CN113040831A

CN113040831A - Inlet instrument for an ion analyzer coupled to a rapid evaporative ionization mass spectrometry apparatus

Info

Publication number: CN113040831A
Application number: CN202110200506.7A
Authority: CN
Inventors: 佐尔坦·塔卡茨; 茱莉亚·巴洛格; 史蒂文·德里克·普林格尔; 塔马斯·卡兰斯; 迈克尔·雷蒙德·莫里斯; 拉约什·高迪尔海兹; 丹尼尔·绍洛伊; 丹尼尔·西蒙
Original assignee: Micromass UK Ltd
Current assignee: Micromass UK Ltd
Priority date: 2015-03-06
Filing date: 2016-03-07
Publication date: 2021-06-29
Also published as: GB2594421A; CA3234867A1; GB2583469A; GB2602212B; GB202014274D0; CN107635477A; GB2598259A; GB202202418D0; GB201905763D0; CN107635477B; GB2587288B; GB202015580D0; GB202110454D0; GB2601954A; GB202019168D0; GB2585167B; GB2601439A; CN111991078A; GB202117492D0; CN112557490A

Abstract

An apparatus is disclosed, comprising: a first device (1) for generating aerosol, smoke or vapor (5) from one or more regions of a target; connected to an inlet of an ion analyzer or mass spectrometer a conduit having an inlet through which said aerosol, smoke or vapour (5) passes; and a venturi pump arrangement arranged and adapted to direct said aerosol, smoke or vapour 5 to the inlet.

Description

Inlet instrument for an ion analyzer coupled to a rapid evaporative ionization mass spectrometry apparatus

Cross Reference to Related Applications

The present application is a divisional application entitled "inlet instrument for an ion analyzer coupled to a rapid evaporative ionization mass spectrometry (" REIMS ") apparatus," filed 2016, number 201680025116.8(PCT/GB2016/050620), filed 2016, year 07, 2016. This application claims priority and benefit from british patent application No. 1503876.3 filed on day 3/6 of 2015, british patent application No. 1503864.9 filed on day 3/6 of 2015, british patent application No. 1518369.2 filed on day 10/16 of 2015, british patent application No. 1503877.1 filed on day 3/6 of 2015, british patent application No. 1503867.2 filed on day 6 of 2015 3/6, british patent application No. 1503863.1 filed on day 3/6 of 2015, british patent application No. 1503878.9 filed on day 3/6 of 2015, british patent application No. 1503879.7 filed on day 3/6 of 2015, and british patent application No. 1516003.9 filed on day 9/9 of 2015. The entire contents of the above application are incorporated herein by reference.

Technical Field

The present invention relates generally to mass spectrometry and/or ion mobility spectrometry, and more particularly to apparatus for performing ambient ionization mass spectrometry and/or ion mobility spectrometry including rapid evaporative ionization mass spectrometry ("REIMS"), mass spectrometry, ion mobility spectrometry, rapid evaporative ionization mass spectrometry, ion mobility spectrometry, and electrosurgical methods, and an electrosurgical apparatus.

Various embodiments are contemplated in which analyte ions are generated by an ambient ionization ion source, followed by: (i) mass analysis by a mass analyser such as a quadrupole mass analyser or a time-of-flight mass analyser; (ii) ion mobility analysis (IMS) and/or differential ion mobility analysis (DMA) and/or asymmetric field ion mobility spectrometry (FAIMS) analysis; and/or (iii) a combination of first performing ion mobility analysis (IMS) and/or differential ion mobility analysis (DMA) and/or asymmetric field ion mobility spectrometry (FAIMS) analysis, and second (or first) performing mass analysis by a mass analyser such as a quadrupole mass analyser or a time of flight mass analyser. Various embodiments also relate to an ion mobility spectrometer and/or mass analyser and a method of ion mobility mass spectrometry and/or mass analysis.

Background

Rapid evaporative ionization mass spectrometry ("REIMS") is a relatively new technology that facilitates the analysis of many different types of samples, including the identification of tissues.

With reference to analytical chemistry (anal. chem.)2014, 86, 6555-6562 of n.strittatter et al, a study of the applicability of rapid evaporative ionization mass spectrometry as a general identification system for bacteria and fungi is disclosed.

Known means of analysing bacterial colonies by rapid evaporative ionisation mass spectrometry include the use of bipolar electrosurgical forceps and an electrosurgical radio frequency generator. Bacterial colonies were scraped from the surface of the agar layer using bipolar electrosurgical forceps and a brief burst of radio frequency voltage generated by an electrosurgical radio frequency generator was then applied between these bipolar electrosurgical forceps. For example, it is known to apply 60w of power in a bipolar mode at a sinusoidal frequency of 470 kHz. The radio frequency voltage applied between the bipolar electrosurgical forceps has the result of rapidly heating a particular portion of the bacterial colony that is under analysis due to its non-zero impedance. The rapid heating of the microbial mass results in the production of an aerosol. The aerosol is delivered directly into the mass spectrometer, and the aerosol sample can then be analyzed by the mass spectrometer. It is known to utilize multivariate statistical analysis to help differentiate and identify different samples.

It is desirable to provide an improved apparatus for analyzing a target or tissue that uses an ambient ionizing ion source.

Disclosure of Invention

According to one aspect, there is provided an apparatus comprising:

first means for generating aerosol, smoke or vapour from one or more regions of a target;

an inlet conduit connected to an ion analyser or mass spectrometer, the inlet conduit having an inlet through which aerosol, smoke or vapour passes; and

a Venturi (Venturi) pump device arranged and adapted to direct the aerosol, smoke or vapour to the inlet.

The ion analyser or mass spectrometer may comprise a mass spectrometer and/or a mass to charge ratio mass spectrometer and/or an ion mobility spectrometer. The ion analyzer may include a tandem mass spectrometer and an ion mobility spectrometer system.

The venturi pump device disclosed in analytical chemistry (anal. chem.)2014, 86, 6555-6562 of n.strittatter et al does not teach or suggest providing a venturi pump device that directs aerosol, smoke or vapor to the inlet of the inlet conduit. The provision of a venturi pump device allows improved inhalation of aerosol, smoke or vapour and improved signal density of analyte ions.

The venturi pump device may be arranged and adapted to direct aerosol, smoke or vapour onto the deflector or deflector surface before the aerosol, smoke or vapour passes through the inlet.

The deflection means may comprise a hollow member having a first side and a second side, wherein the first side may be solid and the second side may comprise one or more apertures arranged and adapted to allow aerosol, smoke or vapour to pass through; and the venturi pump means may be arranged and adapted to direct aerosol, smoke or vapour onto the first surface of the deflector means.

The first side may be arranged and adapted to deflect the oncoming material away from the second side and/or the one or more apertures. In use, relatively large particles of the oncoming material (e.g. contained in aerosol, smoke or vapour) may be deflected away from the inlet duct. Relatively small particles of the oncoming material (e.g. contained in aerosol, smoke or vapour) may be deflected but still drawn into the inlet duct, for example due to a pressure differential between a region adjacent to one or more apertures and the particle analyser or mass spectrometer.

The apertures may be in fluid communication with a cavity or channel in the hollow member, and the inlet may be in fluid communication with the cavity or channel.

The apparatus may further comprise a substrate conduit for introducing and mixing the substrate with the aerosol, smoke or vapour before the aerosol, smoke or vapour passes through the inlet.

The matrix may comprise a polar molecule, water, one or more alcohols, methanol, ethanol, isopropanol, acetone or acetonitrile. The matrix may comprise a molecular weight-locking compound or a calibration compound.

The matrix conduit may be in fluid communication with the cavity or channel.

The hollow member may include an axial channel and a radial channel, wherein the radial channel extends to the second side and the axial channel extends longitudinally along the length of the hollow member. The radial channel may have an exit forming an aperture of the one or more apertures.

The hollow member may include a substantially cylindrical outer surface (e.g., the outer surface forms a cylinder in addition to one or more apertures), and the axial passage may extend from a first axial end of the cylinder to a second axial end of the cylinder. The inlet conduit may be inserted into a first end of the cylinder and the inlet conduit may be inserted into a second end of the cylinder.

The inlet conduit and/or the matrix conduit and/or the axial channel may be coaxial with each other.

The inlet of the inlet conduit and the outlet of the substrate conduit may be located within the cavity or channel and opposite one another, the outlet may be spaced from the inlet of the inlet conduit by a distance x, wherein x may be greater than, less than or equal to about 0mm, about 0.5mm, about 1mm, about 1.5mm, about 2mm, about 2.5mm, about 3mm, about 3.5mm, about 4mm, about 4.5mm or about 5mm and optionally between about 3mm and 4 mm.

