Spray head for electrospray ionization

Abstract

The invention relates to a spray head for electrospray ionization (ESI). The invention also relates to a method for producing a spray head according to the invention and to the use of a spray head according to the invention for electrospray ionization (ESI). The invention also relates to a chromatography column comprising a spray head according to the invention and to a device for carrying out electrospray ionization (ESI) comprising a spray head according to the invention or comprising a chromatography column according to the invention. The invention further relates to the use of selective laser-induced etching (SLE) or two-photon polymerization (2PP) for producing a spray head according to the invention for electrospray ionization (ESI).

Description

[0001] Spray head for electrospray ionization

[0002] The present invention relates to a spray head for electrospray ionization (ESI). The present invention also relates to a method for producing a spray head according to the invention and to the use of a spray head according to the invention for electrospray ionization (ESI). The present invention further relates to a chromatography column comprising a spray head according to the invention and to a device for carrying out electrospray ionization (ESI) comprising a spray head according to the invention or comprising a chromatography column according to the invention. The present invention also relates to the use of selective laser-induced etching (SLE) or two-photon polymerization (2PP) for producing a spray head according to the invention for electrospray ionization (ESI).

[0003] The invention is defined in the appended claims. Preferred aspects of the present invention will become apparent from the following description, including the examples.

[0004] To the extent that certain embodiments are designated as preferred for one aspect of the invention, the corresponding statements also apply to the other aspects of the present invention, mutatis mutandis. Preferred individual features of aspects of the invention (as defined in the claims and / or disclosed in the description) can be combined with one another and are preferably combined with one another, unless otherwise apparent to the person skilled in the art from the present text.

[0005] The generation of ions of, for example, heavy analyte molecules with molecular weights ranging from a few hundred to many thousands of Daltons in an electrospray ion source is widely known. The ability to ionize very large molecules, especially those that are not thermally vaporizable, is extremely important; for the development of the electrospray ion source in the late 1980s, John Bennett Fenn was awarded the Nobel Prize in Chemistry in 2002.

[0006] For electrospray ionization (ESI), a high voltage of several kilovolts is applied to a spray nozzle, which during operation contains spray liquid or an analyte solution with dissolved analyte molecules. This creates a strong electric field around the spray nozzle outlet. This polarizes the surface of the spray liquid at the spray nozzle outlet and becomes highly charged. The electrical pulling force creates a so-called Taylor cone on the liquid surface, from whose tip a fine jet of liquid is drawn by the electric pulling field. This jet is inherently unstable due to its high surface charge, which opposes the surface tension: it breaks up into tiny, highly charged droplets with diameters on the order of a micrometer.

[0007] All droplets, large and small, continue to evaporate, with small droplets evaporating faster and faster due to their ever-decreasing coordination number of the surface molecules and the resulting increase in vapor pressure, until the separation and evaporation processes end relatively quickly in the complete drying of a droplet and only predominantly multiply charged ions of the analyte molecules contained in the droplet remain.

[0008] Electrospray ionization is a preferred method for generating analyte ions for mass spectrometry (MS) and is used in particular in the mass spectrometric analysis of large molecules (such as biomolecules) and in the case of coupling a mass spectrometric analysis with upstream liquid chromatography (LC).

[0009] In practice, so-called "pulled emitters" are often used as spray nozzles for electrospray ionization. These emitters consist of thin-walled capillaries made of quartz glass (also known as fused silica or FS) that are pulled to a fine tip on the outlet side. The pulled tips are very thin to increase the sensitivity when using electrospray ionization as an ion source for mass spectrometric investigations.

[0010] A disadvantage of using pulled emitters for electrospray ionization is that pulling the outlet to a tip reduces the inner diameter of the capillary channel carrying the analyte solution toward the outlet, making pulled emitters more susceptible to clogging. The problem of the increased risk of clogging of pulled emitters is further intensified for pulled emitters intended for use in nano-electrospray ionization (nano-ESI), since pulled emitters for nano-ESI already have a very small inner diameter for the channel carrying the analyte solution. Furthermore, pulled emitters, and especially their tips, are highly susceptible to mechanical damage due to their delicate glass construction.

[0011] An alternative to pulled emitters are spray heads for electrospray ionization, which can be attached to the end of a line carrying the analyte solution, for example, to the end of a liquid chromatography (LC) column. Electrospray ionization spray heads also have a spray nozzle (in addition to an inlet for the analyte solution), which can be obtained by methods other than pulling a glass capillary.

[0012] In this context, US 10,591,451 B2 discloses spray heads for spraying a liquid, which are made of metal or plastic. However, metals and plastics exhibit only limited chemical stability with respect to the analyte solutions exposed to these materials, or only limited thermal stability. At the same time, the manufacturing methods disclosed in US 10,591,451 B2 for producing the spray heads (for example, US 10,591,451 B2 mentions the use of injection molding processes and mechanical processing methods for the production of spray heads made of plastic) exhibit only limited precision, which is often insufficient, particularly for the production of microstructures such as microchannels.

[0013] The production of spray heads for electrospray ionization and especially nano-electrospray ionization, which have precisely manufactured structures (which can, for example, reduce the risk of clogging for structures and channels manufactured in the micrometer scale), has so far represented a major challenge.

[0014] The precise and, above all, reproducible production of, for example, channel structures for ESI spray heads made of a material with both extraordinary chemical resistance and high thermal stability (such as quartz glass) represents a further difficulty, since quartz glass, for example, is difficult to machine with high precision using methods conventional in ESI production due to its brittleness and precisely because of its high resistance.

[0015] Patent publication DE 10 2013 004 871 A1 discloses a chip with multiple spray nozzles for the ionization of dissolved substances by electrospray at atmospheric pressure in the ion source of a mass spectrometer, wherein each individual spray nozzle is surrounded, preferably symmetrically, by sheath gas nozzles for the jet-like supply of a sheath gas. In "A monolithic microfluidic probe for ambient mass spectrometry imaging of biological tissues" (Lab Chip, 2023, 23(21), 4664-4673), Jiang et al. disclose a monolithic microfluidic probe made of quartz glass for the mass spectrometry of biological tissue. However, due to its delicate glass construction, the spray nozzle is also very susceptible to mechanical damage and poses a high risk of damage during handling and, in particular, during probe adjustment.In light of the aforementioned disadvantages of the prior art, a primary objective of the present invention was to provide spray heads for (nano)electrospray ionization with a uniform, precise, and flexibly selectable inner diameter, which simultaneously possess sufficient mechanical strength for easier handling and can also preferably be manufactured from a material with both exceptional chemical resistance and high thermal stability. The spray heads for electrospray ionization to be provided should also be obtainable in a simple (or cost-effective) and reproducible manner. A further objective of the present invention was to provide a method for producing such spray heads.

[0016] Further objects arise from the following description and the patent claims.

[0017] The primary object of the present invention is achieved by a spray head for electrospray ionization (ESI), comprising: an inlet for fluids (in particular for liquids or analyte solution), a spray nozzle comprising an outlet for fluids (in particular for liquids or analyte solution) and comprising a channel through which the inlet is connected to the outlet of the spray nozzle, and a protective structure for protecting the spray nozzle from mechanical damage, which extends in particular laterally of the spray nozzle, which further preferably extends laterally of the spray nozzle to at least the height of the outlet, and which is preferably spaced from the spray nozzle, wherein the inlet and the spray nozzle of the spray head are obtained by selective laser-induced etching (SLE) or by two-photon polymerization (2PP).

[0018] Selective laser-induced etching (also known as SLE) is a two-step manufacturing process for producing complex 3D components from transparent materials such as glass or sapphire. In a first step, ultrashort-pulsed laser radiation is focused into the volume of the transparent workpiece. The pulse energy is absorbed only in the focal volume through a multiphoton process. There, the transparent material is modified without cracking, altering its chemical properties. This allows for subsequent selective chemical etching of the material. By deflecting the focus in the workpiece with a micro-scanning system, contiguous areas of the workpiece to be processed are modified.The areas modified by the focus deflection in the workpiece can be selectively removed by wet-chemical etching in a second process step. This is because the areas modified by laser radiation exhibit a sensitivity and solubility that is many times higher (for example, by a factor of 1000) than unmodified areas compared to conventional wet-chemical etching agents (such as highly concentrated KOH solution). In this way, microchannels and fine, complex structures, for example, can be realized with high precision and reproducibility in materials with high chemical and high temperature resistance, such as quartz glass.

