Characterizing aerosol particles using pneumatic nebulizer-induced disintegration

Abstract

Systems and methods are provided for the disintegration and analysis of analyte aerosol particles. In various embodiments, these systems collect aerosol particles and introduce them into a high-pressure gas stream. This stream atomizes the exiting liquid upon ejection near the outlet of the liquid conduit, promoting high-impact collisions between the aerosol particles and the liquid. This interaction results in complete or partial disintegration of the aerosol particles, with the possibility of their dissolution in the resulting liquid droplets. In certain embodiments, at least some of the resulting analyte species are ions that can be analyzed using a mass spectrometer. These systems and methods are adaptable to analyze a wide range of aerosols and hold particular promise for studying plumes generated during laser ablation of tissue.

Description

[Technical Field]

[0001] Related Applications This application claims priority to Canadian Patent Application No. 3,186,817, filed January 18, 2023, entitled "MOLECULAR CHARACTERIZATION OF AEROSOL PARTICLES THROUGH PNEUMATIC NEBULIZER ASSISTED FRAGMENTATION," which is incorporated herein by reference in its entirety. [Background technology]

[0002] Analyzing the chemical composition of aerosols is important across various scientific disciplines, environmental monitoring, medicine, and industry. Aerosol analysis is essential not only for its intrinsic value but also for understanding aerosol sources and their interactions with different systems. For example, characterizing bioaerosols (such as fungi, pollen, spores, viruses, and bacteria) in the air and human environment is of great importance. Another key area is the analysis of laser plumes produced by ablation of biological tissue. Recent advances have shown that infrared laser pulses with short durations (approximately 0.1–5 ns) and wavelengths near 2.94 μm, resonant with the OH stretching vibration of water, can ablate biological tissue with minimal collateral damage [1]. Such laser ablation works by creating ultrafast acoustic transients within the tissue through strongly localized optical absorption centers, microcavitation, and acoustic impedance mismatch [2]. As a result, the exhaled plume primarily contains tissue fragments with their molecular composition largely preserved, providing an excellent opportunity for rapid chemical characterization. This method has potential applications, for example, in intraoperative molecular biopsy and tissue imaging.[3] However, challenges arise because only a small fraction of the laser plume consists of individual molecules or molecular clusters, with the majority being aerosol particles of various sizes.[4] While some molecular information can be gleaned from the analysis of small amounts of individual molecular species expelled directly from tissue,[5] enhancing the extraction of molecules from these aerosol particles for analysis could significantly improve the signal-to-noise ratio for molecular characterization.

[0003] Aerosol particles can be analyzed either offline or in real time. Offline techniques typically involve trapping aerosol particles in a liquid or solid matrix for subsequent analysis [6], [7]. While these methods achieve chemical characterization, they are labor-intensive and time-consuming. Applications such as environmental monitoring, intraoperative surgical tissue biopsy, or tissue imaging require real-time analysis, which is particularly challenging for fragile components such as biomolecules [8], [9].

[0004] To address this need, several approaches have been explored for rapid molecular extraction from aerosol particles.

[0005] Thermal methods involve heating aerosol particles to desorb molecular components through evaporation or thermal decay.

[10] ,

[11] However, this method may not be suitable for thermally sensitive molecules or those strongly bound to the aerosol particles.

[0006] In contrast, dissolution techniques involve mixing analyte aerosol particles with a liquid solvent aerosol. This combination results in the merging and partial dissolution of the aerosol molecules in the solvent

[12] ,

[13] ,

[14] . Subsequent evaporation of the solvent droplets liberates the dissolved molecules. However, given that both the initial aerosol and the solvent aerosol are dispersed in the gas, the frequency of aerosol merging is relatively low. Additionally, the interaction time between the aerosols is often too short to allow complete dissolution of the particles.

[0007] Another method is the impaction technique, in which aerosol particles are mechanically impacted against a hard surface, expelling some molecules into the surroundings. Combining this with dissolution enhances molecular extraction

[15] ,

[16] ,

[17] , but it requires complex modifications to the mass spectrometer interface and does not allow for easy additional ionization. Furthermore, frequent impacts of wet aerosols can leave residues, leading to cross-contamination and maintenance challenges.

[0008] Given these limitations, there is a clear need for innovative systems and methods capable of rapidly and gently extracting molecular species from aerosol particles.

[0009] Once separated from the aerosol particles, individual analyte molecular species can be characterized using a variety of analytical tools. Mass spectrometry is particularly effective for this purpose because it rapidly provides detailed molecular information about complex samples. An additional ionization step of the desorbed aerosol molecules is required for mass spectrometric analysis. Over the past 30 years, significant progress has been made in developing soft atmospheric pressure ionization methods suitable for real-time analysis

[18] .

[0010] In some scenarios, optical analysis of the desorbed aerosol molecules may also be beneficial.

[0011] Methods for aerosol particle analysis involve determining where these particles should be sampled, modified, and analyzed. In the case of mass spectrometers, one option involves transporting aerosol particles through a gas transport line near the mass spectrometer for ionization.

[19] Alternatively, ions can be generated remotely from the mass spectrometer and transported via an ion transport line.

[20]

[0012] While both methods are effective, practical considerations sometimes favor keeping ion generation separate from the mass spectrometer to reduce the need for frequent cleaning and maintenance of the mass spectrometer interface. However, in some cases, such as inductively coupled plasma (ICP) mass spectrometers, ion creation near the mass spectrometer is necessary due to the nature of the ionization process. Therefore, it is important to have an aerosol disruption device that offers flexibility in ion production location and transport configuration, allowing optimization based on various application requirements. Summary of the Invention

[0013] Aerosols consist of fine solid particles or liquid droplets suspended in a gas and can originate from natural or anthropogenic sources. For clarity, the term "aerosol particles" in this disclosure refers to both solid particles and liquid droplets. Typically, these particles range in size from 1 nm to 100 μm and include a variety of forms, such as laser plumes, fumes, smoke, bioaerosols, pollution particles, and other types found in environmental, medical, agricultural, and industrial contexts.

[0014] For analytical purposes, the term "sample aerosol particle" may be used to describe any aerosol particle ready for capture by an aspirator device. Aerosol particles are subject to various disintegration processes, and applicants define the specific outcomes of these processes for clarity. "Aerosol particle fragments" result from the breakage of an aerosol particle into smaller fragments, while "aerosol molecular species" refers to individual molecules or molecular clusters that detach from the aerosol particle or its fragments through collision, desorption, or dissolution. Aerosol particle fragments and aerosol molecular species, as well as collections of intact particles, are referred to as "aerosol material." Finally, when aerosol molecular species are charged, they are referred to as "aerosol ions."

[0015] The present disclosure centers on a method in which sample aerosol particles are introduced into a high-pressure gas stream, which is then directed toward a liquid volume. The impact of the gas causes nebulization, completely or partially breaking the liquid into droplets. During this nebulization, the aerosol particles undergo strong collisions with the liquid, leading to their partial or complete disintegration. The gas responsible for transporting the aerosol particles and facilitating nebulization is referred to as the "nebulizing gas."

[0016] When the pressure of the nebulizing gas within the conduit is sufficiently high (typically several bar), the mechanical forces generated during nebulization are substantial. In typical nebulizer devices used for liquid chromatography-mass spectrometry (LC-MS), the nebulizing gas can reach impact velocities of 100–300 m / s. Notably, the gas decelerates almost completely within just a few millimeters of the gas nozzle exit, primarily due to collisions with the liquid and subsequent turbulence

[21] . This rapid deceleration, on the order of 340,000 g, transfers sufficient momentum from the gas to the liquid to create a fine spray at velocities of up to approximately 1 mL / min. It is noteworthy that despite these violent collisions, individual molecules of liquid analytes in LC-MS typically remain intact during nebulization, since molecular fragmentation can result in the loss of original sample information. Nevertheless, controlled fragmentation during these collisions can be advantageous for extracting specific information in certain contexts. Because the degree of molecular fragmentation is coupled to the kinetic energy of the impact, adjusting the kinetic energy of the nebulizing gas allows us to tailor the degree of molecular fragmentation to suit specific analytical needs.

[0017] Nebulization offers the added advantage of stable performance over a wide range of parameters, a valuable attribute for analytical tools. Historically, nebulizing gases in analytical chemistry have been used only to nebulize liquid analytes, rather than transport the analyte itself. This technique is exemplified in devices such as mass spectrometers designed for pneumatically assisted electrospray ionization, as well as those based on inductively coupled plasma (ICP) ionization.

[0018] When the target liquid is a solvent, the nebulization process not only causes aerosol disintegration through collisions but also promotes partial or complete dissolution of aerosol particles and fragments upon contact with the liquid. This interaction leads to the desorption of individual molecules or molecular complexes from the aerosol particles and fragments due to solvation, thereby enhancing the disintegration of the aerosol particles. While the use of liquid aerosols to dissolve sample aerosols has been previously reported

[14] ,

[15] , the present disclosure offers the advantage of mixing the analyte aerosol material with a substantially larger volume of solvent in a more concentrated space. This results in vigorous mixing, similar to the disintegration observed in ultrasonic baths, due to the kinetic energy of the nebulization. For example, in laser ablation electrospray ionization (LAESI)

[14] , the mixing of the laser plume aerosol with the electrospray occurs over a distance of approximately 1 cm. 3 This occurs within a gas volume of 1000 times larger, requiring the laser ablation spot to be positioned at a distance for gentle mixing. Additionally, small liquid flow rates and precise geometric adjustments are necessary to maintain electrospray stability. In contrast, with the disclosed systems and methods, a similar volume of laser plume can potentially be mixed with 10 to 1000 times more liquid in a 10 to 100 times smaller volume, achieving more complete mixing due to the spraying process. This approach allows for greater efficiency and effectiveness in the mixing and analysis process.

[0019] In addition to solvation, other properties of liquids can be exploited to further enhance aerosol disintegration or molecular characterization of the aerosol. For example, the solvation rate can be improved by heating the liquid. Warmer liquids evaporate more quickly after nebulization, accelerating the analyte desorption process. However, it can be beneficial to maintain a sufficiently low temperature to prevent undesirable thermal alterations to the aerosol material.

[0020] Another potential advantage involves incorporating molecular labels into the liquid: these labels can specifically target aerosol molecular species during and after nebulization, facilitating more effective molecular detection and quantification.

[0021] Furthermore, the liquid may contain components that promote ionization of aerosol molecular species for mass spectrometric analysis. For example, the liquid may contain an easily ionizable substance, such as toluene, which can serve as a donor molecule in an atmospheric pressure photoionization (APPI) mass spectrometer. This approach offers two advantages: first, the donor substance is thoroughly mixed with the analyte aerosol material during nebulization; and second, the combination of the analyte material and the donor gas occurs within a confined space. This compact mixing can enhance ionization efficiency by allowing for more focused application of UV light.

[0022] Various nebulizer designs, such as those known in the art and listed in

[22] , are compatible with the disclosed embodiments, although specific designs may offer different advantages depending on the use case. For example, introducing nebulizing gas in parallel with the liquid conduit outlet can draw the liquid into the gas flow due to the Bernoulli effect, potentially enhancing the interaction between the aerosol material and the liquid. Modern electrospray ionization (ESI) nebulizers typically feature a liquid capillary concentrically positioned within the gas nebulizer capillary. Alternative configurations are possible in which the nebulizing gas capillary is positioned inside the liquid capillary

[22] ,

[23] . This inverse design may be particularly beneficial for our purposes if the aerosol particles are introduced through a central nebulizing gas capillary. In such a configuration, the majority of collisions between the aerosol particles and the liquid occur within the region surrounded by the liquid drawn into the gas flow. This leads to more violent collisions and better containment of the resulting aerosol particle fragments and aerosol molecular species.

[0023] In a preferred, but not exclusive, embodiment, the atomization of the liquid occurs in an ambient gas environment at or near standard atmospheric pressure.

[0024] For further aerosol disintegration, embodiments of the present disclosure can be configured in a cascade sequence. In this arrangement, aerosol particle fragments and aerosol molecular species output from one device become the input for a subsequent nebulizer for further disintegration. This cascade design is also useful for multiplexing chemical effects when different solvents are used in each nebulizer.

[0025] After being fragmented into smaller fragments, such as particle fragments or molecular species, these aerosol particle fragments and aerosol molecular species can be analyzed using a variety of analytical chemistry tools, including optical methods and mass spectrometry. For mass spectrometric analysis, the individual molecular species derived from the aerosol particles require ionization. This can be achieved through a variety of methods known in the art. The simplest method closely resembles that used in conventional pneumatically assisted electrospray ionization (ESI) devices, in which a charged liquid is nebulized. Here, the liquid is charged prior to nebulization, allowing the aerosol molecular species to acquire a charge, either directly during nebulization or subsequently as they are entrained into charged droplets that gradually disintegrate due to evaporation or Coulomb explosion, as in standard ESI processes. This results in the formation of analyte molecular ions. Other potential ionization methods include atmospheric pressure chemical ionization (APCI)

[21] , atmospheric pressure photoionization (APPI)

[18] ,

[21] ,

[24] , and direct photoionization

[25] .

[0026] Once ions are generated, they can be collected and directed into a mass spectrometer for detailed analysis. However, collecting ions under atmospheric conditions is difficult due to the significant influence of gas flow and electric fields on the ion trajectories. Consequently, in conventional ESI devices, ion collection efficiency often decreases as the nebulizing gas pressure increases, complicating the ion containment process

[21] . Any ion collection method familiar to those skilled in the art can be utilized. Ion funnels that operate effectively under atmospheric conditions are particularly advantageous. They can significantly enhance ion sensitivity and detection limits, potentially improving them by 15–100 times

[26] ,

[27] .

[0027] Suitable mass spectrometers for this application include any type known to those skilled in the art, with certain types being more appropriate for particular aerosol analyses. For biological aerosols, mass spectrometers supporting soft ionization methods are preferred. These include quadrupole mass spectrometers, time-of-flight (TOF) mass spectrometers, ion trap mass spectrometers, orbitrap mass spectrometers, triple quadrupole mass spectrometers, Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometers, and various hybrid systems. To investigate the submolecular composition of aerosols, techniques such as inductively coupled plasma mass spectrometry (ICP-MS) can be particularly useful.

[0028] Apart from mass spectrometry, aerosol fragments and molecular species can be examined using any other established analytical method, such as optical spectroscopy, well known to those skilled in the art. When dealing with aerosols of complex molecular composition, multiplexing a variety of complementary analytical methods can be advantageous. This strategy helps reduce data ambiguity, expands observation capabilities, overcomes individual technical limitations, improves quantitative accuracy, accelerates data acquisition and analysis, and supports data cross-validation.

[0029] Within the scope of this disclosure, two exemplary scenarios illustrate the significant benefits of using such an analysis multiplexing configuration.