The radial passage may intersect the axial passage at a junction and, in use, aerosol, smoke or vapour may pass through the radial passage before passing into the inlet of the inlet duct.

If a substrate conduit is provided, at some point the aerosol, smoke or vapour will mix with the substrate flowing out of the substrate conduit. Depending on the position of the matrix conduit within the axial passage. The substrate conduit may include an outlet end. If this outlet end is located in the axial passage in front of the joint, the substrate flowing out of the substrate conduit and the aerosol, smoke or vapour will initially mix at the joint.

If the outlet end is located within an axial passage and passes through the junction, the aerosol, smoke or vapour may be arranged and adapted to travel (e.g. coaxially) around the substrate conduit and mix with substrate flowing from the substrate conduit passing through the junction.

The matrix conduit may be inserted into an inlet conduit of an ion analyzer or mass spectrometer. For example, the outer diameter of the matrix conduit may be smaller than the inner diameter of the inlet conduit. In this case, the aerosol, smoke or vapour will travel around (e.g. coaxially) the substrate conduit within the axial passage and within the inlet conduit and then mix with the aerosol, smoke or vapour within the inlet conduit.

The matrix conduit and/or inlet conduit and/or axial channel has an inner or outer diameter as follows: (i) about 0.01mm to 0.02 mm; (ii) about 0.02mm to 0.03 mm; (iii) about 0.03mm to 0.04 mm; (iv) about 0.04mm to 0.05 mm; (v) about 0.05mm to 0.06 mm; (vi) about 0.06mm to 0.07 mm; (vii) about 0.07mm to 0.08 mm; (viii) about 0.08mm to 0.09 mm; (ix) about 0.1mm to 0.2 mm; (x) About 0.2mm to 0.3 mm; (xi) About 0.3mm to 0.4 mm; (xii) About 0.5mm to 0.6 mm; (xiii) About 0.6mm to 0.7 mm; (xiv) About 0.7mm to 0.8 mm; (xv) About 0.8mm to 0.9 mm; (xvi) About 0.9mm to 1 mm; (xvii) About 1mm to 2 mm; (xviii) About 2mm to 3 mm; (xix) About 3mm to 4 mm; (xx) about 4mm to 5mm or (xxi) greater than 5 mm.

The matrix conduit and/or the inlet conduit and/or the cavity or channel may be substantially coaxially aligned with each other.

The venturi pump device may comprise an elongate portion having an outlet through which aerosol, smoke or vapour may pass, and the elongate portion may have a longitudinal axis which may be perpendicular or substantially perpendicular to the longitudinal axis of the cavity or channel and/or the inlet conduit and/or the substrate conduit.

The first device may comprise an open ion source.

The target may comprise a natural or unmodified target material.

The native or unmodified target material may not be modified after addition of the matrix or reagent.

The first device may be arranged and adapted to generate aerosol, smoke or vapour from one or more regions of a target, and the target does not need to be prepared in advance.

The first device may comprise an ion source selected from the group consisting of: (i) a rapid evaporative ionization mass spectrometry ("REIMS") ion source; (ii) a desorption electrospray ionization ("DESI") ion source; (iii) a laser desorption ionization ("LDI") ion source; (iv) a thermal desorption ion source; (v) a laser diode thermal desorption ("LDTD") ion source; (vi) a desorption electrokinetic focusing ("DEFFI") ion source; (vii) a dielectric barrier discharge ("DBD") plasma ion source; (viii) an atmospheric pressure solid analysis probe ("ASAP") ion source; (ix) an ultrasonic-assisted spray ionization ion source; (x) A simple open acoustic spray ionization ("EASI") ion source; (xi) A desorption atmospheric pressure photoionization ("DAPPI") ion source; (xii) A paper spray ("PS") ion source; (xiii) A jet desorption ionization ("JeDI") ion source; (xiv) A touch spray ("TS") ion source; (xv) A nano-desorption electrospray ionization ion source; (xvi) A laser ablation electrospray ionization ("LAESI") ion source; (xvii) A real-time direct analysis ("DART") ion source; (xviii) A probe electrospray ("PESI") ion source; (xix) A solid probe-assisted electrospray ionization ("SPA-ESI") ion source; (xx) An ultrasonic surgical suction apparatus ("CUSA") ion source; (xxi) A focused or unfocused ultrasonic ablation ion source; (xxii) A microwave resonance ion source; and (xxiii) pulsed plasma Radio Frequency (RF) dissectors.

The first means may comprise one or more electrodes which may be arranged and adapted to generate aerosol, smoke or vapour from one or more regions of the target.

The one or more electrodes may comprise a bipolar device or a single-stage device.

One or more of the electrodes may comprise a rapid evaporative ionization mass spectrometry ("REIMS") device.

The device may further comprise a voltage source arranged and adapted to apply an AC or RF voltage to the one or more electrodes to generate the aerosol, smoke or vapour.

The voltage source may be arranged and adapted to apply one or more pulses of AC or RF voltage to the one or more electrodes.

The step of applying the AC or RF voltage to one or more electrodes may cause heat to be dissipated into the target.

The first means may comprise a laser source and means for irradiating the target with laser light from the laser source to generate an aerosol, smoke or vapour.

The first device is arranged and adapted to generate an aerosol from one or more regions of the target via direct evaporation or vaporisation of target material from the target by joule heating or diathermy.

The first device may comprise a transducer arranged and adapted to direct ultrasonic energy into the target to generate aerosol, smoke or vapour.

The aerosol may comprise uncharged aqueous droplets, which optionally comprise cellular material.

At least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the mass or substance generated by the first device and forming the aerosol may be in the form of droplets.

The first device is arranged and adapted to generate an aerosol, wherein the aerosol has a Sauter mean diameter ("SMD", d32) in the range: (i) less than 5 μm; (ii)5 μm to 10 μm; (iii)10 μm to 15 μm; (iv)15 μm to 20 μm; (v)20 μm to 25 μm; or (vi) greater than 25 μm.

The aerosol can traverse a flow region having a reynolds number (Re) within the range: (i) less than 2000; (ii)2000 to 2500; (iii)2500 to 3000; (iv)3000 to 3500; (v)3500 to 4000; or (vi) greater than 4000.

Substantially at the time of generating the aerosol, the aerosol may include droplets having a weber number (We) selected from the group consisting of: (i) less than 50; (ii)50 to 100; (iii)100 to 150; (iv)150 to 200; (v)200 to 250; (vi)250 to 300; (vii)300 to 350; (viii)350 to 400; (ix)400 to 450; (x)450 to 500; (xi)500 to 550; (xii)550 to 600; (xiii)600 to 650; (xiv)650 to 700; (xv)700 to 750; (xvi)750 to 800; (xvii)800 to 850; (xviii)850 to 900; (xix) 900 to 950; (xx)950 to 1000; and (xxi) greater than 1000.

Substantially at the time of generating the aerosol, the aerosol may comprise a gas having a stokes number (S)_k) The stokes number is in the following range: (i)1 to 5; (ii)5 to 10; (iii)10 to 15; (iv)15 to 20; (v)20 to 25; (vi)25 to 30; (vii)30 to 35; (viii)35 to 40; (ix)40 to 45; (x)45 to 50; and (xi) greater than 50.

Substantially at the time of generating the aerosol, the aerosol may comprise droplets having a mean axial velocity selected from the group consisting of: (i) less than 20 m/s; (ii)20m/s to 30 m/s; (iii)30m/s to 40 m/s; (iv)40m/s to 50 m/s; (v)50m/s to 60 m/s; (vi)60m/s to 70 m/s; (vii)70m/s to 80 m/s; (viii)80m/s to 90 m/s; (ix)90m/s to 100 m/s; (x)100m/s to 110 m/s; (xi) 110m/s to 120 m/s; (xii)120m/s to 130 m/s; (xiii)130m/s to 140 m/s; (xiv)140m/s to 150 m/s; and (xv) greater than 150 m/s.

The target may comprise a sample containing an organic compound. The target may comprise an organic synthetic or semi-synthetic compound and/or may comprise one or more polymers (e.g. plastics or rubbers).

The meaning of sample or sample portion herein may refer to a sample containing organic compounds, or a sample comprising organic synthetic or semi-synthetic compounds and/or may comprise one or more polymers (e.g. plastics or rubbers).