[0019] Two-photon polymerization (2PP) is a high-precision additive manufacturing technology that enables the high-resolution 3D printing of virtually any micro-, meso-, and macroscale structure with submicrometer features and extremely high dimensional accuracy. Two-photon polymerization (also known as two-photon or multi-photon lithography or direct laser writing) utilizes the fundamental physical effect of two-photon absorption. Two-photon absorption occurs when an atom or molecule absorbs two photons simultaneously, allowing it to enter a higher energy state. The medium is typically a liquid resin, which is light-sensitive and can be cured by UV light. 2PP printing uses lower-energy light, e.g.in the near-infrared (NIR) range, which only solidifies the printing material when the molecules of the photopolymer present simultaneously absorb the energy of two photons. This mechanism is only possible in the focal volume of pulsed light, as it requires a high light intensity within a volume of the photosensitive material.

[0020] The inventors have recognized that selective laser-induced etching (SLE) and two-photon polymerization (2PP) can be used to produce spray heads for (nano) electrospray ionization. These spray heads are not only quick and cost-effective to manufacture, but also feature microchannels with reproducible and uniform inner diameters that are particularly suitable for nano-electrospray ionization, which are ideal for low-clogging guidance of analyte solution to the spray nozzle outlet. SLE also allows for the production of such precisely and reproducibly manufactured ESI spray heads from a thermally and chemically highly resistant material such as quartz glass.

[0021] Neither the uniformity nor the reproducibility of the channel dimensions and other dimensions of the spray heads manufactured using SLE or 2PP, and in particular of the spray nozzles thereof, can be achieved with conventional manufacturing methods used for the production of ESI spray heads.

[0022] By using SLE or 2PP for, among other things, the production of the spray nozzle of the spray head according to the invention, the spray head or the spray nozzle of the spray head is given special technical properties that cannot be achieved otherwise. For example, mechanical processing methods, particularly in the field of glass or plastics processing, cannot produce the uniform microchannel structures that are possible with SLE or 2PP.The spray head according to the invention is already distinguished from the spray heads disclosed in US 10,591,451 B2 by the fact that only certain materials can be processed by means of SLE and 2PP - such as, for example, glass or sapphire in the case of SLE and, in the case of 2PP, liquid photopolymers that can be cured by means of 2PP, such as, for example, epoxies, hybrid polymers and hydrogels suitable for 2PP - (i.e., for example, the spray nozzle of a spray head according to the invention must necessarily consist of a material that can be processed by means of SLE or 2PP), whereas in US 10,591,451 B2 only spray heads or spray nozzles made of a material that cannot be processed by means of SLE or 2PP are disclosed.

[0023] In addition, the inventors have recognized that sufficient mechanical resistance of the spray head, even when manufactured from a fragile material such as glass, can be achieved by providing a protective structure to protect the spray nozzle from mechanical damage, which protective structure extends in particular laterally of the spray nozzle, which further preferably extends laterally of the spray nozzle to at least the height of the outlet, and which is preferably spaced from the spray nozzle, and which thereby makes it significantly easier to handle such a spray head for (nano-)ESI, which may have very delicate structures made of a brittle material.

[0024] The inlet of a spray head according to the invention is preferably designed and configured to accommodate or attach a chromatography column for liquid chromatography (LC column), particularly preferably for nano-liquid chromatography (nano-LC column). For this purpose, the spray head preferably has a recess into which the end of a (nano-)LC column can be guided to the inlet of the spray head, as far as possible while avoiding dead volume. For a permanent and secure hold between the (nano-)LC column and the spray head, the end of a (nano-)LC column is preferably fixed to the spray head according to the invention using an adhesive connection. Epoxy resin adhesives, for example, are suitable for producing the adhesive connection. Preference is given to a spray head according to the invention, wherein the spray head has a recess for attaching a supply line (for example for attaching the end of an LC column) to the inlet.The recess is typically designed so that the supply line can be inserted into it with a precise fit and guided to the inlet. Preferably, however, the recess widens toward the inlet, so that the diameter of the recess at the inlet is preferably larger than the outer diameter of the supply line to be inserted into the recess. It has been shown that such a widening of the recess toward the inlet or at the inlet has a beneficial effect on the connection of the supply line to the inlet and contributes to reducing the dead volume at the connection point between the supply line and the inlet.

[0025] Preferably, the inner diameter of the spray head inlet is smaller than the inner diameter of a supply line (for example, smaller than the inner diameter of the LC column connected to the spray head), through which a fluid or analyte solution is fed into the inlet. By selecting an inlet that is smaller than the supply line, the flow rate applied to the spray head during operation can be influenced and reduced. This ultimately has advantages in terms of a finer spray of the analyte solution upon exiting the outlet and ultimately has a positive effect on the sensitivity achievable with the spray head when using electrospray ionization (ESI) as an ion source for ion spectrometric investigations, in particular ion mobility analyses, mass analyses, or combined ion mobility-mass analyses.Choosing the smallest possible inner diameter for the spray nozzle inlet (and for the channel connecting the inlet to the spray nozzle outlet) also supports the smallest possible Taylor cone during electrospray ionization (ESI), which contributes to improving ionization performance. Manufacturing the inlet using SLE or 2PP offers the possibility of easily and reproducibly realizing such a smaller inner diameter of the inlet (and channel) compared to the size of the supply line. Furthermore, the inner diameter of the inlet can be easily and flexibly adapted and modified depending on the type and size of the supply line.

[0026] A spray head according to the invention is preferred, wherein the inlet of the spray head is designed such that the entry of particles into the channel that could cause a blockage of the channel connecting the inlet and outlet is prevented, while at the same time the flow of fluids or analyte solution into the channel is ensured. The inlet of the spray head therefore preferably has, for example, a sieve-like structure through which larger particles that could cause a blockage of the channel are retained. In this context, the inlet preferably has openings of different sizes (which are each smaller than the inner diameter of the channel) so that, for example, any larger particles can become trapped in the larger openings and be prevented from flowing further, while at the same time further fluid or analyte solution can enter the channel through the further, smaller openings through the inlet.Preferably, the various openings at the inlet have different shapes. In a particularly preferred embodiment, the inlet has a larger opening in its center (e.g., in the shape of a circle) to retain and trap any particles, and one or more smaller openings (e.g., in the shape of rectangles or squares) around this central opening to ensure continued flow of fluid or analyte solution in the event of the central opening becoming blocked.

[0027] As already mentioned above, a spray head according to the invention is preferred, wherein the inner diameter of the channel of the spray nozzle (through which the inlet is connected to the outlet of the spray nozzle) is substantially the same over its entire length, wherein the inner diameter of the channel of the spray nozzle over its entire length particularly preferably fluctuates only within the error tolerance usual within the scope of SLE or 2PP.

[0028] The channel encompassed by the spray nozzle, through which the inlet is connected to the outlet of the spray nozzle, can also extend over other regions of the spray head; however, within the scope of the invention, its extent can alternatively be limited solely to the area of ​​the spray nozzle. If the channel through which the inlet is connected to the outlet of the spray nozzle also extends beyond the spray nozzle, this part of the channel extending beyond the spray nozzle preferably also has largely the same inner diameter, particularly preferably an inner diameter that is the same within the error tolerance typical for SLE or 2PP, as the remaining part of the channel.

[0029] Depending on the design of the channel connecting the inlet and outlet of the spray nozzle, the inlet of the spray head intended for fluids, in particular for analyte solution, can be located either directly on the spray nozzle or at another location on the spray head.