[0030] First, combining mass spectrometry with vibrational spectroscopic imaging offers a powerful analytical approach when aerosol particles are sampled using a laser. Techniques such as spontaneous Raman imaging, stimulated Raman imaging (SRI), or coherent anti-Stokes Raman scattering (CARS) can be used to initially image the sample. These vibrational imaging methods excel at identifying chemical bond concentrations, characterizing molecular environments, and highlighting intermolecular interactions. While they may not match the molecule-specific discrimination capabilities of mass spectrometry, they complement it by providing additional sample attributes. For example, SRI can rapidly distinguish protein-to-lipid ratios and produce color maps similar to histology slides, thus providing insight into tissue morphology.

[28] Due to its inherent speed, noninvasiveness, and excellent spatial resolution, optical imaging is ideal for guiding target region selection for mass spectrometry or aiding in the interpretation of mass spectrometry data. Meanwhile, mass spectrometry excels at identifying and quantifying specific molecular biomarkers, a feat more challenging with vibrational imaging.

[0031] Another promising multiplexing technique is the combination of mass spectrometry with gas chromatography. Mass spectrometry coupled with liquid chromatography (LC-MS) is a proven method for analyzing complex samples

[29] , but its relative slowness can be a limitation in applications such as tissue imaging, environmental monitoring, or surgical biopsy. A faster alternative is integrated gas chromatography with mass spectrometry (GC-MS), a technique that has shown potential

[30] . In this setup, ions are first collected in an ion trap, then ejected into a gas-filled drift tube, and finally introduced into a time-of-flight mass spectrometer. Ions are separated based on their drift time through the gas tube and their time of flight, providing twenty-dimensional separation. Enhancements such as improved ion gating systems can further increase mass-to-charge resolution. This GC-MS technique may be particularly effective for aerosol samples from pulsed laser ablation, as the laser plume expansion and collection time (approximately 100 ms) matches well with the collection timing of the ion trap, presenting an opportunity for practitioners in the art to enhance the signal-to-noise ratio. The embodiments described in this disclosure are suitable for analyzing a wide range of aerosols, including, but not limited to, laser plumes, fumes, smoke, bioaerosols, pollution particles, natural dust, atmospheric aerosols, as well as pharmaceutical, medical, surgical, agricultural, and industrial aerosols.

[0032] Thus, in a first aspect, there is provided a system for performing at least partial disintegration of sample aerosol particles, comprising: a liquid source unit comprising a liquid conduit, the liquid conduit comprising a liquid conduit outlet, the liquid source unit configured to dispense liquid through the liquid conduit outlet; a pneumatic atomizer comprising a high pressure atomizing gas mechanism in gas flow communication with an atomizing gas conduit, the atomizing gas conduit comprising an atomizing gas conduit inlet and an atomizing gas conduit outlet, the atomizing gas conduit outlet being positioned adjacent the liquid conduit outlet to facilitate pneumatic atomization of the liquid exiting the liquid conduit outlet by contact with the high pressure atomizing gas exiting the atomizing gas conduit; an aspirator device comprising an aspirator conduit, the aspirator conduit comprising an aspirator conduit inlet and an aspirator conduit outlet, the aspirator device configured to generate suction suitable for drawing sample aerosol particles into the aspirator conduit through the aspirator conduit inlet; a gas coupler that provides a gas coupling between the aspirator conduit outlet and the nebulizing gas conduit inlet, thereby facilitating the introduction of aerosol particles into the high-pressure nebulizing gas stream, such that the nebulization process promotes collisions between the aerosol particles and the liquid, contributing to at least partial breakup of the aerosol particles; and A system is provided, comprising:

[0033] In some exemplary implementations of the system, the liquid includes a solvent configured to dissolve at least a portion of the aerosol material either during the atomization process, within the liquid droplets resulting from the atomization process, or during both stages.

[0034] In some exemplary implementations of the system, the gas coupler includes at least one gas compressor.

[0035] In some exemplary implementations of the system, the gas coupler includes at least one venturi pump.

[0036] In some exemplary implementations of the system, the gas coupler includes at least one device selected from the group consisting of a scroll compressor, a diaphragm compressor, a screw compressor, an axial compressor, a centrifugal compressor, a rotary vane compressor, a scroll pump, a diaphragm pump, a centrifugal pump, and a rotary vane pump.

[0037] In some exemplary implementations of the system, the system further comprises an additional gas source of additional gas in fluid communication with the gas coupler such that the additional gas is introduced into the atomizing gas conduit and mixed with the aerosol particles.

[0038] In some exemplary implementations of the system, the gas coupler comprises one of a gas compressor and a gas pump as a component, the fluid communication between the additional gas source and the gas coupler is configured to occur before the inlet of the gas compressor or the inlet of the gas pump, and the additional gas source comprises a valve to control the flow rate of the additional gas entering the gas coupler, thereby enabling adjustment of the intake pressure at the inlet of the aspirator.

[0039] In some exemplary implementations of the system, the gas coupler includes a component selected from the group consisting of a gas compressor and a gas pump, and fluid communication between the additional gas source and the gas coupler is established after the outlet of the gas compressor and the outlet of the gas pump, and the introduction of the additional gas into the atomizing gas conduit serves to increase the overall gas flow rate within the conduit.

[0040] In some exemplary implementations of the system, the system is configured such that the additional gas introduced into the nebulizing gas conduit is configured to advantageously enhance the breakup of aerosol particles during the nebulization process and / or to promote advantageous ionization of aerosol molecular species following nebulization.

[0041] In some exemplary implementations of the system, the system further comprises a filter incorporated within the gas coupler and configured to limit the size of aerosol particles that reach the nebulizing gas conduit outlet.

[0042] In some exemplary implementations of the present system, the filter integrated into the gas coupler is a cyclone filter.

[0043] In some exemplary implementations of the system, the system further comprises a check valve integrated within the gas coupler and configured to open only when gas within the gas coupler flows in a direction toward the atomizing gas conduit outlet.

[0044] In some exemplary implementations of the present system, the check valve integrated into the gas coupler is a Tesla valve.

[0045] In some exemplary implementations of the system, the system further comprises a rigid obstacle positioned within the gas coupler, the rigid obstacle configured to induce turbulence within the mixture of nebulizing gas and aerosol particles as they pass around the obstacle, the turbulence contributing to at least partial breakup of the aerosol particles within the mixture.

[0046] In some exemplary implementations of the system, the system further comprises a rigid obstacle located within the gas coupler and positioned in the path of the aerosol particles traversing the gas coupler, such that collision of the aerosol particles with the obstacle contributes to at least partial disintegration of the aerosol particles.

[0047] In some exemplary implementations of the system, the liquid source unit comprises a liquid reservoir and a liquid pump configured to transfer liquid from the liquid reservoir to the liquid conduit.

[0048] In some exemplary implementations of the system, the liquid pump in the liquid source unit is a syringe pump.

[0049] In some exemplary implementations of the system, the liquid conduit outlet and the atomizing gas conduit outlet are integrated into a nebulizer device of a type selected from the group consisting of a cross-flow nebulizer, a V-groove nebulizer, a thin film nebulizer, a parallel path nebulizer, an enhanced parallel path nebulizer, a Hildebrand grid nebulizer, and a flow blurring nebulizer.

[0050] In some exemplary implementations of the system, the liquid conduit and the atomizing gas conduit are concentrically positioned relative to one another near the liquid conduit outlet or the atomizing gas conduit outlet.

[0051] In some exemplary implementations of the system, the liquid conduit resides at least partially within the atomizing gas conduit.

[0052] In some exemplary implementations of the system, the atomizing gas conduit resides at least partially within the liquid conduit.

[0053] In some exemplary implementations of the system, the system further comprises a secondary gas source connected to a secondary gas conduit, the secondary gas conduit comprising a secondary gas conduit outlet positioned in close proximity to the liquid conduit outlet.

[0054] In some exemplary implementations of the system, the secondary gas is configured to aid in the atomization process of the liquid.

[0055] In some exemplary implementations of the system, the system further comprises a heater to preheat the secondary gas, such that upon mixing of the preheated secondary gas with the liquid droplets resulting from the spray, the preheated secondary gas contributes to accelerated evaporation of these droplets.

[0056] In some exemplary implementations of the system, the system further comprises a spray conduit, the spray conduit comprising a spray conduit inlet and a spray conduit outlet, the spray conduit being configured such that the spray conduit inlet encompasses most of the volume from which spraying occurs and such that the flow of spray gas advances the mixture of liquid droplets and aerosol material toward the spray conduit outlet.

[0057] In some exemplary implementations of the system, the system further comprises an infrared radiation source positioned to heat the liquid droplets produced by the spray, thereby contributing to their accelerated evaporation.

[0058] In some exemplary implementations of the system, the system is configured such that at least some aerosol molecular species are produced as a result of the nebulization process.

[0059] In some exemplary implementations of the system, the system further comprises an ionization source configured to ionize aerosol molecular species produced as a result of the nebulization process.

[0060] In some exemplary implementations of the system, the ionization source is an atmospheric pressure ionization source.

[0061] In some exemplary implementations of the present system, the ionization method used by the atmospheric pressure ionization source is selected from the group consisting of electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), atmospheric pressure photoionization (APPI), and direct photoionization.

[0062] In some exemplary implementations of the system, the ionization source comprises a high potential conductor electrode positioned in close proximity to the liquid in the liquid conduit so that the liquid volume exiting the conduit is charged, leading to the aerosol molecular species becoming charged either by acquiring a portion of the liquid's charge during nebulization, or by electrospray ionization if the molecular species are encapsulated in charged liquid droplets resulting from the nebulization process, or by both of these two processes.

[0063] In some exemplary implementations of the system, the system is configured so that the aerosol particle concentration at the nebulizing gas conduit outlet is time-dependent, and the high potential applied to the conductor electrode is pulsed, with such pulses synchronized with the temporal arrival of the aerosol particles at the outlet to optimize the charging process.

[0064] In some exemplary implementations of the system, the system further comprises a microstructured conductor, the microstructured conductor being in electrical contact with the conductor electrode and positioned such that the liquid is in intimate contact with the microstructured features of the microstructured conductor immediately prior to spraying, whereby these microstructured features increase the exposure of the liquid to the strong electric field and consequently promote more efficient charging of the liquid exposed to spraying.

[0065] In some exemplary implementations of the system, the ionization source is an atmospheric pressure chemical ionization (APCI) system that includes an auxiliary corona discharge source through which a portion of the generated aerosol molecular species pass and thereby acquire an electric charge through interaction with the corona discharge region.

[0066] In some exemplary implementations of the system, the ionization source is an atmospheric pressure photoionization (APPI) system that includes a donor substance that mixes with the aerosol molecular species during the nebulization process, after the nebulization process, or both, and the APPI system further includes a UV light source that ionizes molecules of the donor substance, and the donor substance molecules transfer their charge to the aerosol molecular species, thereby achieving ionization of these species.

[0067] In some exemplary implementations of the system, the donor material comprises gas generated from donor liquid components introduced into the liquid conduit that evaporates either during the nebulization process, after it, or at both stages, thereby facilitating the ionization process.

[0068] In some exemplary implementations of the present system, the APPI system is configured such that the donor gas is introduced as a component of the atomizing gas mixture through the atomizing gas conduit outlet, thereby becoming an integral part of the atomizing process.

[0069] In some exemplary implementations of the system, the ionization source is a light source configured to emit radiation capable of directly ionizing aerosol molecular species.

[0070] In some exemplary implementations of the system, the system further comprises an ion funnel positioned to intercept the generated aerosol ions, the electromagnetic field of the ion funnel effectively directing a significant portion of the aerosol ions towards the exit aperture of the ion funnel, thereby increasing ion collection efficiency.

[0071] In some exemplary implementations of the system, the system further comprises an ion transport conduit, the ion transport conduit comprising an ion transport conduit inlet and an ion transport conduit outlet, the ion transport conduit inlet positioned to capture ions exiting the exit hole of the ion funnel and facilitate the transfer of ions towards the ion transport conduit outlet, which is directly connected to the inlet of the mass spectrometer, thereby enabling efficient injection and subsequent analysis of the aerosol ions.

[0072] In some exemplary implementations of the system, the system further comprises a gas funnel positioned such that the aerosol material produced by the atomization process is efficiently guided into the gas funnel by the momentum of the atomization gas jet, ensuring that a significant amount of these particles are efficiently directed toward the exit hole of the gas funnel for subsequent processing or analysis.

[0073] In some exemplary implementations of the system, the system further comprises a transport conduit having a transport conduit inlet and a transport conduit outlet, the transport conduit inlet positioned to receive aerosol particles exiting the exit hole of the gas funnel, the transport conduit configured to efficiently transport these aerosol particles toward the transport conduit outlet, and the transport conduit positioned to facilitate subsequent analysis of the aerosol particles discharged from the gas funnel.

[0074] In some exemplary implementations of the system, the system further comprises a light source, wherein the transport conduit includes an optically transparent area, and the light source is positioned such that its emitted optical radiation passes through the optically transparent area to promote optical interaction with aerosol particle fragments and aerosol molecular species resulting from aerosol decay as they travel through the transport conduit.

[0075] In some exemplary implementations of the system, the system further comprises a photodetector positioned within or adjacent to the transport conduit, the photodetector configured to detect at least a portion of the optical radiation following its interaction with the aerosol particle fraction and aerosol molecular species.

[0076] In some exemplary implementations of the system, the system is further configured such that the interaction of the optical radiation from the light source with the aerosol particle fragments and aerosol molecular species involves one or more of the following processes: direct photoionization, photoexcitation, or photoscattering.

[0077] In some exemplary implementations of the system, the system is positioned such that atomization occurs in an ambient gas environment, the ambient gas being at or near atmospheric pressure.

[0078] In some exemplary implementations of the system, the system is configured such that the ambient gas is selected from the group consisting of air, nitrogen, argon, helium, xenon, carbon dioxide, and combinations thereof.

[0079] In some exemplary implementations of the system, the pneumatic atomizer is configured such that the atomizing gas is selected from the group consisting of air, nitrogen, argon, helium, xenon, carbon dioxide, and combinations thereof.

[0080] In some exemplary implementations of the present system, the pneumatic atomizer is configured such that the pressure of the atomizing gas in the atomizing gas conduit ranges from 1 to 50 bar.

[0081] In some exemplary implementations of the present system, the pneumatic atomizer is configured so that the volumetric flow rate of the atomizing gas in the atomizing gas conduit is in the range of 0.1 to 30 liters per minute.

[0082] In some exemplary implementations of the system, the liquid source unit is configured to maintain a liquid flow rate in the liquid conduit within the range of 1-3000 μL / min.

[0083] In some exemplary implementations of the system, the liquid solvent is selected from the group consisting of water, an organic solvent, an alcohol, methanol, ethanol, isopropanol, acetone, acetonitrile, dimethyl sulfoxide, chloroform, benzene, hexane, ethyl acetate, toluene, an ionic liquid, and mixtures thereof.