The target may comprise biological tissue, biological matter, bacterial colonies or fungal colonies. Biological tissue may be referred to herein as biological material, bacterial colonies or fungal colonies.

The biological tissue may comprise human tissue or non-human animal tissue.

The biological tissue may include biological tissue, biological matter, bacterial colonies, or fungal colonies in vivo.

The biological tissue may comprise ex vivo biological tissue, biological matter, bacterial colonies or fungal colonies.

The biological tissue may comprise biological tissue, biological matter, bacterial colonies or fungal colonies in vitro.

The biological tissue may include: (i) adrenal tissue, appendiceal tissue, bladder tissue, bone, intestinal tissue, brain tissue, breast tissue, bronchi, crown tissue, ear tissue, esophageal tissue, eye tissue, gall bladder tissue, genital tissue, heart tissue, hypothalamus tissue, kidney tissue, large intestine tissue, intestinal wall tissue, larynx tissue, liver tissue, lung tissue, lymph nodes, oral tissue, nose tissue, pancreas tissue, parathyroid gland tissue, pituitary gland tissue, prostate tissue, rectal tissue, salivary gland tissue, skeletal muscle tissue, skin tissue, small intestine tissue, spinal cord, spleen tissue, stomach tissue, thymus tissue, trachea tissue, thyroid tissue, ureter tissue, urethra tissue, soft connective tissue, peritoneal tissue, vascular tissue, and/or adipose tissue; (ii) primary, secondary, tertiary or quaternary cancerous tissue; (iii) metastatic cancerous tissue; (iv) mixed grade cancerous tissue; (v) secondary cancerous tissue; (vi) healthy or normal tissue; or (vii) cancerous or abnormal tissue.

The first device may comprise a point of care ("POC"), diagnostic or surgical device.

The ion analyser or mass spectrometer may be arranged and adapted to ionize at least some of the aerosol, smoke or vapour to generate analyte ions.

The apparatus may further comprise inlet means arranged and adapted to direct at least some of the aerosol, smoke or vapour into the vacuum chamber of the ion analyser or mass spectrometer.

The ion analyser or mass spectrometer may be arranged and adapted to ionize at least some of the aerosol, smoke or vapour located in one or the vacuum chamber of the ion analyser or mass spectrometer to generate analyte ions.

The apparatus may further comprise a collision surface located in one or the vacuum chamber, the vacuum chamber being arranged and adapted such that aerosol, smoke or vapour impinges the collision surface to generate a plurality of analyte ions.

The apparatus may further comprise a mass analyser and/or an ion mobility analyser arranged and adapted to mass analyse or ion mobility analyse the analyte ions to obtain mass spectrum or ion mobility data.

The apparatus may further comprise a mass analyser and/or an ion mobility analyser arranged and adapted to mass analyse or ion mobility analyse the aerosol, smoke or vapour or ions derived therefrom to obtain mass spectrum and/or ion mobility data.

The apparatus may further comprise a control mechanism arranged and adapted to analyse the mass spectrum and/or ion mobility data so as to: (i) distinguishing between healthy and diseased tissue; (ii) distinguishing between potentially cancerous and non-cancerous tissue; (iii) differentiating between different types or grades of cancerous tissue; (iv) distinguishing between different types or categories of target material; (v) determining whether one or more desirable or undesirable substances may be present in the target; (vi) determining the identity or authenticity of the target; (vii) determining whether one or more impurities, illicit substances or unwanted substances may be present in the target; (viii) determining whether the patient or the diseased animal is likely to be at increased risk for suffering adverse consequences; (ix) making or aiding in making a diagnosis or prognosis; and (x) notifying the surgeon, nurse, doctor or robot of the results of the medical, surgical or diagnostic procedure.

The apparatus may further comprise processing means arranged and adapted to analyse the mass spectral and/or ion mobility data via supervised multivariate statistical analysis of the mass spectral and/or ion mobility data.

Or: (i) multivariate statistical analysis may include principal component analysis ("PCA"); (ii) the multivariate statistical analysis may include linear discriminant analysis ("LDA"); (iii) multivariate statistical analysis may be performed by a neural network; (iv) multivariate statistical analysis can be performed by a support vector machine; or (v) the multivariate statistical analysis may comprise subspace discriminant analysis.

The processing means may be arranged and adapted to analyse mass spectral and/or ion mobility data via analysis of a spectrum of the aerosol, smoke or vapour or of ions derived from the aerosol, smoke or vapour.

The spectrum may be selected from the group consisting of: (i) lipidomics profile; (ii) a fatty acid profile; (iii) a phospholipid profile; (iv) phosphatidic Acid (PA) profile; (v) a Phosphatidylethanolamine (PE) profile; (vi) a Phosphatidylglycerol (PG) profile; (vii) a Phosphatidylserine (PS) profile; (viii) a Phosphatidylinositol (PI) profile; or (ix) Triglyceride (TG) profile.

According to one aspect, there is provided an apparatus comprising:

a device arranged and adapted to mix the aerosol, smoke or vapour with the substrate or solvent to produce a mixture of particles of the aerosol, smoke or vapour and the substrate, wherein the device comprises:

a first conduit arranged and adapted to receive the aerosol, smoke or vapour in the first device;

a second conduit arranged and adapted to receive a substrate conduit or tube, wherein the substrate conduit is arranged and adapted to supply substrate or solvent to the device from a substrate or solvent source; and

a third conduit arranged and adapted to receive an inlet tube for conveying a mixture of the substrate or solvent and the aerosol, smoke or vapour to an ion analyser or mass spectrometer.

The apparatus may comprise the matrix conduit and/or the inlet tube. The first, second, and third conduits may be in fluid communication with one another.

The device may comprise or form a hollow member, and the hollow member may comprise a single sheet of material having one or more internal cavities or channels that form the first, second and third conduits.

The first conduit may be arranged orthogonal to the second conduit and/or the third conduit. The first conduit may intersect the second conduit and/or the third conduit at a junction. In use, a sample may flow from the first conduit to the third conduit via the junction before entering or being drawn into the inlet tube.

At some point, the aerosol, mist or vapor will mix with the substrate flowing from the substrate conduit. Depending on the location of the matrix conduit within the device. The substrate conduit may include an outlet end. If this outlet end is located within the device and before the junction (i.e. within the second conduit and before the intersection of the first and second conduits), the substrate flowing from the substrate conduit and the aerosol, smoke or vapour will undergo initial mixing at the junction.

If the outlet end is located within the device and passes through the junction (i.e. within the third conduit and behind the intersection of the first conduit with the third conduit), the aerosol, smoke or vapour may be arranged and adapted to travel (e.g. coaxially) around the substrate conduit and mix with substrate flowing from the substrate conduit passing through the junction.

The matrix conduit may be inserted into an inlet tube. For example, the outer diameter of the matrix conduit may be smaller than the inner diameter of the inlet tube. In this case, the aerosol, smoke or vapour will travel around the substrate conduit within the axial passage and within the inlet tube (e.g. coaxially and/or through a gap between the outer surface of the substrate conduit and the third conduit and/or the surface of the junction) and then mix with the aerosol, smoke or vapour within the inlet tube.

The inner or outer diameter of the matrix conduit and/or inlet tube and/or first conduit and/or second conduit and/or third conduit is as follows: (i) about 0.01mm to 0.02 mm; (ii) about 0.02mm to 0.03 mm; (iii) about 0.03mm to 0.04 mm; (iv) about 0.04mm to 0.05 mm; (v) about 0.05mm to 0.06 mm; (vi) about 0.06mm to 0.07 mm; (vii) about 0.07mm to 0.08 mm; (viii) about 0.08mm to 0.09 mm; (ix) about 0.1mm to 0.2 mm; (x) About 0.2mm to 0.3 mm; (xi) About 0.3mm to 0.4 mm; (xii) About 0.5mm to 0.6 mm; (xiii) About 0.6mm to 0.7 mm; (xiv) About 0.7mm to 0.8 mm; (xv) About 0.8mm to 0.9 mm; (xvi) About 0.9mm to 1 mm; (xvii) About 1mm to 2 mm; (xviii) About 2mm to 3 mm; (xix) About 3mm to 4 mm; (xx) About 4mm to 5mm or (xxi) greater than 5 mm.

The third conduit may be in fluid communication with a vacuum chamber of an ion analyzer or mass spectrometer.

In use, aerosol, smoke or vapour may be drawn into the first conduit by the inherent vacuum of the ion analyser or mass spectrometer. In use, aerosol, smoke or vapour may be drawn into the second conduit by the inherent vacuum of the ion analyser or mass spectrometer.