[0030] As already noted above, the spray head according to the invention is intended for use in nano-electrospray ionization (nano-ESI) and accordingly has the usual and suitable designs and dimensions for use as an ESI spray head or nano-ESI spray head. A spray head according to the invention is preferred, wherein the outer diameter and / or the height of the spray head is in the range from 500 pm to 2000 pm, preferably in the range from 1000 pm to 1500 pm, and / or the channel through which the inlet is connected to the outlet of the spray nozzle has a length in the range from 50 pm to 2000 pm, preferably in the range from 500 pm to 1000 pm, and / or the channel through which the inlet is connected to the outlet of the spray nozzle has an inner diameter in the range from 5 pm to 50 pm, preferably in the range from 10 pm to 20 pm, particularly preferably in the range from 15 pm to 20 pm,and / or the spray nozzle has a length in the range of 100 pm to 500 pm, preferably in the range of 250 pm to 300 pm, and / or the recess for attaching a supply line to the inlet has a diameter in the range of 200 pm to 1000 pm, preferably in the range of 350 pm to 500 pm, and / or the spray nozzle at the outlet has an outer diameter in the range of 15 pm to 50 pm, preferably in the range of 20 pm to 40 pm, particularly preferably in the range of 30 pm to 40 pm, and / or,

[0031] The spray nozzle at the outlet has a wall thickness in the range of 5 pm to 20 pm, preferably in the range of 5 pm to 15 pm.

[0032] The above preferred dimensions have proven to be particularly advantageous for a spray head according to the invention.

[0033] A spray head according to the invention is preferred, wherein the inlet and the spray nozzle of the spray head, preferably the inlet, the spray nozzle and the protective structure of the spray head, particularly preferably the entire spray head, is or are made from one piece (monolithic). The production of as many components of the spray head as possible from one piece offers the great advantage that this avoids connection points which could represent weak points in the structure of the spray head. Monolithic production thus increases the stability of the spray head. Furthermore, the monolithic production of as many components of the spray head as possible simplifies the production of the spray head itself, since this eliminates the need to join the individual components of the spray head (which move on the micrometer scale).Monolithic manufacturing also significantly increases the precision of the spray head's manufacturing and dimensions, as it eliminates any unwanted misalignment when connecting individual components. Monolithic manufacturing of one or more spray head components can also be easily and seamlessly achieved, both when manufacturing the spray head using SLE and when manufacturing the spray head using 2PP.

[0034] A spray head according to the invention is preferred, wherein the outlet of the spray nozzle is designed and positioned such that at least a part of the fluid emerging from the outlet flows along the outer surface of a section of the spray nozzle (usually adjoining the outlet or projecting beyond the outlet) before being spatially separated (separated) from the spray nozzle.

[0035] The background to the aforementioned preferred embodiment is that the outlet of the spray nozzle for electrospray ionization should ideally be as thin and fine as possible in order to keep the size of the Taylor cone that usually forms directly at the outlet during electrospray ionization as small as possible, since a small Taylor cone contributes to improving ionization performance. Spray heads for electrospray ionization typically have the disadvantage in this context that the outer diameter of the outlet or the tip of the spray nozzle must have a minimum size and cannot be chosen to be arbitrarily small. This is because, on the one hand, the channel of the spray nozzle carrying the analyte solution must also have a certain minimum inner diameter at the outlet. In addition, the wall of the spray nozzle must have a certain minimum thickness due to the channel present at the outlet for stability and manufacturing reasons.However, as explained above, a wider outer diameter of the outlet has a detrimental effect on the Taylor cone formed at the outlet and the achievable sensitivity for electrospray ionization.

[0036] By allowing the fluid exiting the spray nozzle outlet to flow along the outer surface of a section of the spray nozzle adjacent to or extending beyond the outlet before separating from the spray nozzle, the location for the formation of the Taylor cone is shifted from the outlet to this section of the spray nozzle extending beyond the outlet. Since the section extending beyond the outlet does not necessarily have to have an internal channel, but can also have a compact structure, for example, the thickness of the tip at the end of this section is not necessarily limited by the presence of an internal channel, but can be designed significantly thinner and finer.By designing a significantly thinner tip for this section extending beyond the outlet and shifting the location for the Taylor cone formation to this tip, a smaller Taylor cone can ultimately be formed, thereby improving the ionization process. The section along which the fluid exiting the outlet flows is preferably made of the same material as the rest of the spray nozzle, and the spray nozzle, including this section, is preferably made from a single piece (monolithic).

[0037] The design of the section adjoining the outlet described above can be realized, for example, by positioning the outlet of the spray nozzle not (centrally) at the end of the spray nozzle, but instead (decentrally) on the side of the spray nozzle.

[0038] In connection with the preferred embodiment described above, it should be expressly pointed out that the section described above and in the claims - which usually adjoins the outlet or projects beyond the outlet - along which at least part of the fluid emerging from the outlet flows along the surface before being separated from the spray nozzle, is to be distinguished from embodiments in which the outlet is located at the end of a spray nozzle and is merely designed as an oblique ground section, as disclosed, for example, in Fig. 16 of DE 202 10 784 U1 or in Fig. 5 of US 2022 / 0328300 A1.A spray nozzle which has only one outlet with an oblique cut at its end therefore does not have, in the sense of the invention, a further section as described above (usually projecting beyond the outlet) along the surface of which the fluid emerging from the outlet can flow before being separated from the spray nozzle.

[0039] The difference observed during operation of a merely obliquely ground outlet at the end of a spray nozzle compared to the preferred embodiment described above is that with a merely obliquely ground outlet at the end of a spray nozzle, the formation of the Taylor cone still occurs directly at the outlet (as shown, for example, in Fig. 5 of US 2022 / 0328300 A1), and the size of the Taylor cone in this case continues to be influenced by the dimensions of the outlet and its wall. A shift in the formation of the Taylor cone away from the outlet towards another (preferably more pointed or thinner) area of ​​the spray nozzle therefore does not occur with the outlets at the end of a spray nozzle with an oblique ground known from the prior art.

[0040] As already mentioned above, the section along whose surface the fluid or analyte solution exiting the outlet flows before being separated from the spray nozzle preferably has a shape that tapers towards its end to a tip that is as thin as possible. Therefore, a spray head according to the invention is preferred, wherein the outlet of the spray nozzle is designed and positioned such that at least a portion of the fluid exiting the outlet flows along the outer surface of a nozzle (adjacent to or adjacent to the outlet) before being spatially separated (separated) from the spray nozzle.projecting beyond the outlet and) designed as a tip, preferably as a conically tapered tip, of the spray nozzle, wherein the part of the spray nozzle designed as a tip, preferably as a conically tapered tip, preferably has an outer diameter of less than 15 pm, particularly preferably less than 10 pm, most particularly preferably 5 pm or less, at its end.

[0041] Preferably, the distance between the outlet and the end of the section of the spray nozzle designed as a tip, preferably as a conically tapered tip, is as small as possible in order to keep the path that a fluid emerging from the outlet has to travel to the end of the tip as short as possible. A shorter path length between the outlet and the end of the tip increases the probability that as much fluid emerging from the outlet as possible reaches the end of the tip and is available there for the electrospray ionization process. Preferably, the distance between the outlet and the end of the section of the spray nozzle designed as a tip, preferably as a conically tapered tip, in the horizontal direction is less than 40 pm, more preferably less than 30 pm, most preferably less than 20 pm, in each case measured from the center point of the outlet to the center point of the end of the tip.

[0042] Within the scope of the preferred embodiment of the invention described above, the spray nozzle can also have a plurality of such partial sections designed as a tip, preferably as a conically tapered tip, to which the fluid emerging from the outlet can flow, so that the overall flow of fluid or analyte solution can be distributed over a plurality of tips and thus reduced per tip, which in turn has a positive effect on the size of the Taylor cone and the efficiency of the ionization.

[0043] The outlet or the section adjoining the outlet is preferably shaped in such a way that the fluid or analyte solution exiting the outlet is not pushed away by the spray nozzle, but instead is given the opportunity to at least partially flow along the outer surface of the section of the spray nozzle adjoining the outlet.

