tube 53 is used to guide gas to atomizer 5. The gas is used to spray the solvent into fine droplets to form a mist. Therefore, the mist has an aerosol form containing fine solvent droplets in the gas guided by gas guide tube 53.

[0073] Interface 1 may also include an atomizing connector 54 in which an atomizer 5 is disposed; the atomizing connector 54 includes an outlet 541 connected to the Venturi system 2.

[0074] The atomizing connector 54 is used to partially accommodate the atomizer 5 and fluidly connect it to the Venturi system 2. The atomizing connector 54 preferably has an optimized shape to efficiently transfer mist into the interior of the Venturi system 2; for example, it is conical (particularly its inner surface), with its smallest cross-section end near the inlet of the Venturi system 2, and houses the tube 511 and hollow needle 512 of the atomizer 5 inside, and is used to concentrate the mist flow into the interior of the Venturi system 2. The atomizing connector 54 extends from the bottom of the socket 55 of the atomizer 5 and beyond its tip, thereby forming an atomizing chamber 56 between its tip and end.

[0075] The distance between the inlets 21 and 22 of the Venturi system 2 and the tip of the atomizer 5 can be 1 to 50 mm, preferably 2 to 10 mm, and more preferably 3 to 5 mm.

[0076] According to the first aspect, interface 1 includes a Venturi system 2. Venturi system 2 includes two inlets 21, 22 and one outlet 23. The two inlets 21, 22 are connected to a guide tube 7 for biomaterials and an atomizer 5. In the case where interface 1 includes an atomizing connector 54, the atomizing connector 54 is connected to one of the inlets 21, 22 of Venturi system 2, instead of the atomizer 5.

[0077] The mist generated by atomizer 5 is fed into Venturi system 2. The flow of mist is used to activate Venturi system 2. A reduced pressure is generated inside Venturi system 2, which is used to draw biomaterials in aerosol form into Venturi system 2. In addition, the mist is also used to break up the aggregates of biomaterials to separate the various molecules of the biomaterials. These biomaterial molecules are solvated in the droplets of mist.

[0078] The choice of solvent guided by solvent guide tube 52 is effective in separating biomaterial aggregates and solvating biomaterial molecules within the solvent droplets. The solvent can be neutral to the biomaterial molecules. Since its primary function is solvation of biomaterial molecules, the solvent does not affect them to avoid altering subsequent analyses performed by the mass spectrometer. However, in some cases, it is necessary to modify the molecules. Therefore, the solvent can be selected to modify the biomaterial molecules and enhance certain types of observations. Solvents can 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; chloroform. In some embodiments, the solvent may include a supercharger, a mass-locking compound (mass measurement compound), or a calibration compound.

[0079] The compressed gas guided through gas guide tube 53 is selected to have no effect on the biomaterial. Since solvation occurs between biomaterial molecules and solvent droplets, the compressed gas must be neutral to the biomaterial molecules to avoid altering them and thus not affecting the mass spectrometry analysis.

[0080] However, in some cases, it is desirable for gases to interact with the molecules of biological materials and / or solvents, such as ammonia, which is used to enhance proton transfer.

[0081] The gas can be selected from molecular nitrogen and compressed air; preferably, the gas is molecular nitrogen.

[0082] The Venturi system 2 may include a guide connector, specifically allowing reception of a guide tube 7 for aerosol-form biological materials. This guide tube 7 may be located within the interface. Alternatively, the guide tube may be part of a laser sample acquisition device.

[0083] The guide tube 7 may be cylindrical, with a diameter of 1 to 12 mm, preferably 1 to 8 mm, or even 1 to 5 mm. Preferably, the guide tube 7 is long and flexible enough to allow the operator to aspirate ablated biological material regardless of the operating area and its accessibility, and to prevent the interface 1 and the mass spectrometer from being too close to the operating area. The guide tube 7 may come into contact with an open surgical incision; in this case, it is made of a sterilizable material suitable for use in the operating room. Preferably, the guide tube 7 is made of a plastic or thermoplastic material selected from: for example, polycarbonate (PC), polypropylene (PP), polyethylene (PE), polyvinyl chloride (PVC), acrylonitrile-butadiene-styrene (ABS), or polytetrafluoroethylene (PTFE).

[0084] The Venturi system 2 has a shape in which, during operation, the flow from the biomaterial guide tube 7 and the flow from the atomizer 5 are tangential to each other, or even orthogonal.