[0084] In some exemplary implementations of the system, the liquid source unit is configured so that the liquid exiting the liquid source contains chemicals that react favorably with at least a portion of the aerosol particle fragments and aerosol molecular species either during the spraying process, within the liquid droplets resulting from the spraying, or in both states.

[0085] In some exemplary implementations of the present system, the chemical agents include molecular labels that preferentially attach to a specific subset of aerosol molecular species, thereby facilitating analysis of that subset.

[0086] In some exemplary implementations of the system, the molecular label is selected from the group consisting of an enzyme, biotin, a Halo tag, a SNAP tag, a nanoparticle, an optical fluorescent label, a Raman label, a luminescent label, a radioisotope, a gold particle, a magnetic label, a quantum dot, a metal ion, or a combination thereof.

[0087] In some embodiments, a system is provided comprising a first subsystem and a second subsystem, each subsystem configured as described above, and the first subsystem positioned relative to the second subsystem such that aerosol material output from the first subsystem is utilized as input aerosol material for the second subsystem.

[0088] In some exemplary implementations of the system, the system further comprises a laser system capable of generating sample aerosol particles through laser ablation of the sample, the aerosol particles being expelled from the sample as a plume.

[0089] In some exemplary implementations of the present system, the laser system operates at one or more wavelengths ranging from 100 nm to 12 μm.

[0090] In some exemplary implementations of the present system, the laser output of the laser system is pulsed, with each laser pulse having a duration ranging from 10 femtoseconds to 1 millisecond.

[0091] In some exemplary implementations of the system, the laser system is a component of a surgical device.

[0092] In some exemplary implementations of the system, the laser system is a component of a tissue imaging device.

[0093] In some exemplary implementations of the system, the system further comprises an imaging device configured such that prior to laser ablation, the sample is imaged using the imaging device to provide data used for selection of a laser sampling spot or to provide additional information about the sample to enhance analysis of the sample aerosol particles.

[0094] In some exemplary implementations of the system, the imaging device is a vibration imaging device.

[0095] In some exemplary implementations of the system, the vibration imaging device employs an imaging modality selected from the group consisting of Raman imaging, stimulated Raman scattering (SRS) imaging, coherent anti-Stokes Raman scattering (CARS) imaging, infrared imaging, and combinations thereof.

[0096] In some exemplary implementations of the system, the system further comprises an optoacoustic imaging device configured such that prior to laser ablation, the sample is imaged using the optoacoustic imaging device to provide data that guides the determination of the laser sampling spot position or to provide additional information about the sample to complement the analysis of the sample aerosol particles.

[0097] In some exemplary implementations of the system, the system further comprises an optical coherence tomography (OCT) device configured to image the sample using the OCT device prior to laser ablation to provide data to assist in determining the location of the laser sampling spot or to provide additional information about the sample to assist in the analysis of the sample aerosol particles.

[0098] In some exemplary implementations of the system, the system further comprises an electrosurgical device configured to generate sample aerosol particles through contact with the biological tissue.

[0099] In some exemplary implementations of the system, the system further comprises a mass spectrometer positioned to receive ions generated from the aerosol particles, allowing the mass spectrometer to analyze the ions, thereby providing information regarding the chemical composition of the sample aerosol particles collected by the aspirator device.

[0100] In some exemplary implementations of the system, the mass spectrometer includes an ion drift tube filled with a buffer gas, the ion drift tube having an ion drift tube inlet and an ion drift tube outlet, an ion trap in ionic communication with the ion drift tube inlet, and an ion gating mechanism located at the ion drift tube outlet for regulating ion ejection, the ion trap accumulates aerosol ions and periodically releases them into the ion drift tube, ion transit times through the ion drift tube depend on ion gas mobility within the buffer gas, and the mass spectrometer measures the mass-to-charge ratio of ions exiting the ion drift tube.

[0101] In another aspect, a method for analyzing aerosol particles is included, the method including providing at least partially disintegrated aerosol particles using a system as described above, and detecting and analyzing the at least partially disintegrated aerosol particles using an analysis system.

[0102] In some exemplary implementations of the method, the analytical system comprises a mass spectrometer.

[0103] In some exemplary implementations of the method, the aerosol particles are collected by an aspirator device, and the at least partially disintegrated aerosol particles contain ions that are subsequently analyzed by a mass spectrometer.

[0104] In some exemplary implementations of the method, at least some of the sample aerosol particles have diameters in the range of 1 nanometer to 100 micrometers.

[0105] In some exemplary implementations of the method, the sample aerosol particles are generated from in vivo biological tissue.

[0106] In some exemplary implementations of the method, the sample aerosol particles are generated from ex vivo biological tissue.

[0107] A further understanding of the functional and advantageous aspects of the present disclosure can be realized by reference to the following detailed description and drawings. [Brief explanation of the drawings]

[0108] Embodiments are now described with reference to the accompanying drawings, in which like reference numbers may indicate identical or functionally similar elements.

[0109] [Figure 1] FIG. 1 illustrates a system for disintegrating aerosol particles, featuring an aspirator conduit to draw in particles, a gas coupler for fluid transfer, an atomizing gas conduit with high-pressure gas for mixing, and a liquid source for collision-induced atomization and particle disintegration near the exit. [Figure 2] FIG. 10 illustrates a scenario in which a pressure intensifier is integrated into the system to increase the gas pressure inside the atomizer gas conduit. [Figure 3] FIG. 10 illustrates the layout of an embodiment with a passive intensifier featuring a gas source supplying motif gas to the intensifier through a conduit, with the option for the source to be a pressure vessel or gas compressor. [Figure 4] FIG. 10 illustrates a passive intensifier design in which gas flows through a constricted area of ​​a T-connector, entraining aerosol particles via the Bernoulli effect and resulting in a mixed flow exiting into the gas coupler outlet. [Figure 5] FIG. 10 illustrates an alternative design of a passive intensifier using the Venturi effect, whereby the motif gas and aerosol particles are drawn together at high velocity through a constricted outlet, resulting in their mixture being expelled to the gas coupler outlet. [Figure 6]FIG. 10 depicts a system having two pressure intensifiers in series within a gas coupler for increasing pressure between the aspirator inlet and the nebulizing gas conduit outlet. [Figure 7] A diagram showing an alternative embodiment in which an auxiliary gas source, either a pressure vessel or a compressor, is integrated in parallel with the gas coupler booster through an additional gas coupler to increase the flow rate of the spray gas at the outlet of the sprayer conduit. [Figure 8] FIG. 8 presents the design of the additional gas coupler introduced in FIG. 7, in which an auxiliary gas conduit integrates with the outlet of the main gas coupler, featuring a concentric arrangement for efficient aerosol particle incorporation and pressure alignment. [Figure 9] FIG. 10 illustrates the enhancement of aerosol particle breakup in a gas coupler through the placement of a hard surface within the coupler, where high velocity particles collide and partially break up at the end of the conduit. [Figure 10] FIG. 10 depicts an embodiment with an obstruction or constriction in the gas coupler that alternates between gas and aerosol particles to create high Reynolds number flow and turbulence, leading to the breakup of softer particles for pre-spray breakup. [Figure 11a] FIG. 1 illustrates a linear aspirator conduit design that offers vast versatility for sampling aerosols over a fairly large spatial area. [Figure 11b] FIG. 10 presents an aspirator conduit with an enlarged tip for targeted sampling at specific locations where aerosol particles are concentrated. [Figure 11c] FIG. 10 depicts an aspirator inlet split into multiple sub-inlets that merge into a main conduit, optimal for efficient capture in scenarios with limited aerosol yield. [Figure 12] FIG. 10 illustrates an embodiment with an additional gas source, either a pressure vessel or compressor, integrated to allow customization of aspirator inspiratory pressure, featuring a valve-controlled intermediate conduit for precise control and optimization of aspirator performance. [Figure 13]FIG. 13 shows an exemplary design for the secondary gas coupler from FIG. 12 in which the intermediate conduit outlet merges with the aspirator conduit inlet in a concentric arrangement to ensure efficient incorporation of aerosol particles into the gas flow. [Figure 14] FIG. 1 illustrates the configuration of the liquid source in the system, which includes two main components for precise delivery of liquid substances to the liquid conduits: a liquid reservoir and a liquid pump. [Figure 15a] FIG. 10 illustrates a particular embodiment using a concentric atomizer, where the atomizing gas conduit is concentric with and encases the liquid conduit within the housing unit. [Figure 15b] FIG. 15b is a front view of the atomizer illustrated in FIG. 15a, emphasizing the concentric arrangement of the atomizing gas conduit with the liquid conduit inside and clarifying the spatial relationship between the atomizer elements. [Figure 16a] FIG. 1 presents an alternative concentric nebulizer design in which the nebulizing gas capillary is inside the liquid capillary and an additional housing unit encloses both, enhancing aerosol particle breakup by maximizing collision impact with the liquid. [Figure 16b] FIG. 1 is a front view of this nebulizer configuration detailing the spatial interrelationships between components and showing a gas capillary within a liquid capillary for improved dissolution efficiency of aerosol material. [Figure 17a] FIG. 10 demonstrates a nebulizer design with a positive offset between the liquid and nebulizing gas capillaries, which affects nebulization efficiency, particle-liquid interaction, and ionization effectiveness. [Figure 17b] FIG. 10 illustrates a nebulizer configuration with a neutral offset that balances efficiency, aerosol-liquid interaction strength, and ionization effects of aerosol molecular species. [Figure 17c] FIG. 1 depicts a nebulizer design with a negative offset where the nebulizer gas conduit outlet is embedded within the liquid capillary, affecting overall nebulizer efficiency and aerosol particle-liquid interaction. [Figure 18a]FIG. 10 illustrates an embodiment involving hot gas reforming in which dry nitrogen is introduced through an outer concentric conduit around the liquid conduit and merges into the atomizing gas jet near the atomization region to accelerate droplet evaporation. [Figure 18b] FIG. 18b is a front view of the atomizer from FIG. 18a highlighting the spatial relationships and interactions of the hot gas, atomizing gas, and liquid within the assembly for an enhanced visual understanding of the system dynamics. [Figure 19] 1A-1C illustrate common configurations of hot gas conduits delivering hot gas to the atomization region, showcasing different geometries possible for the atomization region. [Figure 20] FIG. 1 depicts the use of an infrared lamp to heat liquid droplets to promote accelerated evaporation, emphasizing the alignment of the lamp's infrared wavelength with the liquid's optical absorption peak to enhance heating efficiency. [Figure 21a] FIG. 10 presents a "spray conduit" designed to direct the expanding nebulizer gas and aerosol material toward its outlet, trapping the aerosol material within the conduit and enhancing analyte retention. [Figure 21b] FIG. 1 depicts a spray conduit embodiment with an enlarged cross-section outlet designed to promote laminar flow of gas carrying aerosol material for stable aerosol integration into analytical equipment. [Figure 21c] FIG. 10 shows a spray conduit design with a concentric hot gas conduit featuring perforations in the spray conduit to allow hot gas to penetrate inside the spray conduit, thus enhancing evaporation of spray droplets and preventing droplet accumulation on the inner wall of the spray conduit. [Figure 22] FIG. 1 illustrates the integration of ESI ionization in a design featuring a conductor and a high voltage source in contact with the liquid in a liquid conduit, leading to ionization of aerosol molecular species generated due to nebulization. [Figure 23]FIG. 1 depicts an improved design of the liquid conduit outlet in a concentric nebulizer, featuring a high-potential stainless steel inner capillary with microfabricated channels to increase the surface area for electrochemistry and thereby improve the efficiency of liquid charging and ionization of aerosol molecular species. [Figure 24] FIG. 1 presents a solution for joining a grounded gas coupler with a high-pressure sprayer gas conduit, featuring a gap larger than the dielectric breakdown distance for safe operation and a grounded conductor through the ceramic interface to ensure effective aerosol particle injection. [Figure 25] FIG. 1 illustrates the integration of APCI into a design featuring a corona discharge needle connected to a high voltage source positioned to ionize aerosol molecular species as they pass through the corona region. [Figure 26] FIG. 1 shows a simplified embodiment for APPI integration in which a donor gas mixed with aerosol molecular species is exposed to UV light from a UV lamp, ionizing the donor gas, which then transfers its charge to the aerosol species, leading to their ionization. [Figure 27] FIG. 1 depicts the integration of an ion funnel into the present system, which effectively directs aerosol ions formed during nebulization through the exit hole of the ion funnel and into the ion guiding conduit, significantly increasing ion collection efficiency for the mass spectrometer under atmospheric conditions. [Figure 28] FIG. 1 illustrates the use of a simple gas funnel to collect neutral aerosol particle fractions and aerosol molecular species produced during nebulization, where the funnel, with its collection cone and gas flow, directs the aerosol particle fractions and aerosol molecular species towards its holes and through a conduit for analysis. [Figure 29] FIG. 1 presents an optical excitation setup for aerosol particles in a conduit, featuring an optically transparent window for the passage of radiation from an external source and signal capture by an external device, facilitating detailed optical analysis. [Figure 30]FIG. 10 demonstrates a typical setup for analyzing aerosol from a laser plume, in which a sample undergoes laser ablation to create a plume from which aerosol particles are captured and transported to an analysis system as described in the present invention for processing into ions for mass spectrometry. [Figure 31] FIG. 31 illustrates a variation of the setup in FIG. 30 featuring a sample mounted on a motorized translation stage for multi-point sampling, allowing analysis of the laser plume at different locations and determination of the spatial distribution of molecular species within the sample. [Figure 32] FIG. 31 shows an alternative variation of the setup in FIG. 30 in which the laser light is directed to the sample via an optical fiber, and the output of the fiber and the aspirator inlet are combined into a single ergonomically designed housing unit suitable for handheld use. [Figure 33] FIG. 31 illustrates a scenario in which an electrosurgical tool is used to aerosolize a biological tissue sample, and the resulting aerosol is then analyzed using the system outlined in the context of FIG. 30. [Figure 34] FIG. 10 illustrates that a system incorporating one or more embodiments of the present invention generates ions from sample aerosol particles collected through an aspirator conduit, with ion generation occurring near the orifice of a mass spectrometer, which then collects and analyzes these ions. DETAILED DESCRIPTION OF THE INVENTION

[0110] The following description and accompanying drawings provide an overview of various embodiments and aspects of the present disclosure. These illustrations are intended to be illustrative rather than limiting, and the drawings are not necessarily to scale. Detailed descriptions are included to ensure a comprehensive understanding of the embodiments. However, in some cases, commonly known or standard details may not be described in detail in order to maintain a concise and focused presentation of the present disclosure.

[0111] As used herein, the terms "incorporate," "comprise," and "comprising," along with variations thereof, are to be understood as inclusive and open-ended. They indicate that specified features, steps, or components are included, but do not exclude the potential inclusion of other features, steps, or components.