[0044] A spray head according to the invention is also preferred, wherein the section of the spray nozzle designed as a tip, preferably as a conically tapered tip, has a depression (e.g. in the form of a groove) in its surface, via which the fluid emerging from the outlet can be guided in the direction of the end of the section of the spray nozzle designed as a tip, preferably as a conically tapered tip, wherein the depression (groove) preferably runs from the outlet of the spray nozzle to the end of the section of the spray nozzle designed as a tip, preferably as a conically tapered tip.

[0045] Such a recess or groove advantageously supports the transfer of the fluid or analyte solution exiting the outlet to the end of the section designed as a tip, preferably a conically tapered tip, and the formation of a Taylor cone at this very end of the tip. The recess or groove is preferably designed without sharp edges, e.g., with smooth or rounded transitions, to prevent uncontrolled ionization events on the path from the outlet to the tip of the spray nozzle.

[0046] A spray head according to the invention is preferred, wherein the spray nozzle has an outer shape tapering towards the outlet of the spray nozzle (at least in sections), wherein the spray nozzle preferably has an outer shape tapering conically towards the outlet.

[0047] Such a tapered shape of the spray nozzle, preferably tapering to a point, brings with it the advantages described above with regard to the formation of a smaller Taylor cone and the associated better ionization.

[0048] A tapered or conical shape is preferably chosen for the spray nozzle's stability. Since it is sufficient to create the smallest possible Taylor cone if only the area of ​​the spray nozzle where the fluid or analyte solution separates from the spray nozzle and forms a Taylor cone is designed as thin and fine as possible, the other areas of the spray nozzle are preferably designed wider to increase the spray nozzle's stability and mechanical resistance.

[0049] A spray head according to the invention is preferred, wherein the spray nozzle comprises a cylindrical section in the region of the outlet. The cylindrical section preferably adjoins directly the point at which the taper of the spray nozzle ends in the direction of the outlet (i.e. at which the spray nozzle tapering towards the outlet has its smallest outer diameter), and then preferably extends to the outlet. The cylindrical section preferably has a length in the range from 50 pm to 200 pm, particularly preferably in the range from 100 pm to 200 pm. The cylindrical section spaced liquid emerging from the outlet even further from the wall of the spray nozzle while simultaneously maintaining sufficient stability for the spray nozzle.

[0050] The spray nozzle preferably tapers at an inclination in the range from 5 to 15°, more preferably at an inclination in the range from 10 to 15°. Inclinations of 15° (or even more) can be achieved primarily in those cases in which the tip or the last section of the spray nozzle tapering to a tip has a compact structure (having no internal channel); ie in those preferred embodiments in which the outlet of the spray nozzle is designed and positioned such that at least a portion of the fluid emerging from the outlet flows along the outer surface of a section of the spray nozzle (which can be designed as such a compact tip) before spatially separating from the spray nozzle.

[0051] A spray head according to the invention is preferred, wherein the protective structure has at least the same height as the spray nozzle (i.e. the end or tip of the spray nozzle does not protrude beyond the protective structure) and / or the spray nozzle is at least partially surrounded by the protective structure and / or the protective structure comprises a plurality of segments which are arranged (at least partially) around the spray nozzle, wherein there is preferably an intermediate space (or gap) between each of the segments of the protective structure arranged around the spray nozzle. A protective structure which has at least the same height as the spray nozzle has the particular purpose of protecting the usually most sensitive front part of the spray nozzle from possible mechanical damage or at least of reducing the risk of this.For example, such a protective structure may, under certain circumstances, allow the spray head to be placed on a support with the protective structure and spray nozzle facing forward, without necessarily causing the tip of the spray nozzle to break or bend. A protective structure that is at least the same height as the spray nozzle differs from conventional protective structures known from the prior art, which (for example, as disclosed in US 10,591,451 B2) are often intended only to better grip the spray head and therefore usually extend only around the spray head, but not at least to the same height as the spray nozzle or even beyond.

[0052] Since the protective structure is primarily intended to protect the spray nozzle, it is also advantageous if the spray nozzle is at least partially surrounded by the protective structure. In this context, it is not absolutely necessary for the protective structure to completely surround the sides of the spray nozzle. In most cases, a sufficient protective function is already achieved if the spray nozzle is at least partially surrounded by the protective structure, so that, for example, when gripping the spray head with tweezers, the tweezers do not come into contact with the spray nozzle, but with the protective structure that at least partially surrounds the spray nozzle. The protective structure that surrounds the spray nozzle can, for example, have holes or recesses.

[0053] Additionally or alternatively, the protective structure surrounding the spray nozzle may also comprise several segments, between each of which there is a space or gap.

[0054] A protective structure surrounding the spray nozzle, which is not completely closed, offers the overall advantage that it can direct a gas flow towards the spray nozzle, which preferably flows coaxially to the aerosol originating from the spray nozzle and which supports the spraying process itself and / or the ionization. Such a gas flow directed towards the spray nozzle can, for example, function as a sheath gas. The generation of a gas flow at or around the spray nozzle can be achieved both by actively supplying a gas to the spray nozzle and by the suction effect emanating from a negative pressure source located near the spray head (such as an inlet to a mass analyzer located near the spray head).For the effective inflow of gas through gaps in the protective structure toward the spray nozzle, the greatest possible distance between adjacent segments of the protective structure is advantageous. The greatest possible distance between adjacent segments of the protective structure also promotes the drainage of any liquid that may precipitate around the spray nozzle during electrospray ionization. The distance between adjacent segments of the protective structure is preferably at least one millimeter.

[0055] The inflow of a gas stream toward the spray nozzle can be further enhanced and optimized by further technical configurations of the spray head and its protective structure. In this context, a spray head according to the invention is preferred, wherein the sides of the spray head or the base body of the spray head are at least partially beveled, preferably in the areas of the spaces between segments of the protective structure arranged around the spray nozzle. Such beveling of the sides of the spray head further enhances the delivery of a gas stream to the spray nozzle.

[0056] If segments of the protective structure are arranged around the spray nozzle with gaps between the segments, connecting pieces can preferably be located between adjacent segments, which are preferably streamlined and can further influence a gas flow directed to the spray nozzle. Additionally or alternatively, the walls of segments of the protective structure arranged around the spray nozzle can also have bulges for influencing a gas flow directed to the spray nozzle.

[0057] Preferably, one or more edges of the protective structure are rounded. Rounding the edges of the protective structure (and preferably other edges of the spray head) makes it more difficult for any liquid or analyte solution that comes close to the protective structure to adhere to them and reduces the likelihood of undesired, uncontrolled ionization of molecules at the edges of the protective structure (i.e., the edges of the protective structure serve as a starting point for the formation of further Taylor cones without any control).

[0058] Uncontrolled ionization at any point on the spray head has the disadvantage that it can result in signals that are difficult to define during further analysis of the generated ions, and it can also lead to excessive space charge in the area of ​​the spray head, which impairs the actual ionization at the spray nozzle. The rounded edges of the protective structure also ensure that any gas that is to be directed to the spray nozzle and bypasses the protective structure reaches the spray nozzle more effectively and with less turbulence.

[0059] If segments of the protective structure are arranged around the spray nozzle, the segments of the protective structure preferably taper toward the spray nozzle. Such a taper has a beneficial effect on the supply of a gas flow toward the spray nozzle and also ensures that any liquid that may separate around the spray nozzle during electrospray ionization can flow more easily out of the spray head. At the same time, this maintains a stable and resilient structure for the segments of the protective structure.

[0060] A spray head according to the invention is preferred, wherein the base of the spray head, on which one or more spray nozzles are located, is designed to slope downwards from the one or more spray nozzles toward the outer sides of the spray head. Such a slope toward the outer sides of the spray head also promotes efficient drainage of any liquid that may precipitate around the spray nozzle during electrospray ionization.

[0061] The protective structure is preferably as far apart as possible from the outlet or from the tip of the spray nozzle (preferably a distance of at least 600 μm, particularly preferably a distance of at least 800 μm) in order to minimize any contact of fluid emerging from the outlet or analyte solution emerging from the outlet with the protective structure, wherein the protective structure must of course also be designed and positioned in such a way that it can adequately protect the spray nozzle from mechanical damage. In order to reconcile both concerns, a spray head according to the invention is preferred, wherein the wall or walls of the protective structure facing the spray nozzle are tapered in the direction of the outlet and / or the tip of the spray nozzle. This results in a greater distance between the protective structure and the outlet orthe tip of the spray nozzle while maintaining the highest possible stability of the protective structure.