[0085] The orthogonality between the biomaterials and the mist flow rate particularly allows for the solvation of biomaterials by the mist. In fact, because the flow is orthogonal, the biomaterial aggregates have a good probability of collision with the mist droplets, which helps to increase the separation of the biomaterial aggregates. A larger proportion of biomaterial molecules solvated in the mist droplets contributes to increasing the proportion of separated biomaterial molecules.

[0086] Venturi system 2 can be T-shaped; or it can be Y-shaped.

[0087] The T-shape is characterized by two main axes. Thus, the Venturi system 2 may include a through longitudinal channel 24 having an inlet and an outlet corresponding to an inlet 21 and an outlet 23 of the Venturi system 2, respectively, and a second channel 25 having an inlet corresponding to another inlet 22 of the Venturi system 2 and connected to the through longitudinal channel 24, wherein the through longitudinal channel 24 and the second channel 25 are orthogonal to each other.

[0088] Alternatively, the Venturi system 2 has a shape in which, during operation, the flow from the biomaterial guide tube and the flow from the atomizer 5 are transversely intersecting. Therefore, the second channel can be transversely intersecting the through longitudinal channel, particularly forming an angle of 20° to 120° with it, preferably 30° to 110°, more preferably 80° to 100°, for example 90°.

[0089] The uses of inlets 21 and 22 in the Venturi system 2 are not fixed. Therefore, various inlet flows can be interchanged between the two inlets 21 and 22. Inlet 21 corresponds to one end of the through longitudinal channel 24, and inlet 22 corresponds to the end of the second channel 25.

[0090] The guide tube 7 and the atomizer 5 can be arranged such that the flow leaving the Venturi system 2 during operation is collinear with the flow from the biomaterial guide tube 7.

[0091] In this configuration, the guide tube 7 is connected to the inlet 21, and the atomizer 5 is connected to the inlet 22, specifically via the atomizer connector 54 arranged in this area. This configuration corresponds to Figure 1 and Figure 2 Interface 1 is shown. In this configuration, the flow from the guide 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.

[0092] The guide tube 7 and the atomizer 5 can be arranged such that the flow exiting the Venturi system 2 during operation is collinear with the flow from the atomizer 5. In this configuration, the flow of biomaterial from the guide tube 7 is collinear with the second channel 25 of the Venturi system 2, and the flow from the atomizer 5 is collinear with the through longitudinal channel 24.

[0093] In this configuration, the atomizer 5 is connected to the inlet 21, specifically via the atomizer connector 54 arranged in this area, and the guide tube 7 is connected to the inlet 22. This configuration corresponds to... Figure 3 Interface 1 is shown.

[0094] The through longitudinal channel 24 may have a first circular cross-section at the entrance 21, a second cross-section at the channel exit 23, and a third circular cross-section in the intermediate region 241 between the entrance 21 and the exit 23. The ratio between the third circular cross-section and the first circular cross-section may be 0.25 to 0.75, preferably 0.35 to 0.65, and more particularly 0.5. The ratio between the third circular cross-section and the second circular cross-section may be 0.25 to 0.75, preferably 0.35 to 0.65, and more particularly 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.

[0095] The intermediate region 241 has a smaller circular cross-section than the inlet 21 and outlet 23 of the through longitudinal channel 24 of the Venturi system 2. This difference in cross-section is the origin of the Venturi effect. This difference in cross-section results in lower pressure near the region with the smaller cross-section. Since one end of the guide tube 7 used for biomaterials is at atmospheric pressure, this reduced pressure causes biomaterials to be drawn in from the ablation zone. The smaller the ratio of the third circular cross-section to the first or second circular cross-section, the greater the pressure reduction. Conversely, the flow velocity near the intermediate region 241 of the through longitudinal channel 24 is greater than the flow velocity at the inlet 21 and outlet 23 of the through channel 24. This increase in flow velocity supports a tendency to develop a more turbulent flow pattern than at the inlet 21 or outlet 23 of the Venturi system 2, thereby allowing for improved separation of biomaterial aggregates into separate biomaterial molecules, and thus improved solvation of these molecules.

[0096] The second channel can connect to the middle area of ​​the through longitudinal channel.