[0112] Furthermore, the articles "a" and "an" are used herein to refer to "at least one" or "one or more," unless otherwise indicated.

[0113] Additionally, the term "and / or," when used between two terms A and B, indicates that either A, B, or both A and B may be present in a given context.

[0114] In the context of this document, the terms "including" and "having" are synonymous with "comprising."

[0115] The word "exemplary" as used herein means "serving as an example, instance, or illustration." It should be noted that this term does not imply preference or superiority over other configurations described in this disclosure.

[0116] Additionally, "exemplary" and "typically," when referring to elements, systems, or behavior within an embodiment, indicate that such elements, systems, or behaviors are commonly present in various instances of that embodiment. However, these terms do not imply that such elements, systems, or behaviors are preferred or advantageous over other configurations presented herein.

[0117] In this disclosure, the terms "about" and "approximately," particularly when associated with ranges of particle sizes, mixture compositions, or other physical properties and characteristics, are intended to accommodate slight variations in the upper and lower limits of those ranges. This use ensures that embodiments that generally meet these dimensions on average but may contain statistical outliers are not excluded from the scope of the disclosure.

[0118] In this document, unless otherwise stated, "disintegration" is defined as "at least partial disintegration" and similarly, "disintegrate" is to be understood as "at least partial disintegration."

[0119] Furthermore, the terms "gas compressor" and "pump" are used in their conventional sense as commonly understood in the art. A compressor refers to a mechanical device that increases gas pressure by reducing the volume of the gas. Conversely, a pump is defined as a device that moves a fluid, either a liquid or a gas, from its inlet to its outlet, and is primarily used to facilitate fluid movement through various conduits.

[0120] In this disclosure, "atomization" refers to the process of breaking up a volume of liquid into smaller droplets, facilitated by the pneumatic action of a high-pressure gas.

[0121] Additionally, "conduit outlet" or "conduit outlet" includes all outlets within a conduit having multiple outlets, unless otherwise specified.

[0122] Similarly, "a conduit inlet" or "a conduit inlet" includes all inlets within a conduit having multiple inlets, unless otherwise specified.

[0123] In the context of the present disclosure, characterizing aerosol particles encompasses a variety of techniques and methods aimed at identifying and understanding various properties and aspects of aerosol particles. This process may include, but is not limited to, any one or combination of the following: determining their physical, mechanical, and chemical properties; assessing their chemical composition and molecular structure; quantitatively measuring the concentration or amount of specific substances within the particles; and qualitatively determining the presence or absence of specific compounds within the particles. The particular characterization method used may be selected based on the particular requirements or objectives of the analysis, allowing for personalized investigation of aerosol particles.

[0124] FIG. 1 illustrates a simple embodiment of a system for the disintegration of sample aerosol particles. The process begins by drawing sample aerosol particles 108 into an aspirator conduit 112 through an aspirator conduit inlet 110. Within this conduit, the aerosol particles, designated 114, are conveyed toward a gas coupler, designated 118. The gas coupler 118 features an interface, designated 116, that establishes fluid communication between the aspirator conduit 112 and the gas coupler 118. An additional interface, designated 120, on the gas coupler 118 facilitates fluid communication between the gas coupler 118 and the inlet of an nebulizing gas conduit, designated 122, which is filled with high-pressure nebulizing gas. The primary function of the gas coupler 118 is responsible for introducing the aerosol particles 114 from the aspirator conduit 112 into the high-pressure nebulizing gas stream within the nebulizing gas conduit 122. The resulting mixture, including aerosol particles and high pressure atomizing gas, shown as 124 , is then emitted from atomizing gas conduit 122 through its outlet, designated as 126 .

[0125] In a separate embodiment of the system, a liquid source identified as 100 provides a liquid marked 104 to a liquid conduit designated 102. This liquid 104 is expelled from liquid conduit 102 through its outlet, labeled 106.

[0126] The outlet 106 of the liquid conduit 102 is strategically positioned proximate to the outlet 126 of the atomizing gas conduit 122, allowing the high-pressure mixture 124 exiting the outlet 126 to intersect with the liquid dispensed from the outlet 106. The interaction of the mixture 124 with the ejected liquid leads to atomization of the liquid within a designated atomization space, shown as 128, proximate the outlets 106 and 126. This collision significantly contributes to the partial disintegration of the aerosol particles, which represents the primary objective of this disclosure.

[0127] Furthermore, if the liquid acts as a solvent and the aerosol material is soluble, a portion of the aerosol material may dissolve in the liquid during their interaction in the atomization process. Additionally, some aerosol material may become entrained in the liquid droplets exiting the atomization space 128 and may be partially dissolved therein. Generally, this dissolution process may contribute to the desired breakup of the aerosol particles.

[0128] The atomization process is typically enhanced after primary collisions through turbulence of the atomizing gas within the atomization space 128, which causes the formed droplets to collide with each other and with the aerosol material. These secondary collisions can contribute both to the breakup of the droplets into even smaller droplets and to further disintegration of the aerosol material.

[0129] The efficiency of the aerosol break-up process can be optimized by optimizing various parameters of the nebulization process, including, but not limited to, the specificity of the liquid utilized, its flow rate, the type of gas used for nebulization, and its flow rate and pressure.

[0130] Additionally, the design features of the outlets referenced as 106 and 126 in FIG. 1 are relevant. In particular, the strategic positioning of outlet 126 relative to outlet 106 is important. An exemplary configuration is such that high-velocity gas exiting outlet 126 induces a low-pressure zone adjacent to liquid outlet 106, in accordance with Bernoulli's law. This phenomenon effectively promotes liquid entrainment in the gas stream, thereby encouraging two-way collisions between the liquid and aerosol material. Furthermore, the efficiency of the atomization process is further increased by restricting the extent of atomization space 128. Such a restriction serves to maintain elevated gas pressure and turbulence for a long duration, while simultaneously ensuring that both the liquid droplets and the aerosol material undergo a higher frequency of collisions within the confined space.

[0131] The general underlying principles of the nebulization process are well known to those skilled in the art. This knowledge allows for the adaptation of numerous existing nebulizer designs to incorporate specific features, such as outlets 106 and 126, characterized by their geometric configuration, material composition, and respective spatial relationships. Additionally, these designs may incorporate designated chambers to precisely define the boundaries of the nebulization space, designated region 128. Particular nebulizer designs may exhibit preferential compatibility with specific applications. The process of identifying the most appropriate nebulizer design and fine-tuning the operating parameters of the nebulization process can be effectively guided by employing various diagnostic techniques well known to those skilled in the art. These techniques include laser diffraction spectroscopy, phase Doppler particle analysis, and high-speed imaging. Furthermore, testing the properties of the aerosol material after nebulization serves as a tool for both characterizing and enhancing the nebulization process.

[0132] As used herein, the term “aerosol transport” means transporting aerosol particles from the inhalator inlet 110 to the outlet 126 of the nebulizer conduit 122 .

[0133] As used herein, the term "aerosol collection" means collecting the aerosol particle fractions and aerosol molecular species created during and after a nebulization event and directing these aerosol particle fractions and aerosol molecular species towards an analytical device where analysis of these aerosol particle fractions and aerosol molecular species occurs.

[0134] The liquid source 100 may include various elements required to supply the appropriate liquid at the appropriate flow rate to the liquid conduits. The liquid source may include one or several liquid reservoirs, one or several liquid pumps, a liquid mixer, a liquid heater, various liquid conduits, and various liquid couplers.

[0135] In some cases, the sample aerosol particles may initially be in a gas environment with a pressure great enough to push against the aerosol particles inside the aspirator, causing them to move toward the nebulizer conduit outlet 126 and cause nebulization without any active element in the gas coupler, in which case the gas coupler may just be a simple tubing adapter or connector.

[0136] However, in many cases of interest, it may be beneficial to increase the gas pressure at the outlet of the nebulizer gas conduit relative to the gas pressure at the aspirator inlet to achieve successful nebulization.Typical nebulizer gas pressures are in the range of 2-10 bar, while sample aerosol particles are typically sampled from environments with pressures approaching standard atmospheric pressure of 1 bar.

[0137] This more realistic scenario is illustrated in Figure 2. Here, gas coupler 118 from Figure 1 splits into a pressure intensifier 134 connected to interface 116 through gas coupler inlet conduit 132 and to interface 120 through gas coupler outlet conduit 136. Other elements in Figure 2 have the same annotations and meanings as in Figure 1.

[0138] An intensifier can be any device for increasing pressure within a gas delivery system known to those skilled in the art. Examples are mechanical devices such as gas compressors or passive devices such as venturi pumps. By their nature, intensifiers draw gas into their inlet, so they naturally provide the inspiratory pressure at the aspirator inlet, in this case the present invention.

[0139] Among mechanical gas compressors, scroll compressors may be a good choice because there are already commercially available medical OEM models used for surgical smoke evacuation. These models are oil-free and made with extreme tolerances to avoid gas leakage and noise. Scroll pumps may have the added benefit of creating turbulence during the compression process, which can aid in aerosol particle breakup. In some other cases, embodiments involving diaphragm compressors or some other mechanical gas compressor types may be more beneficial.

[0140] In some cases, passive intensifiers can be advantageous due to their simplicity and reduced interaction between the intensifier and the aerosol particles. Most known passive intensifiers are based on the Venturi effect. Such devices create a negative pressure by forcing the motif gas through a constricted section of a pipe or tube, so that the velocity of the motif gas increases and, at the same time, its pressure decreases according to Bernoulli's law. This negative pressure can be used to draw gas with aerosol particles from the aspirator into the motif gas stream.

[0141] Due to the typically high pressure of the nebulizing gases, only a mixture of these gases and aerosol particles can enter the nebulizing gas conduit with sufficient kinetic energy to effect nebulization.

[0142] The general layout of an embodiment involving a passive intensifier is shown in Figure 3. This layout includes a gas source 140 that supplies motif gas 142 to a motif gas conduit 144 that is in fluid communication with a passive intensifier 139 through an interface 146. The source 140 can be a pressure vessel or a gas compressor. Other elements in Figure 3 have the same annotations and meanings as in Figure 2.

[0143] 4 shows a potential design for a passive intensifier 139. After entering the intensifier 139, the motif gas 142 flows through a constricted section 148 of a T-connector 147, which also has another inlet 149 in fluid communication with the inlet 132 through which the aerosol particles 150 enter. Due to the negative pressure in the constricted section 148 created through the Bernoulli effect, the aerosol particles 150 are drawn into the flow of the motif gas 142, and the mixture of motif gas and aerosol particles 152 exits the intensifier 139 and enters the gas coupler outlet 136.

[0144] Another potential design for a passive intensifier based on the Venturi effect is shown in FIG. 5. In this case, the motif gas conduit 144 is coupled into the passive intensifier 139 through a pipe 154 with a narrowed outlet 156 through which the motif gas exits at high velocity. The conduit 132 carrying the aerosol particles 150 is coupled to another pipe 158, whose outlet 160 is located near the outlet 156. Due to the Venturi effect near the outlet 156, the gas carrying the aerosol particles in the pipe 158 is drawn into the motif gas flow exiting the outlet 156. Both outlets 156 and 160 are enclosed by a conduit 162, the rear end 164 of which is sealed. Finally, the mixture of motif gas and aerosol particles 152 is released into the gas coupler outlet 136.

[0145] If a large pressure jump is required between the aspirator inlet and the outlet of the nebulizing gas conduit, it may be advantageous to add two intensifiers in series within the gas coupler, as shown in Figure 6. In this case, the outlet of the first intensifier 172 is in fluid communication 176 with the inlet of the second intensifier 174. Other elements in Figure 6 have the same annotations and meanings as in Figure 2. The intensifier types may be those discussed above. The design principles of adding two intensifiers in series are known to those skilled in the art.

[0146] In an alternative embodiment for increasing the flow rate of atomizing gas at the exit point of the atomizing gas conduit, a supplemental gas source is incorporated in a parallel configuration with the gas coupler's intensifier. This concept is depicted with reference to FIG. 7, where a gas source, labeled 180, which can be either a pressure vessel or a gas compressor, is designed to establish fluid communication with the gas coupler's outlet 136. This connection is facilitated through an additional gas conduit identified as 182. The integration of the gas source into the system is achieved by an additional gas coupler, labeled 184. This arrangement allows for the introduction of gas from the supplemental source 184 into the pre-existing gas flow emanating from the intensifier 134, thereby increasing the gas flow rate at the discharge point of the atomizer conduit. Note that the other elements presented in FIG. 7 retain the same design and meaning as those detailed in FIG. 2.

[0147] FIG. 8 depicts a possible embodiment for an additional gas coupler 184, as previously introduced in FIG. 7 . Within this additional gas coupler 184, the auxiliary gas conduit 182 seamlessly integrates with the outlet 136 of the main gas coupler. A notable feature of this design is the configuration of the terminal segment 190 of the conduit 186, which connects the output of the intensifier to the input of the additional gas coupler. This terminal segment 190 is strategically positioned to be concentric with and confined within the outlet 136 of the main gas coupler. Such an arrangement ensures that the auxiliary gas envelops the terminal 190 of the conduit 186, thereby facilitating the efficient incorporation of aerosol particles exiting the conduit 186 into the flow within the conduit 136. Design specifications require that the pressure of the auxiliary gas surrounding the terminal end of the conduit 186 closely match the internal gas pressure at the terminal end 190 of the conduit 186. Note that the principles governing the design of gas sources in a parallel configuration are commonly understood by those skilled in the art.

[0148] The additional gas introduced as depicted in Figure 7 can provide benefits that extend beyond a small increase in flow rate in the nebulizing gas conduit. This gas plays an active role in the nebulization process, and due to its intimate mixing with the resulting aerosol material, its chemical composition can be specifically selected to facilitate analysis of the aerosol molecular species produced by nebulization. For example, the selected gas can function as a charge donor during atmospheric pressure photoionization (APPI) of the aerosol molecular species.

[0149] In further embodiments, additional components may be incorporated into the main gas coupler, not limited to the intensifier, to enhance aerosol analysis, simplify maintenance, or enhance the user experience.

[0150] One such example is the integration of a particle filter within a gas coupler. This filter is designed to selectively allow aerosol particles of a specific size to pass through, effectively blocking larger particles. The use of cyclone filter designs is particularly advantageous in this context. Their non-contact sorting mechanism and the ease they offer in disposing of the filter material make them highly suitable. Cyclone filters are generally configured for the control and removal of particulate matter with a diameter greater than 10 micrometers, consistent with one of the envisioned application scenarios.