[0062] A spray head according to the invention is preferred, wherein the inlet and the spray nozzle of the spray head, preferably the inlet, the spray nozzle and the protective structure of the spray head, particularly preferably all parts of the spray head made from one piece (monolithic), very particularly preferably the entire spray head, consists or consist of glass, diamond, sapphire or a cured photopolymer (for example an epoxy, hybrid polymer or hydrogel), preferably of a glass selected from the group containing or consisting of quartz glass (fused silica, FS), borosilicate glass and aluminosilicate glass, particularly preferably of quartz glass.

[0063] All of the above-mentioned materials are ideally suited for the production of an ES I spray head. The use of glass, and especially quartz glass, offers particular advantages due to its extremely high chemical and temperature resistance.

[0064] A spray head according to the invention is preferred, wherein the inlet, the spray nozzle and the protective structure of the spray head, preferably all parts of the spray head made from one piece (monolithic), particularly preferably the entire spray head, is or are obtained by selective laser-induced etching (Selective Laser-induced Etching, SLE) or by two-photon polymerization (2PP).

[0065] Due to the exceptional precision and reproducibility associated with manufacturing using SLE or 2PP, coupled with the fast, simple, and cost-effective production achievable with SLE or 2PP, as many spray head components as possible are preferably manufactured this way. Furthermore, manufacturing as many spray head components as possible using the same manufacturing method simultaneously offers the possibility of manufacturing as many components as possible from a single piece, thus benefiting from the advantages of monolithic manufacturing of multiple components discussed above.

[0066] Within the scope of the present invention, a spray head can also have more than one spray nozzle. Therefore, a spray head according to the invention is preferred, wherein the spray head comprises more than one spray nozzle, preferably two, four, eight, or twelve spray nozzles.

[0067] The presence of multiple spray nozzles can offer various advantages. For example, the flow of fluid or analyte solution coming from a supply line can be distributed among multiple spray nozzles, so that the flow rate at the spray nozzles, particularly at the spray nozzle outlets, can be influenced and reduced compared to the flow rate at the supply line or at the spray head inlet. Implementing different flow rates at the spray head inlet and the spray nozzle outlets is advantageous because a somewhat higher flow rate is generally desired near the inlet (to minimize the effects of any dead volume present at the inlet), while a lower flow rate is generally desired at the outlets (since a lower flow rate has a positive effect on the achievable ionization rate at a spray nozzle).The presence of several spray nozzles thus makes it possible, for example, to achieve a flow of 1 pL / min at the supply line or inlet and, at the same time, a flow of 250 nL / min (in the case of 4 spray nozzles) or 100 nL / min (in the case of 10 spray nozzles) at the outlets.

[0068] The presence of several spray nozzles also enables the controlled generation of several ionization centers.

[0069] In the case of multiple spray nozzles, usually and preferably all spray nozzles are protected by the protective structure.

[0070] With multiple spray nozzles, their outlets can each be connected to an inlet for fluids or analyte solution via a separate channel. However, it is also possible for several or all spray nozzles to share a central section of a channel, which branches off on the way to the spray nozzles, and for several or all spray nozzles to be connected to a branch of this channel.

[0071] In the case of branching of a central section of a channel, the branches usually have a smaller inner diameter than the central section of the channel in order to at least avoid an excessive drop in the flow velocity. In such preferred embodiments, the central section of the channel preferably comprises a constriction and / or a sieve-like structure at at least one location, wherein the maximum extent or the diameter of the largest opening at the constriction and / or sieve-like structure is preferably smaller than the maximum extent or the inner diameter of the branches. This prevents any blockage in one of the branches by previously retaining particles that could cause such a blockage in the central section of the channel.The constriction and / or sieve-like structure is designed (for example by the presence of several and preferably differently sized openings in the sieve-like structure) in such a way that the attachment of a particle to this constriction and / or sieve-like structure does not usually lead to a complete blockage of the central section of the channel.

[0072] In the case of multiple spray nozzles, these are preferably arranged at a largely uniform distance from one another around a central point, preferably around the center point, of the spray head. In the case of three, four, or more than four spray nozzles, these are arranged, for example, at the corners of an imaginary equilateral triangle, square, or quadrilateral. At least one segment of the protective structure is preferably also located in the center of multiple spray nozzles, in particular laterally and spaced from this arrangement of multiple spray nozzles.

[0073] In the case of multiple spray nozzles, the distance between adjacent spray nozzles is preferably in a range between 300 pm and 400 pm, measured from the respective center of the outlet of adjacent spray nozzles or measured from the respective center of the spray nozzle tip. Such a preferred distance between adjacent spray nozzles contributes to the efficient formation of a Taylor cone at the outlets or tips of the multiple spray nozzles.

[0074] If multiple spray nozzles are present, these preferably have an extended support leg at the end facing the base of the spray head, which creates space for a more flexible design of the channels connecting the inlet and outlet of a spray nozzle. This can, for example, avoid right angles in a channel layout, which require more effort to manufacture and lead to a greater susceptibility to blockages during operation of the spray head.

[0075] The reduction of the flow from the supply line or inlet to the outlet of the one or more spray nozzles can also be achieved in other ways. A spray head according to the invention is preferred, wherein the spray head has a bypass line for diverting a portion of the flow reaching the inlet of the spray head. With the aid of such a bypass line, the flow arriving at the outlet of the spray nozzle can also be significantly reduced when, for example, only one spray nozzle is present. The flow diverted via the bypass line is typically not reused but instead directed into a drain line or a waste container.

[0076] A spray head according to the invention is also preferred, wherein the spray head or spray nozzle additionally comprises a channel for supplying solvent to the channel connecting the inlet and outlet of the spray nozzle or for supplying solvent to the outlet of the spray nozzle. In other words, the channel for supplying solvent can be connected both to the channel that connects the inlet and outlet of the spray nozzle and also end directly at the outlet of the spray nozzle, for example via a separate additional outlet. The purpose of such an additional channel for supplying solvent is, among other things, that fluids or analyte solutions which originate from liquid chromatography in particular often have a high proportion of protic solvents (such as water), which have a negative effect on ionization by means of ESI. In order to ensure the ionization of such a fluid orTo improve the ionization of such an analyte solution, an aprotic solvent (such as acetonitrile) can be added through the solvent supply channel. In this way, for example, the concentration of an analyte solution originating from liquid chromatography, which often has an aprotic solvent concentration in the range of 5-35%, can be increased to, for example, 50-70% before ionization, thereby significantly improving the ionization potential of the analyte solution.

[0077] As already explained above, a uniform inner diameter of the channel through which the inlet is connected to the outlet of the spray nozzle - in particular one that does not taper towards the outlet - can help prevent blockages. Therefore, a spray head according to the invention is preferred, wherein the channel through which the inlet is connected to the outlet of the spray nozzle has a (largely) constant inner diameter. In preferred embodiments in which the channel has a central section and several branches, the branches leading to the outlet of a spray nozzle preferably each have a (largely) constant inner diameter.

[0078] A spray head according to the invention is preferred, wherein the spray head is a spray head for nano-electrospray ionization (nano-ESI) and / or is designed and suitable for setting flow rates of less than 1000 nL / min, preferably less than 250 nL / min, particularly preferably less than 10 nL / min.

[0079] Also preferred is a spray head according to the invention, wherein the spray head is designed and suitable for setting flow rates of less than 10,000 nL / min.

[0080] Preferably, the spray head is designed and suitable for setting flow rates of less than 1000 nL / min, preferably less than 250 nL / min, particularly preferably less than 10 nL / min, depending on the spray nozzle present on the spray head.

[0081] Nano-ESI is particularly characterized by the realization of lower flow rates at the spray nozzle outlets, which can be achieved, for example, by smaller dimensions of the outlets and the one or more channels connecting the outlet to the spray head inlet, and / or by other measures, such as splitting the amount of analyte solution coming from the supply line (as explained in various ways above). The advantage of implementing nano-ESI lies in the achievement of higher sensitivity.