The first conduit may intersect the second and third conduits at one or the junction and the outlet end of the substrate conduit may be located within the third conduit and behind the junction such that, in use, the aerosol, smoke or vapour may travel around the substrate conduit (e.g. coaxially and through a gap between an outer surface of the substrate conduit and a surface of the third conduit and/or the junction) and mix with substrate flowing from the substrate conduit through the junction at the outlet end of the substrate conduit.

The substrate conduit may be a substrate tube or a substrate introduction tube.

According to another aspect, there is provided an apparatus comprising:

an inlet conduit connected to an ion analyzer or mass spectrometer;

An aerosol, smoke or vapour introduction conduit which may be arranged and adapted to direct aerosol, smoke or vapour in the inlet conduit; and

a substrate introduction conduit may be arranged and adapted to introduce the substrate (or solvent) in the inlet conduit.

The aerosol, smoke or vapour introduction conduit may be substantially coaxially aligned with the substrate introduction tube.

The aerosol, smoke or vapour introduction conduit may be located concentrically within or around the substrate introduction conduit. The substrate introduction conduit may be located concentrically around the aerosol, smoke or vapour introduction conduit.

The combination of the substrate introduction conduit and aerosol, smoke or vapour introduction conduit may form a venturi pump configured to draw aerosol, smoke or vapour from the aerosol, smoke or vapour introduction conduit and atomise it.

The apparatus may further comprise a pump arranged and adapted to pump the substrate through or around the aerosol, smoke or vapour introduction conduit at a flow rate of greater than 1ml/min, 1.5ml/min, 2 ml/min, 2.5ml/min or 3 ml/min.

The aerosol, smoke or vapour introduction conduit and/or substrate introduction conduit may be arranged and adapted to direct aerosol, smoke or vapour and/or substrate orthogonally through the inlet conduit; in use, aerosol, smoke or vapour may be drawn into the inlet conduit by the inherent vacuum of the ion analyser or mass spectrometer. In use, a matrix or solvent may be drawn into the inlet conduit by the inherent vacuum of the ion analyser or mass spectrometer.

The inner or outer diameter of the substrate introduction conduit and/or the inlet conduit and/or the first conduit and/or the aerosol, smoke or vapour introduction conduit is as follows: (i) about 0.01mm to 0.02 mm; (ii) about 0.02mm to 0.03 mm; (iii) about 0.03mm to 0.04 mm; (iv) about 0.04mm to 0.05 mm; (v) about 0.05mm to 0.06 mm; (vi) about 0.06mm to 0.07 mm; (vii) about 0.07mm to 0.08 mm; (viii) about 0.08mm to 0.09 mm; (ix) about 0.1mm to 0.2 mm; (x) About 0.2mm to 0.3 mm; (xi) About 0.3mm to 0.4 mm; (xii) About 0.5mm to 0.6 mm; (xiii) About 0.6mm to 0.7 mm; (xiv) About 0.7mm to 0.8 mm; (xv) About 0.8mm to 0.9 mm; (xvi) About 0.9mm to 1 mm; (xvii) About 1mm to 2 mm; (xviii) About 2mm to 3 mm; (xix) About 3mm to 4 mm; (xx) About 4mm to 5mm or (xxi) greater than 5 mm.

According to another aspect, there is provided an apparatus comprising:

a venturi pump device arranged and adapted to direct aerosol, smoke or vapour to the junction;

an inlet conduit having an inlet at a junction arranged and adapted to convey aerosol, smoke or vapour to an ion analyser or mass spectrometer;

a substrate introduction conduit arranged and adapted to introduce a substrate or solvent into the junction or the inlet conduit.

In use, the particles of aerosol, smoke or vapour may be mixed with the substrate or solvent at the junction or within the inlet duct.

The venturi pump device may comprise a sample transfer portion arranged and adapted to direct aerosol, smoke or vapour to the junction.

The sample transfer portion may be elongate and have a longitudinal axis along which, in use, the sample transfer portion may be arranged and adapted such that aerosol, smoke or vapour is directed.

The inlet conduit may be orthogonally disposed or positioned relative to the sample delivery portion.

The matrix introduction conduit may be orthogonally disposed or positioned relative to the sample delivery portion.

The matrix introduction conduit may have a first longitudinal axis, the inlet conduit may have a second longitudinal axis, and the first longitudinal axis may be parallel to the second longitudinal axis.

The substrate introduction conduit may have an outlet through which, in use, substrate may pass and the position of which relative to the inlet of the inlet conduit may be adjusted.

The distance between the outlet of the matrix introduction conduit and the inlet of the inlet conduit may be between 0mm to 10mm, 2mm to 8mm, 2mm to 6mm or 2mm to 4 mm.

The outlet may be placed within an inlet conduit such that the aerosol, smoke or vapour may be arranged and adapted to travel around a substrate introduction conduit (e.g. coaxially and/or through a gap between an outer surface of the substrate conduit and an inner surface of the inlet conduit) and mix within the inlet conduit with substrate flowing out of the substrate conduit.

The matrix introduction conduit and/or the inlet conduit and/or the sample transfer section have an inner or outer diameter as follows: (i) about 0.01mm to 0.02 mm; (ii) about 0.02mm to 0.03 mm; (iii) about 0.03mm to 0.04 mm; (iv) about 0.04mm to 0.05 mm; (v) about 0.05mm to 0.06 mm; (vi) about 0.06mm to 0.07 mm; (vii) about 0.07mm to 0.08 mm; (viii) about 0.08mm to 0.09 mm; (ix) about 0.1mm to 0.2 mm; (x) About 0.2mm to 0.3 mm; (xi) About 0.3mm to 0.4 mm; (xii) About 0.5mm to 0.6 mm; (xiii) About 0.6mm to 0.7 mm; (xiv) About 0.7mm to 0.8 mm; (xv) About 0.8mm to 0.9 mm; (xvi) About 0.9mm to 1 mm; (xvii) About 1mm to 2 mm; (xviii) About 2mm to 3 mm; (xix) About 3mm to 4 mm; (xx) About 4mm to 5mm or (xxi) greater than 5 mm.

In use, particles of the aerosol, smoke or vapour may intermix with particles of the substrate within the inlet duct to form molecules comprising molecular constituents of both the particles of the aerosol, smoke or vapour and the particles of the substrate.

The apparatus may further comprise a collision surface, wherein, in use, molecules comprising molecular constituents of both particles of the aerosol, smoke or vapour and particles of the matrix may be accelerated or otherwise directed onto the collision surface to form analyte ions.

The apparatus may further comprise a heater or heating means arranged and adapted to heat the impact surface.

The impingement surface may be located within a vacuum chamber.

The vacuum chamber may form part of the ion analyser or mass spectrometer.

According to another aspect, there is provided an apparatus comprising:

a first device arranged and adapted to emit a stream of electrically-charged droplets towards a target in use;

a transfer capillary arranged and adapted to transfer ions generated by the target to an ion analyser or mass spectrometer; and

heating means arranged and adapted to heat: (i) a capillary of a first device; (ii) a stream of charged droplets emitted by a first device; (iii) a target; or (iv) a transfer capillary.

The first device may comprise a desorption electrospray ionization ("DESI") device.

The heating means may comprise a heater.

The heater may comprise a wire heater.

The heater may be arranged and adapted to heat the capillary tube of the first device, the stream of charged droplets, the target or transport capillary tube emitted by the first device to a temperature above ambient temperature, and/or to a temperature of at least 30 ℃, 50 ℃, 100 ℃, 200 ℃, 300 ℃, 400 ℃, 500 ℃ or above 500 ℃.

The heating means may be located adjacent to the inlet of the ion analyser or mass spectrometer.

The inlet may form the entrance to a first vacuum stage of an ion analyser or mass spectrometer.

According to another aspect, there is provided a method of introducing ions into an ion analyser or mass spectrometer, the method comprising:

generating ions by desorption electrospray ionization ("DESI"); and

the ions are transported into an ion analyzer or mass spectrometer via a heated capillary.

The method may further comprise heating the capillary tube to a temperature above ambient temperature, and/or to a temperature of at least 30 ℃, 50 ℃, 100 ℃, 200 ℃, 300 ℃, 400 ℃, 500 ℃ or above 500 ℃.