[0097] The second channel of the Venturi system 2 may have a mist inlet system and an end for connection to the through longitudinal channel. The longitudinal axis of the inlet portion is not collinear with the longitudinal axis of the connecting portion. In the following description of the angle formed by the through longitudinal channel and the second channel, the reference axis of the second channel is the axis of the inlet portion. Preferably, the longitudinal axis of the connecting portion is configured such that the mist inlet flow F2 and the aerosol flow F3 form an acute angle near their intersection, for example, 10° to 80°, preferably 20° to 50°, more preferably 25° to 40°, for example, about 30°. This angle may advantageously correspond to the slope of the channel between the first and third sections.

[0098] The Venturi system 2 may also include an intake regulation section 26, which is arranged in a through longitudinal channel near the outlet of the Venturi system 2.

[0099] The inhalation regulating portion 26 may have a circular cross-sectional shape, the outer diameter of which allows it to be inserted into the Venturi system 2. This portion may have an annular protrusion 261 on its outer surface, forming a flange to block insertion of the inhalation regulating portion 26 by contacting a corresponding edge of the outlet 23 of the Venturi system 2 with the annular protrusion 261, thereby providing the inhalation regulating portion 26 to protrude beyond the Venturi system 2. The inhalation regulating portion 26 may have a fourth circular cross-section smaller than the second circular cross-section to reduce the circular cross-section near the outlet of the through longitudinal channel, thereby regulating the inhalation of the biomaterial by altering the low pressure generated by the Venturi system 2.

[0100] The ratio between the fourth circular cross section and the second circular cross section can be 0.5 to 1.5, preferably 0.5 to 0.89, more preferably 0.6 to 0.8, and more particularly 0.7.

[0101] The Venturi system 20 may be made wholly or partially of a material selected from metals (e.g., stainless steel, titanium, brass, aluminum or alloys thereof) or plastics (polyetheretherketone (PEEK), polytetrafluoroethylene (PTFE), perfluoroalkoxy (PFA), fluorinated ethylene propylene (FEP), polylactic acid (PLA), acrylonitrile-butadiene-styrene (ABS), polyethylene terephthalate (PETG) or mixtures thereof).

[0102] According to the first aspect, the interface 1 includes 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 singular) for ionizing biomaterial in the form of aerosols leaving the outlet of the transfer tube 6.

[0103] The transfer tube 6 is used to transfer biological material solubilized in solvent droplets from the outlet 23 of 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.

[0104] The transfer tube 6 may have a circular cross-section with a diameter of 2 to 8 mm, preferably 2 to 5 mm, and more particularly 3 mm. It may be made of a material selected from metals (stainless steel, titanium, brass, aluminum), glass, or high-temperature resistant plastics such as polyetheretherketone (PEEK) or polytetrafluoroethylene (PTFE).

[0105] The heater 3 may be a cylindrical heater located around the transfer tube 6, which is used to heat the solubilized biomaterial in the form of an aerosol to desolvate the biomaterial. The cylindrical heater 3 may be configured to deliver heat at 40 to 500°C, preferably 100 to 300°C, and more specifically 250°C.

[0106] Alternatively, the cylindrical heater 3 can be replaced by other heating types, such as heating inside the transfer tube 6 (e.g., a grid heater), a microwave heater arranged around the transfer tube 3, or an ultrasonic breaker.

[0107] At the outlet of transfer tube 6, corona discharge needle 4 ionizes the desolvated aerosol-form biomaterial by delivering corona discharge. The corona discharge needle 4 is arranged such that the flow of desolvated biomaterial at the outlet of transfer tube 6 is transversely or parallel to the direction in which the corona discharge needle 4 points; for example, the angle between the flow of desolvated biomaterial and the plasma plume is 0° to 90°, preferably 20° to 60°, and more preferably 40° to 50°. Thus, corona discharge is delivered onto the flow of desolvated biomaterial.

[0108] The corona discharge needle 4 is typically made of tungsten, but can also be made of pure tungsten or an alloy of one or more metals (such as silver, gold, platinum, iron, nickel, and lithium) to interact with the gaseous analyte. This can be used to improve the detection quality of the analyte, particularly by improving detection sensitivity.

[0109] Interface 1 may also include a current source 41 for supplying power to the corona discharge needle 4 to deliver corona discharge, particularly an absolute voltage of 2 to 10 kV.