[0082] A spray head according to the invention is preferred, wherein the spray head additionally has a layer of a conductive material, preferably a metal layer, particularly preferably a layer comprising or consisting of gold or silver, and / or has a microstructure.

[0083] Preferably, said layer and / or microstructuring is located on the outer surface of the spray nozzles of the spray head, but may also be located at other locations on the spray head and may, for example, extend over the entire outer surface or the entire surface of the spray head, which includes, for example, the protective structure.

[0084] An additional layer of conductive material serves in particular to increase the conductivity of the spray nozzle (which is usually made of glass or a photopolymer due to the manufacturing method used).

[0085] The microstructuring primarily serves to increase the hydrophobicity of the surface of the spray head, in particular the surface of the spray nozzles. Preferably, the surface of one or more spray nozzles of the spray head partially or completely has a sharkskin-like structure.

[0086] Part of the invention is also a method for producing a spray head according to the invention (as defined above and in the claims), comprising the following steps: a) producing or providing a blank or starting material for producing the spray head (or for producing the parts of the spray head made from one piece), b) processing the produced or provided blank or starting material, preferably using selective laser-induced etching (SLE) or two-photon polymerization (2PP), so that the inlet and the spray nozzle of the spray head, preferably the inlet, the spray nozzle and the protective structure of the spray head, particularly preferably all parts of the spray head to be made from one piece (monolithic), very particularly preferably the entire spray head, are obtained.

[0087] Part of the invention is also the use of a spray head according to the invention (as defined above and in the claims) for electrospray ionization (ESI), preferably for nano-electrospray ionization (nano-ESI) and / or for electrospray ionization at flow rates of less than 1000 nL / min, preferably less than 250 nL / min, particularly preferably less than 10 nL / min. After generation, the ions can be subjected to an ion spectrometric analysis method, in particular an ion mobility analysis, mass analysis, or combined ion mobility-mass analysis.

[0088] Part of the invention is also a chromatography column, preferably a chromatography column for liquid chromatography (LC), particularly preferably for nano-liquid chromatography (nano-LC), comprising a spray head according to the invention (as defined above and in the claims) at one end (or at the outlet) of the chromatography column.

[0089] Part of the invention is also a device for carrying out electrospray ionization (ESI), preferably for carrying out nano-electrospray ionization (nano-ESI), comprising a spray head according to the invention (as defined above and in the claims), or comprising a chromatography column according to the invention (as defined above and in the claims).

[0090] A device according to the invention for performing electrospray ionization (ESI) is characterized (in addition to the presence of a spray head according to the invention) in particular by the fact that it comprises all the components required for performing ESI, such as a counter electrode (drawing voltage electrode). The device can be coupled to an ion spectrometric device, in particular an ion mobility analyzer, mass analyzer, or combined ion mobility-mass analyzer, for ion spectrometric analysis of the generated ions.

[0091] Objects posed by the present invention are also achieved by using selective laser-induced etching (SLE) or two-photon polymerization (2PP) for the production of a spray head according to the invention (as defined above and in the claims). The invention is explained in more detail below with reference to exemplary embodiments and the accompanying figures. The exemplary embodiments given below are intended to describe and explain the invention in more detail without limiting its scope.

[0092] The elements in the accompanying drawings are not necessarily drawn to scale, but are primarily intended to illustrate (largely schematically) the principles of the invention. In the drawings, corresponding elements are designated by like reference numerals throughout the different views.

[0093] They show:

[0094] Figure 1A: Illustration of a spray head according to the invention.

[0095] Figure 1B: Representation of a cross-section of the spray head shown in Figure 1A.

[0096] Figure 1C: Front view of the cross-sectional drawing from Figure 1B.

[0097] Figure 2A: Illustration of another example of a spray head according to the invention.

[0098] Figure 2B: Illustration of a cross-section of the spray head shown in Figure 2A.

[0099] Figure 2C: Front view of the cross-sectional drawing from Figure 2B.

[0100] Figure 3A: Illustration of another example of a spray head according to the invention.

[0101] Figure 3B: Illustration of a cross-section of the spray head shown in Figure 3A.

[0102] Figure 3C: Front view of the cross-sectional drawing from Figure 3B.

[0103] Figure 3D: Enlarged view of the end of the spray nozzle of the spray head shown in Figure 3A.

[0104] Figure 3E: Illustration of a cross-section of the spray nozzle shown in Figure 3D.

[0105] Figure 3F: Enlarged view of the inlet of the spray head shown in Figure 3A.

[0106] Figure 4A: Illustration of another example of a spray head according to the invention.

[0107] Figure 4B: A cross-sectional view of the spray head shown in Figure 4A. Figure 5: A cross-sectional view of another example of a spray head according to the invention.

[0108] Figure 6A: Illustration of another example of a spray head according to the invention.

[0109] Figure 6B: Illustration of a cross-section of the spray head shown in Figure 6A.

[0110] Figure 6C: Front view of the cross-sectional drawing from Figure 6B.

[0111] Figure 7A: Illustration of a chromatography column according to the invention comprising a spray head according to the invention.

[0112] Figure 7B: Representation of a cross-section of the chromatography column shown in Figure 7A.

[0113] Figure 8A: Illustration of another example of a spray head according to the invention.

[0114] Figure 8B: Illustration of a cross-section of the spray head shown in Figure 8A.

[0115] Figure 8C: Front view of the cross-sectional drawing from Figure 8B.

[0116] Figure 9A: Illustration of another example of a spray head according to the invention.

[0117] Figure 9B: Illustration of a cross-section of the spray head shown in Figure 9A.

[0118] Figure 9C: Front view of the cross-sectional drawing from Figure 9B.

[0119] Figure 1A shows an example of a spray head 10 according to the invention, comprising an inlet for analyte solution 11 (see Figure 1B, not visible in Figure 1A) and a spray nozzle 12. The spray nozzle 12 has an outlet for analyte solution 121 and a channel 122 through which the inlet 11 of the spray head is connected to the outlet 121 (the channel 122 is not visible in Figure 1A). The spray nozzle 12 has an outer conical shape and tapers to a tip toward the outlet 121.

[0120] The spray head 10 shown in Figure 1A also includes a protective structure 13 to protect the spray nozzle 12 from mechanical damage. The protective structure 13 extends laterally from the spray nozzle 12 to slightly above the height of the outlet 121, is spaced apart from the spray nozzle 12, and consists of a total of four individual segments arranged around the spray nozzle 12. Between the individual segments of the protective structure 13 are spaces which (despite the height of the protective structure 13) allow the supply of a gas flow toward the spray nozzle 12 and its tip.

[0121] Figure 1B shows a cross-section of the spray head 10 shown in Figure 1A. The cross-section allows a view of the channel 122, through which the inlet 11 of the spray head 10 is connected to the outlet 121 of the spray nozzle 12. The channel 122 is a microchannel with an inner diameter of 15 pm. The channel 122 has a uniform inner diameter over its entire length and thus, for example, does not taper towards the outlet 121. Figure 1B also shows a recess 14, which is located in the lower area of ​​the spray head 10 and which enables a supply line, such as an LC column, to be easily and securely attached to the inlet 11 of the spray head 10.

[0122] Figure 1C shows a front view of the cross-sectional drawing from Figure 1B, from which it is clearly visible that the protective structure 13 is designed higher than the spray nozzle 12 and ends only a little above the tip of the spray nozzle 12. As a result, the protective structure 13 provides protection against mechanical damage, particularly for the upper part and the tip of the spray nozzle 12.

[0123] Figure 2A shows another example of a spray head 20 according to the invention. One difference from the spray head 10 shown in Figure 1A is that the spray head 20 shown in Figure 2A has a protective structure 23 with rounded edges. This reduces the likelihood of unwanted ionization regions forming at the edges of the protective structure 23. Furthermore, the rounding of the edges of the protective structure 23 minimizes the occurrence of any turbulence during the inflow of gas through the gaps of the protective structure 23.