The step of generating ions may comprise desorbing ions from a biological sample, wherein the sample may comprise lipids. The sample may include or further include carbohydrates, enzymes, hormones, fatty acids, neurotransmitters, nucleic acids, proteins, peptides, amino acids, lectins, vitamins, lipids.

The sample may include phospholipids.

According to another aspect, there is provided an apparatus comprising:

a portable device comprising one or more instrument stacks, wherein each instrument stack of the one or more instrument stacks may comprise one or more wheels or tracks for facilitating movement of the instrument stack; and

an ion analyser or mass spectrometer is carried by one of the one or more instrument sets and is connected in use to the first device.

One or more instrument sets may be operably coupled to an endoscope including a first device.

The endoscope may comprise one or more gas channels or ports disposed at least partially along its length, wherein the gas channels may be arranged and adapted to convey aerosol, smoke or vapour to an ion analyser or mass spectrometer.

The apparatus may further comprise a first endoscope control system arranged and adapted to control the endoscope and a second control system arranged and adapted to control the first device.

The first control system may comprise a first monitor arranged and adapted to display images relayed from the distal end of the endoscope.

The second control system may comprise a second monitor arranged and adapted to display data or information output from the ion analyser or mass spectrometer.

The first and second monitors may be located on or comprised by a mobile device, such as a mobile tablet device.

The first and second monitors may be the same component.

The ion analyzer or mass spectrometer and endoscope control system may be carried by the same instrument suite.

Each instrument in the one or more instrument sets weighs less than 500kg, 400kg, 300kg, 200kg, 150kg, 100kg, 50kg, 40kg, 30kg, 20kg, 10kg, or 5 kg.

According to another aspect, there is provided a surgical device comprising a device as described above.

The apparatus may further comprise a set of surgical rooms and a track or rail between each surgical room, wherein the wheels or tracks on one or more instrument sets may be configured to move along the track or rail, allowing one or more instrument sets to move between each surgical room.

According to another aspect, there is provided an apparatus comprising:

a first device for generating aerosol, smoke or vapour from one or more regions of a target, wherein the first device may be arranged and adapted for use in surgical applications.

The first device may comprise one or more electrodes arranged and adapted to contact the sample to generate the aerosol, smoke or vapour.

The length of one or more electrodes may be less than 20mm, 15mm, 10mm or 5 mm.

The surface area of the one or more electrodes may be less than 200mm²、100mm²、50mm²、40mm²、30mm²、20 mm²Or 10mm ²、2mm²、1mm²、0.5mm²、0.4mm²、0.3mm²、0.2mm²Or 0.1mm²。

The first device may comprise an internal passage that conveys aerosol, smoke or vapour generated by the one or more electrodes to an external device.

At least one of the one or more electrodes may comprise an aperture arranged and adapted to allow aerosol, smoke or vapour to pass through the aperture in use, wherein the aperture may form an entrance to the internal passage.

One or more of the electrodes may be sharpened toward the distal end that forms the contact area for the one or more electrodes.

The contact area may be defined as the surface area of an electrode arranged and adapted to contact a sample in use.

The contact area may be defined as the surface area of the one or more electrodes within a distance d from the distal end of the one or more electrodes, where d may be 10mm, 5mm, 4mm, 3mm, 2mm, 1mm, 0.8mm, 0.6mm, 0.5mm, 0.4mm, 0.3mm, 0.2mm, or 0.1 mm.

The contact area may be less than 200mm²、100mm²、50mm²、40mm²、30mm²、20mm²Or 10mm²、 2mm²、1mm²、0.5mm²、0.4mm²、0.3mm²、0.2mm²Or 0.1mm²。

The apparatus may further comprise a voltage source arranged and adapted to provide a voltage to the one or more electrodes, wherein the voltage source has a voltage limit of less than 3kV, 2.5kV, 2kV, 1.5kV, 1kV, 500V, 400V, 350V, 300V, 250V, 200V, 150V, 100V, 50V, 20V or 10V peak voltage or effective value voltage (RMS).

The first means may comprise a single monopolar electrode arranged and adapted to generate aerosol, smoke or vapour.

The first means may comprise a pair of bipolar electrodes arranged and adapted to generate aerosol, smoke or vapour.

According to another aspect, there is provided a method of using the apparatus as disclosed above, the method comprising:

scanning the first device across one or more regions of the target;

determining whether one or more compounds of interest are present at one or more locations of the target; and

the surgical procedure is guided, modified, initiated or stopped based on whether the presence of the compound of interest has been determined.

If it has been determined that the compound is present at these locations, the step of directing, modifying, starting or stopping the surgical procedure may comprise removing tissue present at one or more locations.

If it is determined that the compound is not present or is no longer present at these locations, the step of directing, modifying, initiating or stopping the surgical procedure may include stopping the removal of tissue present at one or more locations.

According to another aspect, there is provided a robotic surgical method, the method comprising:

providing a hand-held manipulator that may be operably coupled to the probe via one or more actuators;

manually moving the hand-held manipulator;

automatically causing one or more actuators to move a probe in response to movement of the hand-held manipulator;

energizing the probe to generate aerosol, smoke, or vapor; and

the aerosol, smoke or vapour is analysed. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

According to another aspect, there is provided an apparatus comprising:

a user interface;

a robotic probe responsive to or controlled by a user interface, wherein the robotic probe is arranged for generating aerosol, smoke or vapour; and

a mass analyzer and/or an ion mobility analyzer for analyzing the aerosol, smoke or vapor or for ion mobility analysis. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The user interface may include a hand-held manipulator that may be operatively coupled to the robotic probe to control movement thereof.

The user interface may be arranged and adapted such that, in use, movement of the hand-held manipulator causes movement of one or more actuators.

The robotic probe may comprise one or more electrodes arranged and adapted to generate an analyte, smoke, fumes, liquid, gas, surgical smoke, aerosol or vapour when the probe is in contact with biological tissue, biological matter, bacterial colonies or fungal colonies.

The probe may form part of a robotically controlled endoscopic or laparoscopic device.

The endoscopic or laparoscopic device may include an endoscope and a camera at a distal end of the endoscope, wherein the camera may be arranged and adapted to transmit images to the user interface.

The robotic probe may be located at the distal end of the endoscopic or laparoscopic device.

The endoscopic or laparoscopic device may include one or more instrument channels or ports that travel at least partially along the endoscope, and the robotic probe may be operably coupled to the user interface via one or more actuators located within the one or more instrument channels or ports.

The probe or endoscopic or laparoscopic device may include a rapid evaporative ionization mass spectrometry ("REIMS") electrosurgical tool that includes one or more electrodes.

The one or more electrodes are arranged to generate aerosol, smoke or vapour.

According to another aspect, there is provided an apparatus comprising:

analyzing an aerosol, smoke or vapour or ions derived from the aerosol, smoke or vapour; and

in response to the analysis, one or more ion optics are adjusted and/or one or more ion paths are altered.

The analyzing step may include determining whether one or more particular compounds present in the aerosol, smoke or vapor exceed or fall below a prescribed intensity threshold or limit.

The adjusting step may include adjusting attenuation or otherwise adjusting the transmission of ions if one or more compounds present in the aerosol, smoke, or vapor exceed or fall below a specified intensity threshold or limit.

According to another aspect, there is provided a laparoscopic tool, the tool comprising:

an elongate portion arranged and adapted for insertion into a human or animal body through an incision therein; and

a first device located at the distal end of the elongate portion, wherein the first device may be arranged and adapted to generate an aerosol, smoke or vapour from tissue located within the human or animal body.

The maximum transverse dimension or width of the elongate portion may be less than 20mm, 15mm, 10mm or 5 mm.

The length of the extension may be greater than 5mm, 10mm, 15mm, 20mm, 25mm, 30mm, 35mm, 40mm, 50mm, 60mm, 70mm, 80mm, 90mm, 100mm, 150mm, 200mm, 300mm, 400mm or 500 mm.

The laparoscopic tool may further comprise a handle arranged and adapted to assist in moving and/or guiding the laparoscopic tool.

The laparoscopic tool may further comprise an internal channel for conveying the aerosol, smoke or vapor generated by the first device to an external device.

The first means may comprise an aperture arranged and adapted such that the aerosol, smoke or vapour passes through the aperture in use, wherein the aperture may form an entrance to the internal passage.

The first means may comprise one or more electrodes which may be arranged and adapted to generate the aerosol, smoke or vapour when the probe may be in contact with the tissue.