[0151] In a further embodiment of the present disclosure, the gas coupler may incorporate a check valve, which is particularly advantageous in scenarios where a significant pressure differential exists between the nebulizing conduit outlet and the aspirator inlet. Such inclusion addresses potential complications arising from gas path obstruction that would otherwise cause high-pressure gas to reverse its direction and return to the aspirator inlet, thereby disrupting the procedure. A preferred embodiment of this check valve utilizes a Tesla valve. Its elegantly simple yet highly effective design is characterized by the absence of moving parts, thus increasing reliability and reducing maintenance requirements in the context of the present disclosure.

[0152] Other standard features known to those skilled in the art, such as vents, safety valves, flow meters, pressure gauges, etc., can be added to the gas coupler to control and characterize the aerosol flow through the gas coupler.

[0153] In the present disclosure, atomization serves as the primary method for aerosol particle disintegration, but it may be beneficial to initiate a preliminary phase of aerosol disintegration in the gas coupler prior to the main atomization process. This preliminary disintegration phase is particularly advantageous when the aerosol contains larger sized particles. By promoting an initial reduction in particle size, this pre-atomization disintegration stage ensures the provision of smaller particles for the subsequent main atomization event. Such a process is designed to increase the overall efficiency of particle disintegration, resulting in a more uniform and effective final aerosol composition.

[0154] A straightforward approach to enhancing aerosol particle breakup within a gas coupler involves strategic placement of a hard surface within the gas coupler, as depicted in FIG. 9 . Aerosol particles 196 being advanced from the intensifier traverse a conduit 194. These particles are then accelerated toward a narrowed end 198 of the conduit 194, which has an outlet 200 conveniently positioned within the gas coupler's outlet 136. In close proximity to the outlet 200, a hard surface is strategically located within the outlet conduit 136. This surface acts as an interceptor for the high-velocity aerosol particles exiting the outlet 200. The positive collision of the particles with the hard surface results in their partial breakup. The broken-up aerosol material 204 then continues its passage through the gas coupler's outlet conduit 136.

[0155] Notwithstanding the foregoing, it should be noted that collisions of aerosol particles with hard surfaces, as previously discussed, can present drawbacks, such as the adhesion of particle residue to the hard surface. This can result in diminished signal strength and potential signal contamination. To mitigate these issues, particularly in scenarios where the aerosol particles are of softer structure, an alternative embodiment for pre-spray breakup is proposed and illustrated in FIG. 10 . In this embodiment, an element such as an obstacle 208 or constriction is strategically incorporated into the gas coupler. This configuration is designed to modify the path of the gas carrying the aerosol particles around the obstacle or through the constriction. Such an arrangement induces a flow characterized by a high Reynolds number, leading to the generation of turbulence. Assuming the turbulence is of sufficient intensity, it can effectively break up a portion of the softer aerosol particles, thereby achieving the desired pre-spray breakup. The roles and annotations of the other elements in FIG. 10 are equivalent to those from FIG. 2 .

[0156] 2, the aspirator conduit 112 is characterized as a passive component that functions primarily to facilitate the entry of sample aerosol particles into its inlet by suction, subsequently transporting these particles to the gas coupler. Despite its passivity and the absence of active elements within its structure, certain characteristics of the aspirator conduit—such as its material composition, geometric design, and applied suction pressure—play a central role in influencing the efficiency of aerosol sampling. Consequently, these factors have a significant impact on the overall effectiveness of the aerosol analysis process.

[0157] The construction of the aspirator conduit should utilize materials that are chemically inert with respect to aerosol particles. Typically, but not exclusively, materials such as stainless steel, Teflon, and PEEK (Polyether Ether Ketone) plastic are preferred in these applications for their inert properties. Additionally, regulating the temperature of the aspirator conduit has been found to be advantageous in minimizing interaction between the aerosol and the conduit's surface. This can be achieved by positioning heating and cooling elements in close proximity to the conduit. An exemplary implementation of this strategy involves maintaining the conduit's temperature significantly above the dew point to prevent surface condensation.

[0158] The geometric configuration of the aspirator conduit plays a role in its functionality. This includes the design of the aspirator conduit's inlet and the specific cross-sectional area of ​​both the conduit and its inlet. Among other things, a reduced cross-sectional area within the conduit contributes to an increased velocity of gas passing therethrough. This acceleration helps reduce aerosol particle adhesion to the conduit's inner surface, as the rapid gas flow facilitates their removal. Conversely, an excessively small cross-sectional area can lead to circulating obstructions within the conduit, requiring more frequent maintenance. Additionally, in certain cases, gas velocity at the inlet can become excessively high due to significant intake pressure. In such scenarios, it can be beneficial to integrate vents along the conduit wall. These vents are designed to draw in additional gas, thereby reducing the gas velocity at the inlet.

[0159] Various illustrative, but non-limiting, geometric configurations for the aspirator conduit and its inlet are presented in Figure 11. In Figure 11a, we see a straightforward linear aspirator conduit design that exhibits wide versatility due to its ability to effectively sample a sizable spatial region. Moving to Figure 11b, we encounter an exemplary implementation of an aspirator conduit customized for sampling aerosol generated at a specific location. In this embodiment, the aspirator conduit features a tip 219 characterized by an enlarged cross-sectional area that strategically encompasses the volume where the majority of aerosol particles tend to concentrate.

[0160] Finally, Figure 11c explores an embodiment in which the inlet 110 of the aspirator is split into multiple sub-inlets, typically two or more, that subsequently merge into the main conduit 112. This configuration is promising, for example, in scenarios where a finite volume produces a relatively small amount of aerosol particles. The positioning of the sub-inlets can be optimized to increase the capture efficiency for as many aerosol particles as possible, thus increasing the overall effectiveness.

[0161] If the aerosol particles are produced by a device (such as a laser), it may be advantageous to incorporate the aspirator conduit into an all-in-one apparatus that encompasses both the aspirator conduit and the device.

[0162] Sampled aerosol particles typically originate from a variety of environments, with the majority occurring in gaseous atmospheres approximating standard atmospheric pressure. In many cases, it has been found advantageous to optimize the inhaler's inlet pressure to match specific operating requirements. Potential embodiments, as detailed in FIG. 12, have been devised to facilitate this personalized customization.

[0163] Within this configuration, an additional gas source, designated 220, is seamlessly integrated into the system. This gas source may appear as a pressure vessel or gas compressor, thus providing versatility in fitment. Fluid connectivity is established between the gas source and the gas coupler's inlet conduit 132 through an intermediate conduit 222, which is coupled to the inlet 132 through a secondary gas coupler 226. Valves 224 are strategically positioned along the conduit 222 to control the quality of gas released from the gas source into the inlet 132.

[0164] It is important to note that the gas flow rate within inlet 132 results from the combined contributions of the gas drawn into the aspirator inlet and the auxiliary gas introduced from source 220. Determined primarily by the operation of intensifier 132, increasing the gas flow through valve 224 inversely decreases the inhalation pressure at the inlet of aspirator 110, and vice versa. This dynamic adjustment mechanism gives the user the ability for precise control, facilitating fine-tuning of the aspirator's inhalation pressure to match specific requirements, thereby optimizing its performance.

[0165] 13 presents an exemplary embodiment of the secondary gas coupler 226 from FIG. 12. The outlet of the intermediate conduit 222 is harmoniously integrated with the inlet of the conduit 132. The outlet of the aspirator conduit 114 is strategically positioned to be concentric with and confined within the outlet of the intermediate conduit 222. Such an arrangement ensures that additional gas originating from the source 220 envelops the outlet of the conduit 114, thereby facilitating efficient incorporation of aerosol particles exiting the conduit 114 into the flow within the conduit 132.

[0166] Beyond its role in controlling the inhaler inhalation pressure, the utilization of the auxiliary gas supplied from 220 provides several other versatile applications within the gas coupler. For example, the gas can be selectively heated to impart beneficial thermal treatment to the aerosol particles within the gas coupler. Furthermore, specific gases with beneficial chemical properties can be used to interact with the aerosol particles within the gas coupler. Generally, however, dry nitrogen can be used due to its inert properties.

[0167] To ensure efficient transport of a significant proportion of the aerosol particles from the inlet of the inhaler to the outlet of the nebulizing conduit, it is essential to minimize losses of the aerosol particles within the delivery system.

[0168] This requires careful consideration of individual components, including conduits, pumps, connectors, and the like, with a focus on reducing obstructions to gas flow and minimizing dead volume. Furthermore, maintaining an elevated temperature within the delivery system is essential to prevent undesired condensation of the gas in which the aerosol particles are suspended. It should also be noted that the materials from which the delivery system is made are chemically inert and do not chemically interact with the aerosol particles in an undesirable way. Typical materials for constructing such systems typically include stainless steel, Teflon, and PEEK plastic.

[0169] Of more subtle, but still significant concern, is the mitigation of static electricity within the transport system. Given the lightweight and small nature of aerosol particles, they are susceptible to adhesion and entrapment by statically charged surfaces. Plastic pipes pose a particular challenge in this regard, as gas flow through such pipes can easily induce static charges on the plastic material, resulting in the inadvertent attraction of aerosol particles within the gas stream.

[0170] Skilled practitioners in the relevant fields have devised various strategies to address this problem. One commonly adopted approach involves using tubes with partially conductive inner walls, allowing them to be grounded for static discharge. In this context, an exemplary implementation for an embodiment of the present invention involves the use of carbon-doped PTFE tubes. This specialized PTFE tube incorporates a carbon dopant, typically in the range of 2-3%, which makes the tube sufficiently conductive to effectively dissipate charge from the inner conduit wall without losing the chemically inert properties of pure PTFE.

[0171] Another potential solution to combat the challenge of aerosol particle adhesion to surfaces due to static electricity involves the deployment of ultrasonic transducers affixed to the surface, which induce vibrations within the surface to effectively remove particles that have adhered due to electrostatic attraction.

[0172] The integral function of the liquid source within the system of the present invention, identified in the previous discussion as 100, is to facilitate the precise delivery of liquid substance 104 to liquid conduit 102. As detailed in Figure 14, a typical configuration of this liquid source consists of two main components: a liquid reservoir (referred to as 230) and a liquid pump (designated as 232).

[0173] The choice of liquid pump can encompass a variety of types familiar to those skilled in the art, but pumps capable of dispensing small amounts of liquid with high precision are preferred. Syringe pumps are a good example of such preferred devices, providing precision in delivering small liquid volumes.

[0174] In more advanced applications, there is an opportunity to use more complex liquid sources that include multiple reservoirs, each containing a separate liquid. Such diverse liquids can be advantageously combined in predetermined proportions in a liquid mixer, and the resulting mixture is subsequently conveyed to a liquid conduit by a shared pump. This configuration provides versatility to accommodate diverse liquid configurations, increasing the adaptability and capacity of the system for advanced applications.

[0175] Another valuable enhancement to the liquid source involves the inclusion of a liquid temperature controller designed to control the temperature of the liquid prior to nebulization. This temperature control offers several benefits, including increasing the stability of the analytical signal. Furthermore, it provides the ability to increase the temperature of the liquid. The application of an elevated liquid temperature can promote the breakup of aerosol particles, potentially optimizing their behavior. Additionally, the increased temperature can hasten the evaporation of liquid droplets produced during the nebulization process.

[0176] The choice of liquid used for nebulization is carefully determined by the characteristics of the aerosol particles in question and the particular analytical method used for aerosol analysis. Frequently, the use of a solvent is found to be advantageous due to its ability to promote partial or complete dissolution of the aerosol particles and particles. This dissolution can occur either during the nebulization process or later within the liquid droplets produced as a result of nebulization.

[0177] A wide spectrum of solvents can be used depending on the specific requirements of the application, including organic solvents, water, various alcohols such as methanol, ethanol, isopropanol, and acetone, along with acetonitrile, dimethyl sulfoxide, chloroform, benzene, hexane, ethyl acetate, ionic liquids, or mixtures thereof.

[0178] An additional promising application of liquid components lies in their ability to enhance the ionization process of aerosol molecular species. One illustrative scenario involves the introduction of a certain amount of toluene into a liquid medium. After the formation of a fine spray through the atomization process and the subsequent evaporation of the spray droplets, the resulting aerosol molecular species can undergo ionization using atmospheric pressure photoionization (APPI), with toluene serving as the charge donor.

[0179] A further advantageous application of the liquid component lies in its potential use as a conduit for the delivery of molecular labels. These labels have broad applications in the areas of biological and medical research, serving the important function of detecting, identifying, and monitoring specific molecules or entities within biological systems. Exemplary molecular labels include various substances, such as enzymes, biotin, Halo tags, SNAP tags, nanoparticles, optical fluorescent labels, luminescent labels, radioisotopes, metal isotopes, gold particles, metal magnetic labels, quantum dots, metal ions, or any synergistic combination thereof. Within the framework of the present disclosure, a unique means is provided for real-time labeling of aerosolized molecular species of interest, characterized by their rapid intermixing with the liquid medium during nebulization and within the resulting liquid droplets derived therefrom. This capability is contingent on the initial presence of the label in the liquid medium subjected to nebulization, thereby facilitating dynamic molecular labeling.

[0180] As previously mentioned, the present disclosure is compatible with a variety of existing sprayer designs, including, but not limited to, cross-flow, V-groove, thin film, parallel-passage, enhanced parallel-passage, Hildebrand grid, and flow-blurring sprayers. In this application, some embodiments are presented utilizing a concentric sprayer, a sprayer type commonly used in analytical instruments.

[0181] In a concentric pneumatic nebulizer, the liquid conduit and the nebulizer gas conduit are concentric. The inner and outer diameters of these conduits are typically small enough that they can be considered capillaries, and we refer to them as liquid and nebulizer gas capillaries. The narrower inner tube is typically used to transport the liquid sample. The wider outer tube typically carries the nebulizer gas.

[0182] These nebulizer types predominate in pneumatic electrospray ionization (ESI) sources utilized in mass spectrometers. Over the past 40 years, they have undergone extensive development, characterization, and testing. As a result, their basic design parameters, such as liquid and gas flow rates and capillary cross-sectional area, have been established and are recognized by experts in the art. These parameters can serve as basic guidelines for the initial design of other nebulizer embodiments in this disclosure, which can then be fine-tuned to achieve optimized performance.

[0183] Liquid flow rates in commercially available pneumatic ESI devices for mass spectrometers are typically between 50 μL / min and 1 mL / min, and the inner diameter of the liquid capillary is typically in the range of 10-200 μm. To nebulize this volume of liquid, nebulizing gas flow rates in the range of 0.1-5 L / min are used, and the nebulizing gas conduit typically has an inner cross-sectional area comparable to a capillary with an inner diameter of 100-200 μm. Typical gauge pressures of the nebulizing gas source required to achieve these flow rates are in the range of 20-60 PSI. The actual set of parameters used depends primarily on the given sample flow rate (as in liquid chromatography) and solvent properties (e.g., surface tension and viscosity).