[0124] In the spray head 20 shown in Figure 2A, the outer wall of the spray head 20 is also flattened at those points where the gaps of the protective structure 23 are located. This further facilitates the supply of a gas flow toward the spray nozzle 22.

[0125] Furthermore, the tip of the spray nozzle 22 of the spray head 20 shown in Figure 2A has a greater distance from the segments of the protective structure 23 than the spray head 10 shown in Figures 1A, 1B, and 1C. This is achieved, on the one hand, by selecting a larger outer diameter of the spray head 20 shown in Figure 2A, amounting to 1.5 mm (instead of 1 mm in the case of the spray head 10 shown in Figures 1A, 1B, and 1C). By increasing the outer diameter of the spray head 20, a greater distance between the tip of the spray nozzle 22 and the segments of the protective structure 23 arranged around the spray nozzle can generally be achieved.Furthermore, in the spray head 20 shown in Figure 2A, the inner walls of the segments of the protective structure 23 taper towards the tip of the spray nozzle 22, thereby creating a greater distance between the tip of the spray nozzle 22 and the protective structure 23 and simultaneously maintaining the stability of the protective structure 23 and sufficient protection of the spray nozzle 22 by the protective structure 23. By means of the measures implemented in the spray head 20 shown in Figure 2A to increase the distance between the tip of the spray nozzle 22 and the protective structure 23, the horizontal distance between the tip of the spray nozzle 22 and the protective structure 23 can be increased, for example, from 285 pm to 600 pm compared to the spray head 10 shown in Figures 1A, 1B and 1C, which simultaneously leads to less transfer of analyte solution emerging from the outlet of the spray nozzle 22 to the protective structure 23.

[0126] In the cross-sectional drawings of the spray head 20 shown in Figure 2A, shown in Figures 2B and 2C, it can be seen that its recess 24 for attaching a supply line to the inlet 21 of the spray head 20 has a widened portion both in the lower region and in the upper region (in the area of ​​the inlet 21). The widened portion 241 in the lower region of the recess 24 allows for easier insertion of a supply line into the recess 24, and the widened portion 242 in the area of ​​the inlet 21 allows for somewhat more play and flexibility when adjusting and attaching a supply line to the inlet 21, thereby achieving an improved connection between the supply line and the inlet 21 with less dead volume.

[0127] From the cross-sectional drawings shown in Figures 2B and 2C, it is also evident that the spray head 20 shown here has a sieve-like structure 25 at its inlet 21, which is intended to prevent the penetration of particles into the channel 222 connecting the inlet 21 and the outlet 221 of the spray nozzle 22, which could cause a blockage in the channel 222. Further details on the design of this sieve-like structure 25 are explained below in connection with Figure 3F.

[0128] The spray head 20 shown in Figures 2A, 2B and 2C has preferred dimensions for a spray head according to the invention, which can be summarized as follows:

[0129] Height of spray head 20: 1000 pm;

[0130] Diameter of the spray head 20: 1500 pm; total height of the recess 24: 300 pm;

[0131] Height of the widening 241 of the recess 24 in the lower area: 25 pm;

[0132] Height of the widening 242 of the recess 24 in the upper area: 40 pm;

[0133] Diameter of the recess 24 in the middle: 370 pm; widest diameter of the recess 24 in the lower area: 350 pm; widest diameter of the recess 24 in the upper area: 320 pm; height of the spray nozzle 22: 550 pm;

[0134] Height of protective structure 23: 600 pm.

[0135] Of course, a spray head according to the invention can also have other dimensions suitable for suitability as an ESI spray head, in particular for suitability as a nano-ESI spray head.

[0136] Figure 3A shows a further example of a spray head 30 according to the invention, which represents a modification of the spray head 20 shown in Figures 2A, 2B and 2C. In the spray head 30 shown in Figure 3A, the outlet 321 of the spray nozzle 32 is not located at the end of the spray nozzle 32. Instead, the outlet 321 is positioned and configured such that at least a portion of the analyte solution exiting the outlet 321 flows, before separating from the spray nozzle 32, along the outer surface of a section 323 of the spray nozzle 32 that adjoins the outlet 321 or projects beyond the outlet 321 to the tip of the spray nozzle 32. Because the outlet 321 is not located at the tip of the spray nozzle 32, the tip of the spray nozzle 32 can be manufactured more compact (without an internal channel) and thinner.In the presently shown embodiments, the outer diameter for the tip of the spray nozzle 32 shown in Figure 3A can be reduced from 25 pm to 5 pm compared to the outer diameter for the tip of the spray nozzle 22 shown in Figure 2A, which brings with it the advantages described above with regard to the formation of a smaller Taylor cone at the tip and the improved ionization.

[0137] The cross-sectional drawings of the spray head 30 shown in Figure 3A, shown in Figures 3B and 3C, can illustrate the structure of this embodiment and in particular the positioning and design of the outlet 321 of the spray nozzle 32 even better.

[0138] Figure 3D shows an enlarged view of the end of the spray nozzle 32 of the spray head 30 shown in Figure 3A. Figure 3E shows a cross-section of this enlarged view. This also shows that the section 323 of the spray nozzle 32 adjacent to the outlet 321 has a spout through which the analyte solution emerging from the outlet 321 is guided along the surface of this section 323 toward the tip of the spray nozzle 32.

[0139] The spray head 30 shown in Figure 3A - like the spray head 20 shown in Figure 2A - has a sieve-like structure 35 at its inlet 31, which is intended to prevent the penetration of particles into the channel 322 connecting the inlet 31 and the outlet 321 of the spray nozzle 32, which could cause a blockage in the channel 322. Figure 3F shows an enlarged cross-sectional view of this sieve-like structure 35. The sieve-like structure 35 is designed such that it has a round opening in the center, from which several rectangular openings, each smaller in area (with a length of the two long sides of the rectangles of 5 μm each), branch off. The diameter of the round opening of the sieve-like structure 35 is smaller than the inner diameter of the channel 322 adjoining the sieve-like structure 35.The rectangular openings of the sieve-like structure 35 also each have a taper in depth, which extends over a length of 20 pm and via which the sieve-like structure 35, with its various openings, is adapted downstream to the size of the inner diameter of the channel 322 adjoining the sieve-like structure 35. The presence of such a sieve-like structure 35 has proven particularly advantageous for preventing blockages in the channel 322 of the spray head 30.

[0140] Figure 4A shows an example of a spray head 40 according to the invention, which has four spray nozzles 42, each of which is identically configured. In the cross-section of the spray head 40 shown in Figure 4B, it can be seen that the channel 422, through which the inlet 41 of the spray head is connected to the outlets 421 of the spray nozzles 42, has several branches 4221, each of which leads to a respective outlet 421 of the spray nozzles 42.

[0141] Figure 5 shows the cross-section of another example of a spray head 50 according to the invention, which represents a modification of the spray head 40 shown in Figures 4A and 4B. In addition to a tapering of the inner walls of the segments of the protective structure 53, a further change compared to the spray head 40 shown in Figures 4A and 4B can be seen that the spray head 50 has a separate inlet 51 for each existing spray nozzle 52, and these inlets are each connected to the outlets 521 of the spray nozzles 52 via separately designed channels 522. Figure 6A and the corresponding cross-sectional drawings in Figures 6B and 6C show another example of a spray head 60 according to the invention, which is characterized in particular by the presence of several spray nozzles 62 and the simultaneous presence of a protective structure 63 optimized in its shape.

[0142] Figure 7A and the corresponding cross-section shown in Figure 7B show an example of a chromatography column 76 according to the invention comprising a spray head 70 according to the invention. The chromatography column 76, in its type and dimensions, represents an LC column for performing nano-LC. One end of the chromatography column 76 is attached to the inlet 71 of the spray head 70. A firm hold between the chromatography column 76 and the spray head 70 is ensured by bonding both components with an epoxy resin adhesive. Such a combination of chromatography column 76 and spray head 70 offers the possibility of directly ionizing an analyte solution after liquid chromatographic separation.