According to another aspect, there is provided an analytical method comprising:

providing a tool comprising a first device located within a conduit or housing, wherein the conduit or housing may comprise a tool deployment opening and one or more individual puncture ports;

Generating aerosol, smoke or vapour from one or more regions of a target using the first device; and

chemical or other data is obtained from one or more regions of the target.

The first means may comprise one or more electrodes.

One or more of the electrodes may comprise a collar, optionally wherein the collar comprises a polypectomy collar.

The one or more electrodes may include one or more hooks, one or more graspers, one or more blades, one or more knives, one or more serrated knives, one or more probes, one or more biopsy tools, one or more robotic tools, one or more electrosurgical styluses, one or more forceps, one or more bipolar forceps, one or more coagulation devices, one or more irrigation devices, and one or more imaging tools.

The method may further comprise providing a separate return electrode.

One or more of the electrodes may comprise a bipolar device.

The one or more electrodes may include: (i) a single stage device, wherein the apparatus optionally further comprises a separate return electrode; (ii) a bipolar device; or (iii) a multi-phase radio frequency device, wherein the apparatus optionally further comprises one or more separate return electrodes.

According to another aspect, there is provided an apparatus comprising:

an ultrasonic blade, probe, aspirator or dissector for use in surgery and arranged and adapted to liquefy, destroy or otherwise disrupt tissue in contact with the ultrasonic blade, probe, aspirator or dissector; and

an analysis device arranged and adapted to analyze particles of the tissue (e.g. using ambient ionization techniques).

The device may further comprise an endoscope comprising an ultrasonic blade and a distal end for insertion into a human or animal body, wherein the ultrasonic blade may be located at the distal end.

The apparatus may further comprise an electrosurgical tool arranged and adapted to contact tissue to generate an aerosol, smoke or vapour, wherein the analysis means may comprise an ion analyser or a mass spectrometer arranged and adapted to analyse the aerosol, smoke or vapour.

The ultrasonic blade, probe, aspirator or dissector and electrosurgical tool may be housed within or on the same assembly (e.g., endoscope).

The ultrasonic blade, probe, aspirator, or dissector may include electrodes such that the ultrasonic blade, probe, aspirator, or dissector forms an electrosurgical tool.

According to another aspect, there is provided an apparatus comprising:

a surgical laser arranged and adapted to generate an aerosol, smoke or vapour from a sample; and

an ion analyser or mass spectrometer arranged and adapted to analyse the aerosol, smoke or vapour.

According to another aspect, there is provided a method comprising:

providing a surgical laser arranged and adapted to generate an aerosol, smoke or vapour from a sample;

scanning the surgical laser across one or more regions of the sample to generate an aerosol, smoke, or vapor; and

the aerosol, smoke or vapour generated at one or more regions of the sample is conveyed to an ion analyser or mass spectrometer.

The method may further comprise analysing the aerosol, smoke or vapour using ambient ionisation techniques.

The method may further comprise a control device arranged and adapted to control the frequency and/or power and/or energy and/or wavelength and/or pulse duration of the surgical laser.

The control system is arranged and adapted to modify the frequency and/or power and/or energy and/or wavelength and/or pulse duration of the surgical laser in response to analysis of an aerosol, smoke or vapour by an ion analyser or mass spectrometer.

According to another aspect, there is provided an electrosurgical tool or probe arranged and adapted to:

applying an electrical current to the sample to cut, coagulate, dry or electrocautery the sample or a portion thereof; and

particles from the portion of the sample that has been vaporized are captured by the electrosurgical tool and are transmitted to an analysis device.

The analysis means may comprise an ion analyser or mass spectrometer arranged and adapted to analyse vaporised particles, for example using ambient ionisation techniques.

The electrosurgical tool may comprise a rapid evaporative ionisation mass spectrometry apparatus or probe.

The electrosurgical tool may comprise an electrode arranged and adapted to vaporise or vaporise the sample to form an aerosol, smoke or vapour.

The electrosurgical tool may further comprise a counter or return electrode arranged and adapted to contact the sample.

According to another aspect, there is provided an apparatus comprising:

a laparoscope comprising a first device for generating aerosol, smoke or vapour from one or more regions of a target; and

one or more outlets for the injected gas for delivery of the injected gas from the gas source to the human or animal body.

The apparatus may further comprise a control system arranged and adapted to control the flow of gas from the gas source to the gas outlet, wherein the control system may be arranged and adapted to modify the flow of gas based on analysis of the aerosol, smoke or vapour by an ion analyser or mass spectrometer.

The apparatus may further comprise an ion analyser or mass spectrometer arranged and adapted to analyse aerosol, smoke or vapour using ambient ionisation techniques. The ion analyser or mass spectrometer may comprise a mass spectrometer and/or a mass to charge ratio mass spectrometer and/or an ion mobility spectrometer. The ion analyzer may include a tandem mass spectrometer and an ion mobility spectrometer system.

The apparatus may further comprise an injection device comprising a source of injection gas and a control system arranged and adapted to control the flow of gas from the source to the gas outlet.

According to another aspect, there is provided a method comprising:

providing first means for generating aerosol, smoke or vapour from one or more regions of a target;

scanning the first device across one or more regions of the sample to generate an aerosol, smoke, or vapour;

conveying the aerosol, smoke or vapour generated at one or more regions of the sample to an ion analyser or mass spectrometer; and

the aerosol, smoke or vapour is analysed to determine the molecular composition of one or more regions of the sample. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

According to another aspect, there is provided an apparatus comprising:

a first device for generating aerosol, smoke or vapour from one or more regions of a sample, wherein the first device comprises one or more electrodes arranged and adapted to apply a voltage to one or more regions of the sample to generate aerosol, smoke or vapour from one or more regions of the sample, and wherein the largest dimension of the electrode is less than 5cm, 2 cm, 1cm, 5mm, 2mm, 1mm, 0.5mm or 0.1 mm.

The apparatus may further comprise a robot arranged and adapted to move the first device or the one or more electrodes.

The robot is arranged and adapted to move the first device or one or more electrodes in a single motion, which may be less than 10mm, 5mm, 4mm, 3mm, 2mm, 1mm, 0.5mm, 0.4mm, 0.3mm, 0.2mm or 0.1 mm.

The robot is arranged and adapted to move the first device or the one or more electrodes in a stepwise manner, wherein each step corresponds to an action of less than 10mm, 5mm, 4mm, 3mm, 2mm, 1mm, 0.5mm, 0.4mm, 0.3mm, 0.2mm or 0.1 mm.

According to another aspect, there is provided an apparatus comprising:

a first device arranged and adapted to generate aerosol, smoke or vapour from one or more regions of a target;

an ion analyser or mass spectrometer arranged and adapted to analyse the aerosol, smoke or vapour; and

a delivery means arranged and adapted to deliver the aerosol, smoke or vapour to an inlet portion of an ion analyser or mass spectrometer, wherein the inlet portion may comprise an inlet port of a first vacuum chamber of the ion analyser or mass spectrometer;

wherein the first means and the transport means are removable and/or replaceable from said ion analyser or mass spectrometer.

According to another aspect, there is provided an apparatus comprising:

second means arranged and adapted to mix the aerosol, smoke or vapour with a substrate or solvent at the joint;

A third means for conveying the mixture of aerosol, smoke or vapour and substrate or solvent to an ion analyser or mass spectrometer; and

a delivery means arranged and adapted to deliver the aerosol, smoke or vapour to the joint;

wherein the first means and the transport means are removable and/or replaceable from said third means and said ion analyser or mass spectrometer.

The ion analyser or mass spectrometer may comprise a first vacuum chamber and, in use, the third means is arranged and adapted to maintain the same pressure as the first vacuum chamber.

In any of the aspects disclosed herein, the matrix can include a polar molecule, water, one or more alcohols, methanol, ethanol, isopropanol, acetone, or acetonitrile. The matrix may comprise a molecular weight-locking compound or a calibration compound.

According to another aspect, there is provided a method comprising:

providing a surgical tool having an identification means, wherein the surgical tool may be arranged and adapted to generate aerosol, smoke or vapour from one or more regions of a target; and

In response to the identification device, an operating parameter of the surgical tool is set or controlled.

The identification device may include a radio frequency identification ("RFID") tag.

The method may further include restricting the surgical tool from using the operating parameter indicated by the identification device.

The method may further comprise using a database, the database being limited or determined by the identification means.

The database may further comprise tissue identification data, which is limited or determined by the identification means.

The operating parameter may include a power setting or a setting of a maximum power of the surgical tool.

The operating parameter may include a setting of a power duration or power interval of the surgical tool.