[0184] Referring to Figure 15a, a specific embodiment employing a concentric nebulizer is depicted. This embodiment is equivalent to the arrangement and function of elements detailed in Figure 1, with corresponding annotations for clarity. In this design, the terminal segment of the atomizing gas conduit envelops the terminal segment of the liquid conduit, and both are seamlessly integrated into the housing unit 240. During operation, as the gas facilitates atomization of the liquid, subsequent aerosol particles undergo collisions with the residual liquid, resulting in their disintegration, a phenomenon previously detailed. Figure 15b depicts a front view of the nebulizer to illustrate the spatial relationship between the nebulizer elements.

[0185] While effective for liquid atomization, the atomizer design discussed herein presents a limitation in certain applications of the present invention: aerosol particles largely exit the periphery of the atomizer conduit. As a result, a significant amount of these particles may be deflected away from the central axis before any substantial interaction with the liquid. To address this, an alternative concentric atomizer configuration is presented in which the positions of the liquid and atomizing gas capillaries are reversed; specifically, the atomizing gas traverses the inner capillary while the liquid is passed through the outer capillary. This design is illustrated in FIG. 16a, which directly repeats the structural arrangement and function of the components as depicted in FIG. 1, maintaining annotation consistency for clarity. This design also integrates an additional housing unit 244 that encloses the end segments of both the liquid capillary and the atomizing gas capillary.

[0186] In this configuration, aerosol particles are ejected along the central axis of the concentric nebulizer, where the liquid concentration is at its peak. This alignment promotes maximum impact between the aerosol particles and the liquid, thereby enhancing aerosol particle breakup. Furthermore, as the aerosol particles are encased within the liquid volume, most are retained within the resulting liquid spray. Such containment significantly increases the efficiency of dissolution of the aerosol material. Figure 16b provides a front view of the nebulizer, depicting the spatial interrelationships between the nebulizer components for comprehensive understanding.

[0187] In improving the concentric atomizer design, a key factor is determining the offset (d) between the liquid capillary and the atomizing gas capillary. This offset can be positive, neutral, or negative, as illustrated in Figures 17a-c, where a negative offset indicates that the atomizing gas conduit outlet is recessed within the liquid capillary. The annotations of other elements in Figures 17a-c correspond to those established in Figure 16a. Notably, a negative offset (d<0) creates a space 250 within the liquid conduit before the atomizing gas outlet, which serves as an atomizing chamber, as shown in Figure 17c. In this case, the first interaction between the atomizing gas and the liquid occurs immediately before the atomizing gas conduit, so the cross section of the liquid conduit at the location of the atomizing gas conduit outlet can be considered the effective outlet of the liquid conduit. The confinement of the space 250 enhances the spray breakup effect due to prolonged gas-liquid interactions under high pressure, as previously discussed. The choice of offset balances several important factors: overall nebulizer efficiency, the strength of the aerosol particle-liquid interaction, and, if the liquid is charged, the effectiveness of ionization of the aerosol molecular species. Given the complex and nonlinear nature of this process, a systematic approach to system optimization is advisable. This involves a series of performance characterizations followed by incremental adjustments of parameters in search of the most favorable operating results, as discussed previously.

[0188] A further improvement often incorporated into established pneumatic ion source devices is the integration of a hot gas stream mixed with the liquid spray. The primary purpose of this modification is to accelerate the evaporation of the liquid droplets, thereby facilitating the rapid release of analyte molecules and / or ions. This process contributes to increased ion collection efficiency. Typically, the hot gas used is dry nitrogen, and as a general guideline, the flow rate is generally about 10-20 times that of the nebulizing gas. Determining the optimal temperature of the hot gas involves considering the enthalpy of vaporization of the solvent used for nebulization, along with its flow rate. It is important to adjust the temperature to avoid thermal degradation of the analyte while ensuring complete evaporation of the solvent. These temperature ranges are within the knowledge base of those skilled in the art. For example, when using primarily aqueous solvents at a flow rate of 200 μl / min, the hot gas is typically heated to approximately 250 °C.

[0189] FIG. 18a illustrates an exemplary embodiment incorporating hot gas modification as an extension of the design depicted in FIG. 17a. In this configuration, hot gas 264 (typically dry nitrogen) is introduced through conduit 262 positioned concentrically and externally to the liquid conduit. The outlets of all conduits are harmonically integrated into the housing 260. The hot gas is discharged through outlet 266 located near the atomization region 128. Here, due to the Bernoulli effect, the hot gas is efficiently entrained and then merges into the atomizing gas jet. This integration promotes immediate mixing with the liquid droplets, thereby significantly accelerating their evaporation. For improved visual understanding, FIG. 18b provides a front view of the atomizer, specifically highlighting the spatial relationships and interactions between the various components within the atomizer assembly.

[0190] Another advantage of this design is that the gas introduced through the concentric outlet 266 can also contribute to atomization of the liquid if its flow rate is high enough.

[0191] The hot gas conduit 270 can be configured to deliver the hot gas 272 in different geometries to the spray region 128 as shown in FIG.

[0192] Liquid droplets can also be heated for accelerated evaporation using an infrared lamp 274 as shown in Figure 20. If the characteristic infrared wavelength of the radiation 276 emitted by the lamp is close to one of the optical absorption peaks of the liquid, illumination of the liquid droplets by that source will heat the droplets and thus contribute to their accelerated evaporation.

[0193] The atomization process, as outlined previously, begins with the impact of the atomizing gas on the liquid, resulting in the primary breakup of the aerosol particles. However, this mechanical impact is only the initial step in a multifaceted process. Atomization can also induce a variety of additional phenomena that further contribute to the breakup of the aerosol particles. These phenomena, particularly effective in designing aerosol particles to be thermodynamically favorable, include, but are not limited to, liquid fragmentation resulting from tensile stress, cavitation, phase explosion, and spinodal dissolution. Such events occur when the thermodynamic coordinates of a specific location within the liquid align within a specific region of the liquid's thermodynamic phase diagram.

[0194] The inherently energetic nature of nebulization subjects the liquid to repeated collisions, resulting in acoustic transients through both mechanical shock and turbulence. These transients can cause rapid pressure fluctuations within the liquid volume, initiating a cascade of thermodynamic responses. For example, cavitation, a prominent response, generates secondary acoustic transients. These secondary transients can then induce further thermodynamic reactions, creating a self-perpetuating cycle. Consequently, these amplified acoustic phenomena can significantly enhance the breakup of aerosol particles, playing a role in the effectiveness and kinetics of the nebulization process.

[0195] However, the excessive destructive power of these secondary thermodynamic phenomena can unintentionally alter aerosol materials in undesirable ways. For example, the collapse of cavitation bubbles can create extreme local conditions characterized by extremely high temperatures, pressures, and shock waves. Such harsh environments are capable of breaking chemical bonds, resulting in molecular fragmentation of the aerosol material. While such significant cavitation bubbles are not typically observed in laboratory pneumatic devices, especially LC-MS systems equipped with robust pneumatic nebulizers, careful investigation of these phenomena is recommended when devising new nebulizer designs.

[0196] Immediately after nebulization, a common occurrence is widespread dispersion of the liquid droplets, primarily due to the expansion of the high-pressure nebulizing gas as it exits the nebulizing gas conduit. However, such dispersion often results in loss of analyte and a consequent reduction in the intensity of the analytical signal, which is generally undesirable in analytical applications.

[0197] To alleviate this problem, the introduction of an additional component called a "spray conduit" 280, as depicted in FIG. 21a, can be beneficial. Such a design of the spray conduit is equivalent to elements 102, 104, 122, 124, 128, and 130, consistent with previously described embodiments. Strategic placement of the spray conduit inlet encompasses most of the spray volume 128, effectively directing the expanding atomizing gas—and consequently, the aerosol material—primarily toward the spray conduit outlet. Such orientation ensures that the aerosol material remains confined within the spray conduit and its outlet.

[0198] The geometric design of the spray conduit, including its outlet, can be specifically tailored to meet the requirements for efficient aerosol material delivery. An example is illustrated in FIG. 21b, where spray conduit embodiment 282 features an outlet 284 with an enlarged cross-sectional area. This particular design is advantageous for achieving a more laminar flow of the aerosol-laden gas stream, facilitating more controlled and stable integration of aerosol particle fragments and aerosol molecular species into the analytical instrument.

[0199] An obvious consideration with this configuration is the possibility of liquid droplet condensation along the inner wall of the spray conduit. To address this, the incorporation of hot gas into the spray conduit is recommended to hasten the evaporation of these droplets. This can be achieved longitudinally via a concentric secondary gas conduit, as described in connection with FIG. 18a. An alternative approach is depicted in FIG. 21c, which shows a design in which a hot gas conduit 288 is concentrically aligned with a spray conduit 291. A spray conduit characterized by perforated walls and enclosed within the hot gas conduit allows hot gas 286 to penetrate the interior of the spray conduit through perforations 300. This not only aids droplet evaporation, but also effectively prevents droplet accumulation on the inner wall of the conduit, since the flow of hot gas through the perforations actively blows droplets off the inner wall of the spray conduit.

[0200] A further enhancement to the spray conduit design involves implementing heating of the spray conduit. Such modifications, well known to those skilled in the art, involve maintaining the spray conduit at an elevated temperature. The primary benefit of this approach is the increased evaporation rate of the spray droplets as they traverse the conduit. Consequently, this accelerated evaporation process leads to higher ion desorption rates.

[0201] Heated capillaries, similar to the proposed heating configuration, are routinely used at the inlet of conventional mass spectrometers equipped with atmospheric ion sources. Their main function in such a context is to rapidly remove any residual droplets coming from an external source, such as those produced by electrospray. The design and operating principles of such heated capillaries are well established and widely recognized by experts in the field.

[0202] As detailed in the Summary of the Invention, aerosol breakup can have a variety of outcomes. A portion of the aerosol particles may break down into smaller fragments, another portion may dissolve into molecular aerosol species, while some particles may remain unchanged. For a particular aerosol type, the specific proportion of these fragments in the resulting aerosol material depends primarily on the parameters of the nebulization system, including the type of liquid, the liquid flow rate, the nebulization gas flow rate, the pressure in the nebulization gas conduit, and the geometry of the nebulizer. Adjusting these parameters allows for optimization of the aerosol breakup results based on the characteristics of the aerosol particles.

[0203] In the context of this disclosure, when the aerosol decay process produces at least some molecular species, and when the goal is to analyze these aerosol molecular species using a mass spectrometer, ionization of these species is a key step. A wide range of ionization methods are applicable in such a scenario. In practice, ionization of molecules typically occurs either under vacuum or atmospheric pressure.

[0204] When operating in vacuum, common ionization techniques include electron ionization (EI) and direct photoionization (PI). Photoionization can be achieved through single-photon UV absorption or by using more advanced multiphoton techniques such as resonance-enhanced multiphoton ionization (REMPI). The major advantage of direct photoionization methods is their deterministic nature and the potential for selectivity, achieved by tuning the optical properties of the ionizing light. This selectivity is invaluable for quantitative measurements, which are crucial yet often present significant challenges. However, it should be noted that direct photoionization methods are typically only effective for molecules of relatively small molecular mass. The practical upper limit for these methods is usually around 3000 Daltons (Da).

[0205] Atmospheric pressure ionization techniques are by far more popular in biomedical research due to their simplicity, compatibility with complex biological samples, ability to softly ionize large biomolecules, high sensitivity, and minimal sample preparation. The most popular atmospheric pressure ionization methods are electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and atmospheric pressure photoionization (APPI).

[0206] A conventional ESI mechanism begins with an analyte solution being injected through a fine needle to create a mist. The needle is held at a high voltage, creating an electric field that imparts an electric charge to droplets within the mist. As these charged droplets move through the electric field, they undergo both evaporation and Coulomb fission, which causes the droplets to become progressively smaller. This process continues until the droplets reach a point where they can no longer hold solvent and analyte molecules, and are ionized and expelled into the gas phase.

[0207] Electrospray ionization (ESI) essentially requires only a high-voltage source and capillaries for effective operation. Two conditions are essential for ESI: First, the liquid in the system must be in contact with a conductor that is charged to a high potential, either positive or negative. Second, a significant electric field gradient must exist at some point within the liquid conduit, promoting charge separation and electrochemistry. The site of this strong electric field gradient need not be near the conductor, since the conductor can be electrically shielded. Typically, in conventional ESI systems, the majority of the electrochemistry and liquid charging occurs at the tip of the capillary, where the electric field is strongest. Early ESI devices used metal capillaries to establish this gradient, but later innovations successfully utilized nonconductive capillaries. This advancement is possible because the solvent itself acts as a conductor and naturally creates an electric field at the capillary tip.

[0208] At high liquid flow rates, an electric field alone is insufficient to break the liquid into a fine spray. In such cases, a pneumatic atomizer is used in addition to the electric field to create the electrospray. This general method provides a simple and effective approach to ionizing aerosol molecular species in the present case, as it is a natural extension of embodiments of the present invention.

[0209] Figure 22 demonstrates the implementation of ESI ionization in our design, with elements and reference numbers consistent with those detailed in Figure 1. Important additions include an electrical conductor 310 designed to maintain electrical contact with the liquid 104 in the liquid conduit 102, and a high-voltage source 312 connected to the conductor 310. Specific electrical configurations, such as grounding, are omitted as they are standard knowledge to those skilled in the art. In this setup, the charged liquid exits the conduit 102, where it is atomized by an atomizing gas carrying aerosol particles. The aerosol molecular species that result from the atomization are further ionized as molecules in a conventional electrospray device.

[0210] Optimizing pneumatic ESI operation within our device presents a more complex challenge than conventional ESI systems due to the dual objective of enhancing both aerosol breakup and ESI efficiency, which are interdependent with the nebulization process. For example, in the case of a concentric nebulizer, a factor in this optimization is the offset between the gas and liquid capillaries, as illustrated in Figures 17a-c. This offset not only affects the electric field strength experienced by the liquid, which in turn influences the ESI process, but also significantly impacts aerosol breakup efficiency. Other important design considerations include the material selection of the capillaries and their respective inner and outer diameters. An effective approach to optimization may involve starting with a proven basic design, such as that shown in Figure 17a, in which both capillaries are constructed from stainless steel. Subsequent adjustments to various parameters may be made while continuing to evaluate the device's overall analytical parameters. Supplementing this empirical approach with numerous simulations of fluid dynamics and electric fields may provide valuable insights and help fine-tune the device design.

[0211] On the other hand, the use of pure liquid for nebulization in our approach offers several advantages over traditional ESI. Traditional ESI systems use analyte-containing liquids, which can lead to potential deposit accumulation on the capillary over time due to electrochemistry occurring between the analyte and the capillary. This can affect the consistency and continuity of the ionization signal. Our method alleviates this issue by using pure nebulization liquid, increasing the operational efficiency and reliability of the device.