[0110] Since the biomaterial molecules had previously been separated from the biomaterial aggregates in the Venturi system 2, the biomaterial desolvated by the heat provided by the heater 3 was mostly in the form of separated molecules. This therefore helps to improve the ionization achieved by the corona discharge from the corona discharge needle 4.

[0111] After ionization, the ionized biomaterial molecules can be transferred to a mass spectrometer for analysis. Improvements to the interface for ionization of biomaterials particularly contribute to increasing the analytical signal of the mass spectrometer, thereby improving system performance by enhancing the identification of the analyzed molecules. Consequently, the operator of the analytical signal can better identify the composition of biological tissues and determine the presence or absence of pathological or abnormal elements.

[0112] method

[0113] Now for reference Figure 4 .

[0114] According to the second aspect, this disclosure provides a method for preparing materials, particularly biological materials, for transferring them into a mass spectrometer, comprising:

[0115] -Guide the material in aerosol form to S1 into the Venturi system.

[0116] The method is characterized in that it further includes:

[0117] - Inject a mist containing solvent droplets into the Venturi system described in S2.

[0118] - In the Venturi system, the material in aerosol form is solvated S3 into the solvent droplets of the mist.

[0119] - The mixture of materials solvated from the solvent droplets of the mist is heated by a heater located around the transfer tube connected to the outlet of the Venturi system, resulting in the desolvation of the materials.

[0120] - The material described in S5 is ionized by corona discharge delivered through the outlet of the transfer tube.

[0121] Step S1:

[0122] Step S1 involves guiding biomaterials in the form of aerosols.

[0123] Biological materials exist in the form of molecular aggregates as explained above.

[0124] The flow rate of the biomaterial can be from 0.5 L / min to 5 L / min, preferably 1 L / min.

[0125] The guidance of biomaterials can be accomplished through the pressure difference generated by the Venturi system.

[0126] Since biomaterials in aerosol form are ablated or collected in an atmospheric pressure region, the pressure difference generated by the Venturi system is used to draw biomaterials in aerosol form into the Venturi system.

[0127] Step S2:

[0128] Step S2 includes injecting a mist containing solvent droplets into the Venturi system.

[0129] The mist is injected into the Venturi system. It is used to activate the Venturi system by generating low pressure, so as to inhale and guide biological materials into the Venturi system.

[0130] A mist containing solvent droplets can be generated by an atomizer, preferably a compressor atomizer. The compressor atomizer ejects an aerosol containing solvent droplets dispersed in a carrier gas. As previously described, the carrier gas is used to generate the mist. The solvent can be selected from: one or more organic solvents; one or more volatile compounds; one or more polar molecules; one or more nonpolar 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 can be acidified or alkalized, including by superchargers, mass-locking or calibration compounds.

[0131] The mist can be sprayed at a flow rate from 100 nL / min to 2 mL / min. In some cases, the flow rate can be from 100 nL / min to 500 nL / min. In other cases, the flow rate can be from 100 μL / min to 2 mL / min.

[0132] The generation rate is used to regulate the low pressure generated in the Venturi system to alter the rate at which biomaterials in aerosol form are guided.

[0133] Step S3:

[0134] Step S3 involves solubilizing the biomaterial in aerosol form into solvent droplets of mist in a Venturi system.

[0135] The streams of biomaterial in aerosol form and the streams of mist converge in the Venturi system. As explained earlier, the collision of the two streams helps to break up the biomaterial aggregates to separate the various biomaterial molecules. The separated molecules are then solvated in solvent droplets.

[0136] Step S3 can be performed such that the flow of biomaterial and the flow of mist are orthogonal to each other. Preferably, the mist inlet flow F2 and the aerosol flow F3 form an acute angle near their intersection, for example, 10° to 80°, more preferably 20° to 50°, more preferably 25° to 40°, for example, about 30°. This angle can advantageously correspond to the slope of the channel between the first and third sections.

[0137] As explained earlier, the orthogonality of these two streams helps to improve the conversion of biomaterial aggregates into solvated biomaterial molecules by improving the separation of aggregates into separate biomaterial molecules.

[0138] Step S4:

[0139] Step S4 includes heating the biomaterial solubilized in the mist solvent droplets by configuring a heater for heating the transfer tube connected to the Venturi system outlet, resulting in desolvation of the biomaterial.