The method may further comprise using a statistical model or algorithm, wherein the data contained on the identification device forms or comprises a portion of the parameters or inputs of the statistical model or algorithm.

The results of the model or algorithm may be used to determine operating parameters of the surgical tool or instrument parameters of the analyzer.

The method may further comprise setting an operating parameter, such as an optimal operating parameter indicated by the identification means.

The operating parameters may include the mass or mass-to-charge ratio range of the mass filter, the mode of operation of the mass spectrometer and/or ion mobility spectrometer (fragmentation, secondary mass spectrometry (MS/MS), multi-stage mass spectrometry (MS/MS), and the like ⁿ) Etc.), ion optical settings (e.g., resolution, transmission or attenuation), enhanced duty cycle, target ion current, capture time, analysis time (e.g., resolution when using an orbitrap device), scan time or scan rate (e.g., coupled to a time-of-flight mass spectrometer),

the method may further comprise setting a mode of operation of the mass spectrometer and/or the ion mobility spectrometer and/or the tandem mass spectrometer and/or the ion mobility spectrometer system, the mode of operation being indicated by the identification means. For example, ion mobility separation can be performed based on information or data provided by the identification device.

Instead of ion mobility separation or other means, for example in the case of a trapping device, the target ion current, trapping time analysis time (with respect to resolution of the orbitrap device), ion trapping rate (e.g. coupled to a ToF MS), or coupled to a quadrupole device (e.g. may be a parent ion scan mode with high duty cycle)

The identification device may limit the surgical device from performing a limited number of procedures.

The identification device may limit the surgical device from performing a single procedure or a predetermined number of procedures.

The identification device may set an operational time limit for the surgical tool.

The electrosurgical tool may include a rapid evaporative ionization mass spectrometry ("REIMS") device or probe.

According to another aspect, there is provided an apparatus comprising:

a surgical tool having an identification device, wherein the surgical tool is arranged and adapted to generate aerosol, smoke or vapour from one or more regions of a target.

The apparatus may further comprise a controller, wherein the controller is arranged and adapted to communicate with the identification means and/or to receive information from and/or interrogate the identification means.

The controller is arranged and adapted to set or control an operating parameter of the surgical tool in response to communicating with and/or receiving information from and/or interrogating the identification device.

The controller may be arranged and adapted to limit the use of the surgical tool by the operating parameter indicated by the identification means.

The controller may further comprise using a database, the database being limited or determined by the identification means.

The operating parameter may include a power setting or a maximum power setting of the surgical tool.

The operating parameter may include a power duration or power interval setting of the surgical tool.

The controller may be arranged and adapted to utilise a statistical model or algorithm, wherein the data contained on the identification means forms or comprises part of the parameters or inputs of the statistical model or algorithm.

The controller may be arranged and adapted to determine an operating parameter of the surgical tool or an instrument parameter of the analyzer using the results of the model or algorithm.

According to another aspect, there is provided a method of processing a sample, the method comprising:

identifying a first portion of a sample to be analyzed;

vaporizing or otherwise generating an aerosol, smoke, or vapor from the first sample portion in an atraumatic or minimally invasive procedure;

analyzing and/or ion mobility analyzing the aerosol, smoke or vapor; and

Determining whether the aerosol, smoke or vapour contains any compound of interest. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The biological sample and/or the first sample portion may comprise skin.

The non-invasive or minimally invasive procedure may generate an aerosol, smoke, or vapor from the sample portion via penetration into the sample portion of no more than 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 10 μm, 20 μm, 25 μm, 30 μm, 35 μm, 50 μm, 100 μm, 200 μm, or 250 μm.

The method may further comprise treating the first sample portion based on the type or amount of any compound of interest that may be contained in the aerosol, smoke, or vapor.

The method may further comprise removing tissue from the first sample portion based on the type or amount of any compound of interest that may be contained in the aerosol, smoke, or vapor.

The method may further comprise: if the aerosol, smoke, or vapor contains (or does not contain) the compound of interest, the first sample portion is treated and/or tissue is removed from the first sample portion.

The method may further comprise, after the step of treating and/or removing the tissue:

Further vaporizing or otherwise generating aerosol, smoke or vapor from the first sample portion in an atraumatic or minimally invasive procedure;

analyzing and/or ion mobility analyzing the aerosol, smoke or vapor; and

it is determined whether the aerosol, smoke or vapor still contains any compounds of interest. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The method may further comprise, after the step of determining whether any compounds of interest are still contained in the aerosol, smoke or vapour:

processing the first sample portion and/or removing tissue from the first sample portion if the following are met: (i) aerosols, smokes, or vapors containing the compound of interest; or (ii) the aerosol, smoke or vapour does not contain the compound of interest; and/or

Ceasing processing and/or removing tissue from the first sample portion if the following are met: (i) aerosols, smokes, or vapors containing the compound of interest; or (ii) the aerosol, smoke or vapour does not contain the compound of interest.

If the following is met: (i) the compound of interest is contained in an aerosol, smoke or vapor; or (ii) the aerosol, smoke or vapour does not contain the compound of interest, the method may further comprise identifying a second portion of the sample to be analysed and carrying out the steps described above on this second sample portion.

Mass analysis (mass analysis or and/or ion mobility analysis and/or a combination of mass and ion mobility analysis) and/or ion mobility analysis or analysis of mass spectrometry and/or ion mobility data on the aerosol, smoke or vapour may comprise analysing one or more sample spectra to classify the aerosol, smoke or vapour sample.

The one or more sample spectra may comprise one or more sample mass and/or mass-to-charge ratio and/or ion mobility (drift time) spectra. Ion mobility spectra are obtained using different ion mobility drift gases, or by adding dopants to the drift gases to induce a change in the drift time of one or more species. These spectra may be combined or concatenated.

Analyzing the one or more sample spectra to classify the aerosol, smoke, or vapor sample may include supervised analysis of the one or more sample spectra and/or unsupervised analysis of the one or more sample spectra.

Analyzing one or more sample spectra to classify the aerosol, smoke or vapour sample may comprise using one or more of: analyzing a single variable; multivariate analysis; principal Component Analysis (PCA); linear Discriminant Analysis (LDA); maximum spacing criterion (MMC); an analysis based on a spectrogram library; soft Independent Modeling Classification Analogy (SIMCA); factor Analysis (FA); recursive distribution (decision tree); random forest; independent Component Analysis (ICA); partial least squares discriminant analysis (PLS-DA); orthogonal (partial least squares) projection to underlying structures (OPLS); OPLS discriminant analysis (OPLS-DA); a Support Vector Machine (SVM); (artificial) neural networks; a multilayer sensor; a Radial Basis Function (RBF) network; bayesian analysis is carried out; clustering analysis; a nuclear method; and subspace discriminant analysis.

Analyzing the one or more sample spectra to classify the aerosol, smoke, or vapor sample may include creating a classification model or library using one or more reference sample spectra.

Analyzing one or more sample spectra to classify an aerosol, smoke, or vapor sample may include performing Linear Discriminant Analysis (LDA) after performing Principal Component Analysis (PCA).

Analyzing one or more sample spectra to classify an aerosol, smoke or vapor sample may comprise performing a Maximum Margin Criteria (MMC) method after performing Principal Component Analysis (PCA).

Analyzing the one or more sample spectra to classify the aerosol, smoke, or vapor sample may include defining one or more classes within a classification model or library.

Analyzing the one or more sample spectra to classify the aerosol, smoke, or vapor sample may include manually or automatically defining one or more categories within a classification model or library according to one or more classification or clustering criteria.

One or more classification or clustering criteria for each category may be based on one or more of the following: distances between one or more pairs of reference points of the reference sample spectrum in model space; variance values between sets of reference points of a reference sample spectrum in model space; and variance values in a set of reference points of the reference sample spectrum in model space.

The one or more categories may each be defined by one or more classification definitions.

The one or more classification definitions may include one or more of the following: a set of one or more reference points, values, boundaries, lines, planes, hyperplanes, variances, volumes, Voronoi cells, and/or locations of reference sample spectra within the model space; and one or more locations in the category hierarchy.

Analyzing one or more sample spectra to classify an aerosol, smoke, or vapor sample may include classifying one or more unknown sample spectra using a classification model or library.

Analyzing the one or more sample spectra to classify the aerosol, smoke, or vapor sample may include manually or automatically classifying the one or more sample spectra according to one or more classification criteria.