[0212] FIG. 23 illustrates enhancements to the liquid conduit outlet of a concentric nebulizer, as previously detailed in FIGS. 16a-b, aimed at improving ionization efficiency. In this design, the inner capillary conducting the nebulizer gas is constructed from stainless steel and placed at a high potential. A key feature in this embodiment involves the incorporation of microfabricated channels 320 into the outer surface of the capillary at its outlet. These channels serve to increase the surface area available for electrochemistry occurring between the liquid traversing the inner capillary and the capillary itself. This increase increases the efficiency of liquid charging. Furthermore, a higher concentration of charge within the liquid enhances the ionization process, leading to more effective ionization of aerosol molecular species. Microfabrication of spatial features on this scale can be easily achieved with laser microfabrication tools. The presence of such channels without compromising signal stability is possible in this case due to the pure liquid. The geometry of the microfabricated features presented in FIG. 23 is non-limiting. Other microfabricated features with various geometries are possible. The key concept is to increase the surface area of ​​contact between the liquid and the conductor where the majority of the electrochemistry occurs in order to charge the liquid more efficiently.

[0213] A further optimization strategy based on leveraging the use of pure liquid to enhance the signal-to-noise ratio is feasible when aerosol particles are generated in a pulsed manner, such as with a laser. This method involves pulsing the potential applied to a conductor in contact with the liquid. When the aerosol production duty cycle is significant, maintaining a constant voltage at the capillary is unnecessary when there are no aerosol particles in the nebulizer. Unnecessary charging of the liquid during these intervals can result in background noise. Synchronizing the high potential pulse with the arrival of new aerosol particles ensures that the voltage is active only when necessary, thereby reducing noise and increasing signal clarity.

[0214] In addressing the challenge of coupling aerosol particles from the gas coupler outlet to the high-pressure atomizer gas conduit, a key consideration is the interface between these two components, as defined in connection with FIG. 2. Our previous implementation recommended grounding the aerosol transport system to prevent static electricity issues. The question arises: How can we effectively interface the grounded gas coupler with the high-pressure atomizer gas conduit? FIG. 24 introduces a solution using an interface 120 between the grounded outlet of the gas coupler 136 and the high-pressure atomizer gas conduit 122. Here, the gas coupler outlet passes through the ceramic interface 120 and terminates in a grounded conductor. The atomizer gas conduit inlet, a high-voltage conductor, surrounds this interface. This design ensures sufficient clearance between the gas coupler outlet and the inner wall of the atomizer conduit, which is larger than the dielectric breakdown distance, typically several millimeters.

[0215] In this configuration, the aerosol particles 124 are electrically shielded within the grounded outlet 136 until they are rapidly injected into the nebulizer gas conduit. With carefully selected interface parameters, the kinetic energy of the gas jet passing through the interface 120 can suppress any boundary electric fields, thus preserving the presence of previously charged or polarized aerosol particles while still maintaining safe operation of the overall device.

[0216] Integrating APCI and APPI ionization methods with embodiments of the present invention is simpler and more straightforward than ESI because in APCI and APPI, the ionization process is decoupled from nebulization. Once aerosol molecular species are generated as in the methods of the present invention, APCI and APPI can be used using techniques well known to those skilled in the art. For simplicity, details of these well-known techniques will be skipped in the following description.

[0217] Figure 25 presents a streamlined configuration for integrating APCI into the design of the present invention. Component functions and reference numbers correspond to those outlined in Figure 1. A key addition is a corona discharge needle 332 connected to a high voltage source 330 and optimally positioned near the point of emergence of the aerosol molecular species. As these species traverse the corona region, they undergo ionization through interaction with ions produced by the corona discharge.

[0218] Figure 26 presents a simplified embodiment for APPI integration. In this embodiment, a donor gas is combined with aerosol molecular species. This mixture is then exposed to ultrasonic (UV) light 336 from a UV lamp 334, which ionizes the donor gas. The ionized donor gas then transfers its charge to the aerosol molecular species, resulting in their ionization.

[0219] For APPI, a design choice must be made regarding how to introduce the donor gas into the volume where the aerosol molecular species are located. FIG. 26 illustrates that the donor gas 340 is supplied via a separate source 338. However, the design of the present invention provides a more streamlined approach. One option involves incorporating a liquid component, such as toluene, into the liquid 104, which is ionized by a UV lamp upon atomization and evaporation. An alternative is to introduce the donor gas through a secondary gas source 180, as shown in FIG. 7. In both scenarios, atomization effectively mixes the donor substance with the aerosol material, enhancing APPI efficiency.

[0220] In both APCI and APPI implementations, it can be beneficial to ensure that a large portion of the liquid is evaporated before ionization. Methods for enhancing liquid evaporation are detailed earlier in this disclosure. For clarity, these methods are not depicted in Figures 25 and 26.

[0221] The present disclosure provides the additional benefit of facilitating straightforward signal calibration across various ionization methods. During calibration, the nebulizer gas remains uncontaminated, while the calibrant is dissolved in liquid 104. Provided that aerosol decay is a reliable mechanical process independent of ionization and ion collection efficiency, the signal intensity produced by the calibrant exhibits what would be expected from aerosol analysis. Additionally, for real-time signal calibration, the calibrant can be introduced into the nebulizer volume along with the aerosol.

[0222] Ion collection at atmospheric conditions poses challenges for mass spectrometers because gas flows can significantly affect ion trajectories, making them as influential as electric fields and difficult to control. Historically, this has resulted in lower ion collection efficiencies, averaging approximately 1-5% in conventional LC-MS systems with pneumatic nebulizers. However, recent advances have improved these efficiencies. Ion optics traditionally used at low-pressure conditions in mass spectrometers use various electrode configurations, such as ring electrodes, to guide ions through their central apertures. These electrodes are subjected to static or transient DC and RF voltages. A prominent configuration is the ion funnel, which consists of stacked ring electrodes of decreasing diameter. Ion funnel designs are well established in the art.

[0223] Recent developments have shown that ion funnels are equally effective under atmospheric conditions, significantly enhancing ion collection efficiency. Such designs are applicable to embodiments of the present invention. Figure 27 illustrates the integration of an ion funnel in a system of the present invention. Aerosol ions 350, which form as a result of the spray in volume 128 and are propelled through mixture 130 by the gas flow, are intercepted by ion funnel 352. The funnel directs the ions through its exit aperture 354, after which an ion-guiding conduit 356 passes collected ions 358 to the mass spectrometer.

[0224] In certain scenarios, it may be beneficial to analyze the neutral aerosol particle fractions and aerosol molecular species produced during nebulization. In these cases, a simple gas funnel can be used for collection, as depicted in FIG. 28. The aerosol particle fractions and aerosol molecular species produced as a result of nebulization in nebulization region 128 and carried in the gas flow by mixture 130 are collected by gas funnel 360. This funnel, with the aid of its collection cone and gas flow, directs the aerosol particle fractions and aerosol molecular species toward its opening 362 and subsequently through funnel conduit 364 for analysis.

[0225] In some applications, optical methods of testing also offer significant advantages. Optical excitation, typically performed using a laser or focused light source, benefits from having conduits that confine the movement of ionic or neutral aerosol particle fragments and aerosol molecular species within specific dimensions. We have previously described such conduits in this disclosure, followed by ion and gas funnels, to facilitate these analyses.

[0226] 29, we present an exemplary embodiment depicting an optical excitation setup for aerosol particles 370 passing through a conduit 372. This setup includes an optically transparent window 378 integrated into the wall of the conduit, allowing the passage of optical radiation 376 from an external source 374. The radiation penetrates window 378 and interacts with aerosol particles inside the conduit. To detect the optical signal, another transparent window 380 can be incorporated opposite the first window, allowing for external detection by device 382. This design allows for precise optical excitation and efficient signal capture, enhancing the potential for detailed optical analysis.

[0227] The methodology of the present disclosure is particularly applicable to analyzing aerosols generated from laser plumes. This disclosure does not delve into the details of laser ablation or its various applications, as these are widely covered in the existing literature, and the inventors highlight a selection of general applications in which the techniques disclosed in this disclosure can be effectively utilized.

[0228] 30 illustrates a typical setup, presented in a non-limiting manner. In this scenario, a condensed-phase sample 400 is subjected to ablation by a laser 402, with the laser beam directed by delivery optics 404. This ablation process generates a laser plume 406, from which aerosol particles 108 are partially or wholly captured by an aspirator inlet 110. These particles 114 are then transported through an aspirator conduit 112 to an analysis system 410. This system, which represents one of the previously described embodiments in this disclosure for aerosol analysis, processes the particles to produce ions 412 that are subsequently analyzed by a mass spectrometer.

[0229] Ablation lasers feature peak emission wavelengths ranging from 100 nm to 12 μm, optimally tuned for strong absorption by the sample, thereby effectively localizing energy deposition. Lasers typically operate in pulsed mode, with pulse durations ranging from 10 fs to 1 ms. Shorter pulses are generally preferred to minimize residual damage in the sample. This technique is applicable to a variety of condensed matter samples, including both in vivo and ex vivo biological tissues.

[0230] Figure 31 depicts a variation of the embodiment shown in Figure 30. In this setup for sample imaging, a sample 400 is mounted on a motorized translation stage 420. This allows for sampling at multiple spatial points on the sample, correlating each point with its specific location. The resulting laser plumes from these points are then analyzed using system 410. This approach allows for the determination of the spatial distribution of specific molecular species within the sample.

[0231] The sample imaging analysis depicted in Figure 31 can be multiplexed with other imaging methods. In particular, combining it with optical imaging methods such as vibrational spectroscopy, such as stimulated Raman scattering (SRS) imaging or coherent anti-Stokes Raman scattering (CARS) imaging, offers significant advantages. These methods provide detailed molecular insights by exploiting the Raman scattering process, in which photons interact with molecular vibrations. SRS and CARS imaging use their high-resolution molecular images to guide laser sampling spot selection, enabling precise targeting of specific sample regions. Additionally, they provide complementary information about the chemical and structural composition of the sample. This integrated approach enhances the analysis obtained from mass spectrometry of aerosol particles, leading to a more comprehensive understanding of the sample. The effectiveness and instrumentation details of vibrational spectroscopy are well documented in the academic literature, highlighting its role in enhancing molecular specificity and spatial resolution in sample analysis.

[0232] Figure 32 presents an alternative to the general embodiment shown in Figure 30. In this design, laser light is directed to the sample 400 via an optical fiber 432. The output of the fiber and the aspirator inlet 110 are combined in a single housing unit 434. This housing is designed to be ergonomic and allow for handheld use.

[0233] In addition to lasers, alternative methods can generate aerosols from biological tissue. Figure 33 depicts a scenario in which an electrosurgical tool 450 is used to aerosolize a sample 400. This aerosol is then analyzed using system 410, as previously outlined in the context of Figure 30.

[0234] Once ions are created from the aerosol particles by the non-limiting embodiments described in this disclosure, these ions can be analyzed by a mass spectrometer. Mass spectrometer designs, as well as types and methods of mass spectrometry, are well known to those skilled in the art. Standard mass spectrometers that can be used include time-of-flight (TOF) mass spectrometers, quadrupole mass spectrometers, ion trap mass spectrometers, orbitrap mass spectrometers, triple quadrupole mass spectrometers, Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometers, and various hybrid systems.

[0235] The disclosed embodiments facilitate versatile spatial configurations in which aerosol molecular species are initially generated in a first location, then transported to a second location for ionization, and finally the resulting ions are collected and analyzed using a mass spectrometer at a third location. We only describe the general configuration and mass spectrometer for the systems comprising this disclosure.

[0236] 34, a non-limiting configuration is illustrated with a system 410 incorporating one or more embodiments of the present disclosure, which produces ions 412 from sample aerosol particles 108 that are collected using an aspirator conduit 114 having an inlet 110, where the ions are generated near an orifice 460 of a mass spectrometer 462, where the ions are collected and analyzed by the mass spectrometer. The system 410 can include an ion collection and ion transport system that efficiently transports the ions into the orifice 460.

[0237] A potential enhancement to conventional mass spectrometry instruments involves the incorporation of an ion drift tube, as detailed in the Summary of the Invention section of this disclosure. This tube facilitates ion separation based on both gas mobility and mass-to-charge ratio. Such an enhancement mimics the analytical capabilities of LC-MS systems and has proven particularly beneficial in analyzing complex biological samples.

[0238] It should be understood that the specific embodiments described above are shown by way of example, and that these embodiments are susceptible to various modifications and alternative forms. It is to be further understood that the claims are not intended to be limited to the particular forms disclosed, but rather to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure.

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Claims

1. 1. A system for performing at least partial disintegration of sample aerosol particles, comprising: a liquid source unit comprising a liquid conduit, the liquid conduit comprising a liquid conduit outlet, the liquid source unit configured to dispense liquid through the liquid conduit outlet; a pneumatic atomizer comprising a high pressure atomizing gas mechanism in gas flow communication with an atomizing gas conduit, the atomizing gas conduit comprising an atomizing gas conduit inlet and an atomizing gas conduit outlet, the atomizing gas conduit outlet being positioned adjacent to the liquid conduit outlet to facilitate pneumatic atomization of a liquid exiting the liquid conduit outlet by contact with high pressure atomizing gas exiting the atomizing gas conduit; an aspirator device comprising an aspirator conduit, the aspirator conduit comprising an aspirator conduit inlet and an aspirator conduit outlet, the aspirator device configured to generate suction suitable for drawing the sample aerosol particles into the aspirator conduit through the aspirator conduit inlet; a gas coupler that provides a gas coupling between the aspirator conduit outlet and the nebulizing gas conduit inlet, thereby facilitating introduction of the aerosol particles into the high-pressure nebulizing gas stream, such that the nebulization process promotes collisions between the aerosol particles and the liquid, contributing to at least partial breakup of the aerosol particles; and A system comprising:

2. 10. The system of claim 1, wherein the liquid comprises a solvent configured to dissolve at least a portion of the aerosol material either during the atomization process, within liquid droplets resulting from the atomization process, or during both stages.

3. 3. The system of claim 1 or 2, wherein the gas coupler includes at least one gas compressor.

4. 3. The system of claim 1, wherein the gas coupler includes at least one venturi pump.

5. 3. The system of claim 1 or 2, wherein the gas coupler comprises at least one device selected from the group consisting of a scroll compressor, a diaphragm compressor, a screw compressor, an axial compressor, a centrifugal compressor, a rotary vane compressor, a scroll pump, a diaphragm pump, a centrifugal pump, and a rotary vane pump.

6. 6. The system of claim 1, further comprising an additional gas source in fluid communication with the gas coupler such that the additional gas is introduced into the atomizing gas conduit and mixed with the aerosol particles.

7. 7. The system of claim 6, wherein the gas coupler comprises one of a gas compressor and a gas pump, the fluid communication between the additional gas source and the gas coupler is configured to occur before an inlet of the gas compressor or an inlet of the gas pump, and the additional gas source comprises a valve for controlling a flow rate of the additional gas entering the gas coupler, thereby enabling adjustment of the intake pressure at the inlet of the aspirator.