[0143] Figure 8A and the corresponding cross-sectional drawings in Figures 8B and 8C show a further example of a spray head 80 according to the invention. The spray head 80 shown in Figures 8A, 8B, and 8C is characterized, among other things, by the fact that the segments of the protective structure 83 taper towards the spray nozzle 82 and the distance between adjacent segments of the protective structure 83 has been chosen to be as large as possible. This facilitates, on the one hand, the inflow of a gas stream flowing from the outside towards the spray nozzle 82 and, on the other hand, also facilitates the outflow of any liquid accumulating around the spray nozzle 82 during electrospray ionization from the spray head 80. The outflow of any liquid precipitating in the spray head 80 is further facilitated by the fact that the base of the spray head 80, on which the spray nozzle 82 is located, is designed to slope towards the outer sides of the spray head 80.

[0144] The spray head 80 shown in Figures 8A, 8B and 8C is also characterized in that the gradual taper of its spray nozzle 82 does not extend to the outlet 821, but instead the spray nozzle 82 has a section with a cylindrical shape 824 in the region of the outlet 821, through which liquid emerging from the outlet 821 can be spaced even further from the wall of the spray nozzle 82.

[0145] Figure 9A and the corresponding cross-sectional drawings in Figures 9B and 9C show a further example of a spray head 90 according to the invention, which, compared to the previously explained embodiments, is characterized in particular by the presence of extended support legs 925 for the spray nozzles 92 present on the spray head 90. Such extended support legs 925 not only provide more stability for the spray nozzles 92, but above all create more space for the design of the channel guide for the channel 922 connecting the inlet 91 of the spray head 90 with the outlets 921 of the spray nozzles 92, or for its branches 9221.

[0146] The spray heads shown in Figures 1A, 2A, 3A, 4A, 5, 6A, 7A, 8A and 9A are each made entirely from a single piece of quartz glass and manufactured using SLE.

[0147] List of reference symbols:

[0148] 10, 20, 30, 40, 50, 60, 70, 80, 90 spray head

[0149] 11, 21, 31, 41, 51, 61, 71, 81, 91 Inlet for fluids or analyte solution

[0150] 12, 22, 32, 42, 52, 62, 72, 82, 92 spray nozzle

[0151] 13, 23, 33, 43, 53, 63, 73, 83, 93 Protective structure to protect the spray nozzle

[0152] 14, 24, 34, 44, 54, 64, 84, 94 Recess for attaching a supply line to the inlet of the spray head

[0153] 25, 35, 65, 85, 95 sieve-like structure at the inlet of the spray head

[0154] 76 Chromatography column

[0155] 121, 221, 321, 421, 521, 621, 721, 821, 921 Spray nozzle outlet

[0156] 122, 222, 322, 422, 522, 622, 722, 822, 922 Channel through which the inlet of the spray head is connected to the outlet of the spray nozzle

[0157] 241, 341, 641, 841, 941 Widening in the lower area of ​​the recess

[0158] 242, 342, 642, 842, 942 Widening of the recess towards the inlet of the spray head

[0159] 323 Partial section of the spray nozzle adjoining the outlet or projecting beyond the outlet, over the outer surface of which at least a part of the analyte solution emerging from the outlet flows to the tip of the spray nozzle

[0160] 824, 924 cylindrical section of the spray nozzle in the area of ​​the outlet

[0161] 925 extended spray nozzle support leg

[0162] 4221, 6221, 9221 Branching of the channel through which the inlet of the spray head is connected to the outlet of the spray nozzle

Claims

Patent claims:

1. A spray head for electrospray ionization, comprising: an inlet for fluids, a spray nozzle comprising an outlet for fluids and comprising a channel through which the inlet is connected to the outlet of the spray nozzle, and a protective structure for protecting the spray nozzle from mechanical damage, wherein the inlet and the spray nozzle of the spray head are obtained by selective laser-induced etching or by two-photon polymerization.

2. Spray head according to claim 1, wherein the inlet and the spray nozzle of the spray head, preferably the inlet, the spray nozzle and the protective structure of the spray head, particularly preferably the entire spray head, is or are made from one piece.

3. Spray head according to one of the preceding claims, wherein the outlet of the spray nozzle is designed and positioned such that at least a part of the fluid emerging from the outlet flows along the outer surface of a partial section of the spray nozzle before spatially separating from the spray nozzle.

4. Spray head according to one of the preceding claims, wherein the outlet of the spray nozzle is designed and positioned such that at least a part of the fluid emerging from the outlet flows along the outer surface of a partial section of the spray nozzle designed as a tip, preferably as a conically tapered tip, before a spatial separation from the spray nozzle, wherein the partial section of the spray nozzle designed as a tip, preferably as a conically tapered tip, preferably has an outer diameter of less than 15 pm, particularly preferably less than 10 pm, most particularly preferably 5 pm or less, at its end.

5. Spray head according to one of the preceding claims, wherein the section of the spray nozzle designed as a tip, preferably as a conically tapered tip, has a recess in its surface, via which the fluid emerging from the outlet can be guided towards the end of the section of the spray nozzle designed as a tip, preferably as a conically tapered tip, wherein the recess preferably extends from the outlet of the spray nozzle to the end of the partial section of the spray nozzle designed as a tip, preferably as a conically tapered tip.

6. Spray head according to one of the preceding claims, wherein the protective structure has at least the same height as the spray nozzle and / or the spray nozzle is at least partially surrounded by the protective structure and / or the protective structure comprises a plurality of segments which are arranged around the spray nozzle, wherein there is preferably an intermediate space between each of the segments of the protective structure arranged around the spray nozzle.

7. Spray head according to one of the preceding claims, wherein the inlet and the spray nozzle of the spray head, preferably the inlet, the spray nozzle and the protective structure of the spray head, particularly preferably all parts of the spray head made from one piece, very particularly preferably the entire spray head, consists or consist of glass, diamond, sapphire or a cured photopolymer, preferably of a glass selected from the group containing or consisting of quartz glass, borosilicate glass and aluminosilicate glass, particularly preferably of quartz glass.

8. Spray head according to one of the preceding claims, wherein the inlet, the spray nozzle and the protective structure of the spray head, preferably all parts of the spray head made from one piece, particularly preferably the entire spray head, is or are obtained by selective laser-induced etching or by two-photon polymerization.

9. Spray head according to one of the preceding claims, wherein the spray head comprises more than one spray nozzle, preferably two, four, eight or twelve spray nozzles.

10. Spray head according to one of the preceding claims, wherein the channel through which the inlet is connected to the outlet of the spray nozzle has a constant inner diameter.

11. Spray head according to one of the preceding claims, wherein the spray head is a spray head for nano-electrospray ionization and / or is designed and suitable for setting flow rates of less than 1000 nL / min, preferably less than 250 nL / min, particularly preferably less than 10 nL / min.

12. Spray head according to one of the preceding claims, wherein the spray head additionally has a layer of a conductive material, preferably a metal layer, particularly preferably a layer comprising or consisting of gold or silver, and / or has a microstructure.

13. A method for producing a spray head as defined in any one of claims 1 to 12, comprising the following steps: a) producing or providing a blank or starting material for producing the spray head, b) processing the produced or provided blank or starting material, preferably using selective laser-induced etching or two-photon polymerization, so that the inlet and the spray nozzle of the spray head, preferably the inlet, the spray nozzle and the protective structure of the spray head, particularly preferably all parts of the spray head to be manufactured from one piece, very particularly preferably the entire spray head, are obtained.

14. Use of a spray head as defined in any one of claims 1 to 12 for electrospray ionization, preferably for nano-electrospray ionization and / or for electrospray ionization at flow rates of less than 1000 nL / min, preferably less than 250 nL / min, particularly preferably less than 10 nL / min.

15. Chromatography column, preferably chromatography column for liquid chromatography, particularly preferably for nano-liquid chromatography, comprising a spray head as defined in any one of claims 1 to 12 at one end of the chromatography column.

16. Apparatus for performing electrospray ionization, preferably for performing nano-electrospray ionization, comprising a spray head as defined in any one of claims 1 to 12 or comprising a chromatography column as defined in claim 15.

17. Use of selective laser-induced etching or two-photon polymerization for the manufacture of a spray head for electrospray ionization as defined in any one of claims 1 to 12.

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