[0140] After solvation of the biomaterial molecules, the solvated biomaterial in the atomized solvent droplets is passed through a transfer tube. This transfer tube is used as a heater to heat the solvated biomaterial molecules. The choice of heating temperature affects the proportion of desolvated biomaterial molecules. Step S4 can be performed at a temperature of 40 to 500°C, preferably 100 to 300°C.

[0141] More generally, the flow rate and temperature within the transfer tube can be selected to provide heat transfer from 50 to 300°C, preferably 250°C.

[0142] This temperature range helps to maximize the proportion of desolvated biomaterial during step S4. The proportion of desolvated material at the end of step S4 can be 60% to 100%, preferably 90% to 100%.

[0143] Step S5:

[0144] Step S5 includes the corona discharge ionization of biomaterials delivered through the outlet of the transfer tube.

[0145] Following the desolvation of the biomaterial molecules in step S4, the biomaterial molecules are ionized by a corona discharge delivered by a corona discharge needle at the transfer tube outlet. The voltage of the delivered corona discharge affects the proportion of ionized desolvated biomaterial molecules. The absolute value of the delivered corona discharge can be from 2 to 8 kV, preferably 5 kV.

[0146] The corona discharge delivered at this voltage helps to maximize the proportion of ionized biomaterial molecules during step S5.

[0147] At the end of step S5, the biomaterial molecules are ionized and ready to be transferred to a mass spectrometer for analysis. The method according to the second aspect of this disclosure helps to improve the ionization of biomaterial molecules and extend the signal quantity analyzable by the mass spectrometer, thereby improving the quality of analysis.

Claims

1. An interface (1) for preparing materials, particularly biomaterials, for transferring them into a mass spectrometer, wherein the material is in aerosol form, the interface comprising: - The Venturi system (2) has two inlets (21, 22) and one outlet (23). - Heater (3), - Corona discharge needle (4), which is used to ionize materials in the form of aerosols, The interface is characterized in that it further includes: -Atomizer (5), which is used to generate mist, - Transfer tube (6), which is connected to the outlet of the Venturi system (2), And it is characterized by: The heater is configured to heat the transfer tube. - The corona discharge needle is located at the outlet of the transfer tube, and The Venturi system is configured to receive the material in aerosol form through one of its inlets and to be connected to the atomizer through the other inlet, causing the material in aerosol form to be solubilized by mist within the Venturi system.

2. The interface of claim 1, further comprising a guide tube (7) for biomaterial in aerosol form, and the guide tube being connected to the inlet of a Venturi system for receiving the biomaterial.

3. The interface as described in any of the preceding claims, The atomizer is a compressor atomizer, and the compressor atomizer also includes an emitter (51) for generating mist, a solvent guide tube (52) and a gas guide tube (53).

4. The interface as described in any of the preceding claims, It also includes an atomizing connector (54) in which the atomizer (5) is housed. Furthermore, the atomizing connector includes an outlet that connects to the venturi system.

5. The interface as described in any of the preceding claims, in, During operation, the flow from the guide tube used for the biomaterial and the flow from the atomizer are orthogonal or transverse to each other.

6. The interface as described in any of the preceding claims, in, During operation, the flow leaving the Venturi system is collinear with the flow from the atomizer.

7. The interface as described in any of the preceding claims, It also includes a current source (41) for supplying power to the corona discharge needle, particularly at a potential difference of 2 to 8 kV.

8. The interface as described in any of the preceding claims, The cylindrical heater is configured to deliver heat at a temperature of 40 to 500°C, preferably 100 to 300°C.

9. A method for preparing materials, particularly biological materials, for transferring them into a mass spectrometer, comprising: -Guide the material in aerosol form (S1) to the Venturi system, The method is characterized in that it further includes: - Inject a mist containing solvent droplets into the Venturi system (S2). - In the Venturi system, the material in aerosol form is solvated (S3) into solvent droplets of the mist. - The mixture of materials solvated in the solvent droplets from the mist is heated (S4) by a heater located around the transfer tube connected to the outlet of the Venturi system, resulting in the desolvation of the materials, and - The material is ionized by corona discharge (S5) delivered through the outlet of the transfer tube.

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

11. The method as described in claim 9 or 10, Step (S4) is performed at a temperature of 40 to 500°C, preferably 100 to 300°C.

12. The method as described in any one of claims 9 to 11, The delivered corona discharge is 2 to 10 kV, preferably 5 kV.

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