8. 7. The system of claim 6, wherein the gas coupler includes a component selected from the group consisting of a gas compressor and a gas pump, the fluid communication between the additional gas source and the gas coupler is established after an outlet of the gas compressor and an outlet of the gas pump, and the introduction of the additional gas into the atomizing gas conduit serves to increase the overall gas flow rate in the conduit.

9. 9. The system of claim 8, wherein the additional gas introduced into the nebulizing gas conduit is configured to advantageously enhance the breakup of aerosol particles during the nebulization process and / or to promote advantageous ionization of aerosol molecular species following nebulization.

10. 10. The system of claim 1, further comprising a filter integrated into the gas coupler and configured to limit the size of aerosol particles reaching the nebulizing gas conduit outlet.

11. 11. The system of claim 10, wherein the filter integrated into the gas coupler is a cyclone filter.

12. 12. The system of claim 1, further comprising a check valve integrated within the gas coupler and configured to open only when gas within the gas coupler flows in a direction toward the atomizing gas conduit outlet.

13. 13. The system of claim 12, wherein the check valve integrated within the gas coupler is a Tesla valve.

14. 14. The system of claim 1, further comprising a rigid obstacle positioned within the gas coupler, the rigid obstacle configured to induce turbulence in the mixture of nebulizing gas and aerosol particles as they pass around the obstacle, the turbulence contributing to at least partial breakup of the aerosol particles in the mixture.

15. 15. The system of claim 1, further comprising a rigid obstacle located within the gas coupler and positioned in a path of the aerosol particles traversing the gas coupler, whereby collision of the aerosol particles with the obstacle contributes to at least partial disintegration of the aerosol particles.

16. A system according to any preceding claim, wherein the liquid source unit comprises a liquid reservoir and a liquid pump, the liquid pump being configured to transfer liquid from the liquid reservoir to the liquid conduit.

17. The system of claim 16 , wherein the liquid pump in the liquid source unit is a syringe pump.

18. 18. The system of any one of claims 1 to 17, wherein the liquid conduit outlet and the atomizing gas conduit outlet are integrated within an atomizer device of a type selected from the group consisting of a cross-flow atomizer, a V-groove atomizer, a thin film atomizer, a parallel path atomizer, an enhanced parallel path atomizer, a Hildebrand grid atomizer, and a flow blurring atomizer.

19. 18. The system of any one of claims 1 to 17, wherein the liquid conduit and the atomizing gas conduit are arranged concentrically with respect to each other near the liquid conduit outlet or the atomizing gas conduit outlet.

20. 20. The system of claim 19, wherein the liquid conduit resides at least partially within the atomizing gas conduit.

21. 20. The system of claim 19, wherein the atomizing gas conduit resides at least partially within the liquid conduit.

22. 22. The system of any one of claims 1 to 21, further comprising a secondary gas source connected to a secondary gas conduit, the secondary gas conduit comprising a secondary gas conduit outlet positioned in close proximity to the liquid conduit outlet.

23. 23. The system of claim 22, wherein the secondary gas is configured to assist the atomization process of the liquid.

24. 23. The system of claim 22, further comprising a heater for preheating a secondary gas, wherein upon mixing of the preheated secondary gas with the liquid droplets resulting from the spray, the preheated secondary gas contributes to accelerated evaporation of the droplets.

25. 25. The system of any one of claims 1 to 24, further comprising a spray conduit, the spray conduit comprising a spray conduit inlet and a spray conduit outlet, the spray conduit configured such that the spray conduit inlet encompasses a majority of the volume from which spray occurs and such that a flow of atomizing gas advances a mixture of liquid droplets and aerosol material toward the spray conduit outlet.

26. 26. The system of any one of claims 1 to 25, further comprising an infrared radiation source positioned to heat the liquid droplets produced by the spraying, thereby contributing to their accelerated evaporation.

27. 27. The system of any one of claims 1 to 26, configured such that at least some aerosol molecular species are produced as a result of the nebulization process.

28. 28. The system of claim 27, further comprising an ionization source configured to ionize the aerosol molecular species produced as a result of the nebulization process.

29. 30. The system of claim 28, wherein the ionization source is an atmospheric pressure ionization source.

30. 30. The system of claim 29, wherein the ionization method used by the atmospheric pressure ionization source is selected from the group consisting of electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), atmospheric pressure photoionization (APPI), and direct photoionization.

31. 29. The system of claim 28, wherein the ionization source comprises a high potential conductor electrode positioned in close proximity to the liquid in the liquid conduit so that the liquid volume exiting the conduit is charged, leading to the aerosol molecular species becoming charged either by acquiring a portion of the liquid's charge during nebulization, or by electrospray ionization if the molecular species are encapsulated in the charged liquid droplets resulting from the nebulization process, or by both of these two processes.

32. 32. The system of claim 31, wherein the system is configured such that the aerosol particle concentration at the nebulizing gas conduit outlet is time-dependent, and the high potential applied to the conductor electrode is pulsed, such pulses being synchronized with the temporal arrival of the aerosol particles at the outlet to optimize the charging process.

33. 32. The system of claim 31, further comprising a microstructured conductor, the microstructured conductor being in electrical contact with the conductor electrode and positioned such that the liquid is in intimate contact with microstructured features of the microstructured conductor immediately prior to spraying, whereby these microstructured features increase the exposure of the liquid to a strong electric field, thereby facilitating more efficient charging of the liquid exposed to spraying.

34. 30. The system of claim 28, wherein the ionization source is an atmospheric pressure chemical ionization (APCI) system including an auxiliary corona discharge source through which a portion of the generated aerosol molecular species pass and thereby acquire an electric charge through interaction with a corona discharge region.

35. 29. The system of claim 28, wherein the ionization source is an atmospheric pressure photoionization (APPI) system that includes a donor substance that mixes with the aerosol molecular species during the nebulization process, after the nebulization process, or both, and the APPI system further includes a UV light source that ionizes molecules of the donor substance, and the donor substance molecules transfer their charge to the aerosol molecular species, thereby achieving ionization of these species.

36. 36. The system of claim 35, wherein the donor material comprises gas generated from donor liquid components introduced into the liquid conduit that evaporates either during the atomization process, after it, or at both stages, thereby facilitating the ionization process.

37. 36. The system of claim 35, wherein the APPI system is configured such that the donor gas is introduced as a component of the atomizing gas mixture through the atomizing gas conduit outlet, thereby becoming an integral part of the atomizing process.

38. 30. The system of claim 28, wherein the ionization source is a light source configured to emit radiation capable of directly ionizing the aerosol molecular species.

39. 39. The system of any one of claims 28 to 38, further comprising an ion funnel positioned to intercept generated aerosol ions, the electromagnetic field of the ion funnel effectively directing a substantial portion of the aerosol ions towards an exit aperture of the ion funnel, thereby increasing ion collection efficiency.

40. 40. The system of claim 39, further comprising an ion transport conduit, the ion transport conduit comprising an ion transport conduit inlet and an ion transport conduit outlet, the ion transport conduit inlet positioned to capture ions exiting the exit aperture of the ion funnel and facilitate transmission of the ions towards the ion transport conduit outlet, which is directly connected to an inlet of a mass spectrometer, thereby enabling efficient injection and subsequent analysis of the aerosol ions.

41. 29. The system of any one of claims 1 to 28, further comprising a gas funnel positioned such that the aerosol material produced by the atomization process is efficiently guided into the gas funnel by the momentum of the atomizing gas jet, ensuring that a significant amount of these particles are efficiently directed towards an exit hole of the gas funnel for subsequent processing or analysis.

42. 42. The system of claim 41, further comprising a transport conduit having a transport conduit inlet and a transport conduit outlet, the transport conduit inlet positioned to receive aerosol particles exiting the exit hole of the gas funnel, the transport conduit configured to efficiently transport these aerosol particles toward the transport conduit outlet, and the transport conduit positioned to facilitate subsequent analysis of aerosol particles exiting the gas funnel.

43. 43. The system of claim 42, further comprising a light source, wherein the transport conduit includes an optically transparent area, and the light source is positioned such that its emitted optical radiation passes through the optically transparent area to promote optical interaction with the aerosol particle fragments and aerosol molecular species resulting from aerosol breakup as they travel through the transport conduit.

44. 44. The system of claim 43, further comprising a photodetector positioned within or adjacent to the transport conduit, the photodetector configured to detect at least a portion of the optical radiation following its interaction with aerosol particle fractions and aerosol molecular species.

45. 44. The system of claim 43, wherein the system is further configured such that interaction of the optical radiation from the light source with the aerosol particle fragments and aerosol molecular species involves one or more of the following processes: direct photoionization, photoexcitation, or photoscattering.

46. 46. ​​A system according to any preceding claim, wherein the system is positioned so that atomisation occurs in an ambient gas environment, the ambient gas being at or near atmospheric pressure.

47. 47. The system of claim 46, wherein the system is configured such that the ambient gas is selected from the group consisting of air, nitrogen, argon, helium, xenon, carbon dioxide, and combinations thereof.

48. 48. The system of any one of claims 1 to 47, wherein the pneumatic atomizer is configured such that the atomizing gas is selected from the group consisting of air, nitrogen, argon, helium, xenon, carbon dioxide, and combinations thereof.

49. 49. The system of any one of claims 1 to 48, wherein the pneumatic atomizer is configured such that the pressure of the atomizing gas in the atomizing gas conduit ranges from 1 to 50 bar.

50. 50. The system of any one of claims 1 to 49, wherein the pneumatic atomizer is configured such that the volumetric flow rate of the atomizing gas in the atomizing gas conduit is in the range of 0.1 to 30 liters per minute.

51. A system according to any preceding claim, wherein the liquid source unit is configured to maintain a liquid flow rate in the liquid conduit within the range of 1 to 3000 μL / min.

52. 3. The system of claim 2, wherein the liquid solvent is selected from the group consisting of water, organic solvents, alcohols, methanol, ethanol, isopropanol, acetone, acetonitrile, dimethyl sulfoxide, chloroform, benzene, hexane, ethyl acetate, toluene, ionic liquids, and mixtures thereof.

53. 53. The system of any one of claims 1 to 52, wherein the liquid source unit is configured such that the liquid exiting the liquid source contains a chemical that reacts favorably with at least a portion of the aerosol particle fragments and aerosol molecular species either during the atomization process, within the liquid droplets resulting from the atomization, or both.

54. 54. The system of claim 53, wherein the chemical agent comprises a molecular label that preferentially attaches to a specific subset of the aerosol molecular species, thereby facilitating analysis of that subset.

55. 55. The system of claim 54, wherein the molecular label is selected from the group consisting of an enzyme, biotin, a Halo tag, a SNAP tag, a nanoparticle, an optical fluorescent label, a Raman label, a luminescent label, a radioisotope, a gold particle, a magnetic label, a quantum dot, a metal ion, or a combination thereof.

56. A system comprising a first subsystem and a second subsystem, each subsystem configured in accordance with any one of claims 1 to 55, and wherein the first subsystem is positioned relative to the second subsystem such that the aerosol material output from the first subsystem is utilized as input aerosol material for the second subsystem.

57. 57. The system of any one of claims 1 to 56, further comprising a laser system capable of generating sample aerosol particles through laser ablation of a sample, the aerosol particles being expelled from the sample as a plume.

58. 58. The system of claim 57, wherein the laser system operates at one or more wavelengths ranging from 100 nm to 12 μm.

59. 58. The system of claim 57, wherein the laser output of the laser system is pulsed, with each laser pulse having a duration ranging from 10 femtoseconds to 1 millisecond.

60. 58. The system of claim 57, wherein the laser system is a component of a surgical device.

61. 58. The system of claim 57, wherein the laser system is a component of a tissue imaging device.

62. 58. The system of claim 57, further comprising an imaging device configured such that prior to laser ablation, the sample is imaged using the imaging device to provide data used for selection of a laser sampling spot or to provide additional information about the sample, thereby enhancing analysis of the sample aerosol particles.

63. 63. The system of claim 62, wherein the imaging device is a vibration imaging device.

64. 64. The system of claim 63, wherein the vibration imaging device employs an imaging modality selected from the group consisting of Raman imaging, stimulated Raman scattering (SRS) imaging, coherent anti-Stokes Raman scattering (CARS) imaging, infrared imaging, and combinations thereof.

65. 58. The system of claim 57, further comprising an optoacoustic imaging device configured such that prior to laser ablation, the sample is imaged using the optoacoustic imaging device to provide data to guide determination of a laser sampling spot position or to provide additional information about the sample, complementing analysis of the sample aerosol particles.

66. 58. The system of claim 57, further comprising an optical coherence tomography (OCT) device, wherein prior to laser ablation, the sample is configured to be imaged using the OCT device to provide data to assist in determining a location of a laser sampling spot or to provide additional information about the sample to aid in analysis of the sample aerosol particles.

67. 57. The system of any one of claims 1 to 56, further comprising an electrosurgical device configured to generate the sample aerosol particles through contact with biological tissue.

68. 68. The system of any one of claims 1 to 67, further comprising a mass spectrometer positioned to receive ions generated from the aerosol particles, the mass spectrometer analyzing the ions and thereby enabling the system to provide information regarding the chemical composition of the sample aerosol particles collected by the aspirator device.

69. 69. The system of claim 68, wherein the mass spectrometer includes an ion drift tube filled with a buffer gas, the ion drift tube comprising an ion drift tube inlet and an ion drift tube outlet, an ion trap in ionic communication with the ion drift tube inlet, and an ion gating mechanism located at the ion drift tube outlet for regulating ion ejection, the ion trap accumulates aerosol ions and periodically releases them into the ion drift tube, the ion transit time through the ion drift tube is dependent on ion gas mobility within the buffer gas, and the mass spectrometer measures the mass-to-charge ratio of ions exiting the ion drift tube.

70. 1. A method for analyzing aerosol particles, comprising: obtaining aerosol particles that have been at least partially disintegrated using the system of claim 57; detecting and analyzing the at least partially disintegrated aerosol particles with an analysis system; and A method comprising:

71. 71. The method of claim 70, wherein the analysis system comprises a mass spectrometer.

72. 71. The method of claim 70, wherein the aerosol particles are collected by the aspirator device, and the at least partially disintegrated aerosol particles comprise ions, which are subsequently analyzed by the mass spectrometer.

73. 72. The method of claim 70 or 71, wherein at least some of the sample aerosol particles have diameters in the range of 1 nanometer to 100 micrometers.

74. 72. The method of claim 70 or 71, wherein the sample aerosol particles are generated from in vivo biological tissue.

75. 72. The method of claim 70 or 71, wherein the sample aerosol particles are generated from ex vivo biological tissue.

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