The one or more classification criteria may include one or more of:

the distance between one or more projected sample points of one or more sample spectra within a model space and a set of one or more reference points, values, boundaries, lines, planes, hyperplanes, variances, volumes, voronoi cells or locations of one or more reference sample spectra located within the model space is below a distance threshold or is the lowest such distance;

The location of one or more projected sample points of one or more sample spectra within a model space is located on one or other sides of one or more reference points, values, boundaries, lines, planes, hyperplanes, or locations of one or more reference sample spectra in the model space;

the locations of one or more projected sample points of one or more sample spectra within a model space are located in one or more volumes or voronoi cells within the model space; and

the probability or classification score is above a probability or classification score threshold or is the highest such probability or classification score.

Various embodiments are contemplated relating to the generation of smoke, aerosol or vapor from a target using an ambient ionizing ion source (details are provided herein in their entirety). The aerosol, smoke or vapour may be mixed with the substrate and drawn into the vacuum chamber of the mass spectrometer and/or ion mobility spectrometer. The mixture may be caused to impact a collision surface, causing ionization of the aerosol, smoke, or vapor via impact ionization, which results in the generation of analyte ions. These obtained analyte ions (or fragments or product ions derived from the analyte ions) may be subjected to mass spectrometry and/or ion mobility analysis, and the obtained mass spectrometry data and/or ion mobility spectrometry may be subjected to multivariate analysis or other mathematical processes to determine one or more properties of interest in real time.

According to one embodiment, the first means for generating aerosol, smoke or vapour from a target may comprise a tool utilising a radio frequency voltage (e.g. a continuous radio frequency waveform).

Other embodiments are envisaged in which the first means for generating aerosol, smoke or vapour from a target may comprise an argon plasma coagulation ("APC") device. Argon plasma coagulation devices involve the use of a beam of ionized argon gas directed through a probe. The probe may be passed through an endoscope. Since the probe is placed at a distance from the target, the argon plasma coagulation is essentially a non-contact method. Argon gas is emitted from the probe and then ionized by a high voltage discharge (e.g., 6 kV). High frequency current is then conducted through the beam gas, causing the target at the other end of the beam gas to solidify. The depth of coagulation is typically only a few millimeters.

The first device, surgical or electrosurgical tool, device or probe or other sampling device or probe disclosed in any aspect or embodiment of the invention may comprise a non-contact surgical device, such as one or more of a hydro-surgical device, a surgical water jet device, an argon plasma coagulation device, a hybrid argon plasma coagulation device, a water jet device and a laser device.

A non-contact surgical device may be defined as a surgical device arranged and adapted to dissect, fragment, liquefy, aspirate, electrocautery, or otherwise destroy biological tissue without physically contacting the tissue. Examples include laser devices, hydrotherapy surgical devices, argon plasma coagulation, and hybrid argon plasma coagulation devices.

Since the non-contact device may not make physical contact with the tissue, the surgical procedure may be considered relatively safe and may be used to treat delicate tissue (e.g., skin or fat) with low intracellular binding.

According to various embodiments, mass spectrometers and/or ion mobility spectrometers may acquire data in a single anion mode, a single cation mode, or a combination of both anion and cation modes. The cation mode spectral data may be combined or concatenated with the anion mode spectral data. The anion pattern may provide a particular useful spectrum for classifying aerosol, smoke or vapor samples, such as those from an aerosol, smoke or vapor sample in a target comprising lipids.

Ion mobility spectrometry data is obtained using different ion mobility drift gases, or dopants are added to the drift gases to induce a change in the drift time of one or more species. The data may be combined or concatenated.

It is evident that the requirement to incorporate a matrix or reagent directly into the sample may prevent the ability to perform in vivo analysis of tissue and more generally may prevent the ability to perform rapid and simple analysis of the target material.

According to other embodiments, the ambient ionization ion source may comprise an ultrasonic ablation ion source or a hybrid electrosurgical-ultrasonic ablation ion source that generates a liquid sample that is then aspirated as an aerosol. The ultrasonic ablation ion source may include focused or unfocused ultrasonic waves.

Optionally, the first device may comprise an ion source selected from the group consisting of: (i) a rapid evaporative ionization mass spectrometry ("REIMS") ion source; (ii) a desorption electrospray ionization ("DESI") ion source; (iii) a laser desorption ionization ("LDI") ion source; (iv) a thermal desorption ion source; (v) a laser diode thermal desorption ("LDTD") ion source; (vi) a desorption electrokinetic focusing ("DEFFI") ion source; (vii) a dielectric barrier discharge ("DBD") plasma ion source; (viii) an atmospheric pressure solid analysis probe ("ASAP") ion source; (ix) an ultrasonic-assisted spray ionization ion source; (x) a simple open acoustic spray ionization ("EASI") ion source; (xi) A desorption atmospheric pressure photoionization ("DAPPI") ion source; (xii) A paper spray ("PS") ion source; (xiii) A jet desorption ionization ("JeDI") ion source; (xiv) A touch spray ("TS") ion source; (xv) A nano-DESI ion source; (xvi) A laser ablation electrospray ionization ("LAESI") ion source; (xvii) A real-time direct analysis ("DART") ion source; (xviii) A probe electrospray ("PESI") ion source; (xix) A solid probe-assisted electrospray ionization ("SPA-ESI") ion source; (xx) An ultrasonic surgical suction apparatus ("CUSA") ion source; (xxi) Hybrid ultrasonic surgical suction-diathermy device; (xxii) A focused or unfocused ultrasonic ablation ion source; (xxiii) A hybrid focused or unfocused ultrasound ablation and diathermy device; (xxiv) A microwave resonance device; (xxv) A pulsed plasma Radio Frequency (RF) dissector; (xxvi) An argon plasma coagulation device; (xxvi) A mixed pulse plasma radio frequency and argon plasma coagulation device; (xxvii) A mixed pulse plasma radio frequency and jet type desorption ionization device; (xxviii) Surgical water/saline injection devices; (xxix) A hybrid electrosurgery and argon plasma coagulation device; and (xxx) mixed argon plasma coagulation and water/brine spray devices.

Drawings

Preferred embodiments of the present invention are illustrated by way of example only and with reference to the accompanying drawings, in which:

FIG. 1 illustrates the general principles of the rapid evaporative ionization mass spectrometry techniques disclosed herein, including, for example, methods of rapid evaporative ionization mass spectrometry ("REIMS"), in which an RF voltage is applied to a bipolar forceps resulting in the generation of an aerosol or surgical plume, which is then captured via the irrigation port of the bipolar forceps and then transmitted to a mass spectrometer and/or ion mobility spectrometer for mass and/or ion mobility analysis;

figure 2A shows an inlet arrangement of an ion analyser or mass spectrometer and shows a venturi pump device arranged to direct aerosol particles towards an inlet conduit of the ion analyser or mass spectrometer, figure 2B shows a close-up of a sampling device comprising a whistle arrangement, wherein the sampling device is arranged to introduce a mixture of aerosol particles and substrate into the ion analyser or mass spectrometer and figure 2C shows a view of the whistle arrangement of the sampling device as shown in figure 2B separated from other features of the sampling device, according to an embodiment;

Figure 3 shows in more detail the general inlet set-up arrangement as shown in figures 2A to 2C connected to the initial stage of an ion analyser or mass spectrometer;

figure 4A shows a different inlet set-up arrangement for an ion analyser or mass spectrometer according to another embodiment and comprising a T-tee arrangement for introducing aerosol and matrix, and figure 4B shows the T-tee arrangement of figure 4A in more detail;

FIG. 5A shows a modified version of the inlet set-up arrangement shown in FIGS. 4A and 4B and incorporating a venturi pump, and FIG. 5B shows another embodiment similar to that shown in FIG. 5A except that a dedicated matrix introduction conduit is provided;

FIG. 6A shows a mass spectrum generated using a skimmer atmospheric pressure inlet ("API"), FIG. 6B shows a mass spectrum generated from Bacteroides fragilis using a cold collision ball, and FIG. 6C shows a mass spectrum generated from Bacteroides fragilis using a heated collision ball;

fig. 7A shows a mass spectrum generated from candida albicans using a heating coil interface into which isopropanol was introduced as a substrate, fig. 7B shows a mass spectrum generated from candida albicans using a heating coil interface into which isopropanol was not introduced, and fig. 7C shows a mass spectrum generated from candida albicans using a cold ball collision surface;

Fig. 8A shows a mass spectrum generated from proteus mirabilis using a heating coil interface into which isopropyl alcohol was introduced as a substrate, fig. 8B shows a mass spectrum generated from proteus mirabilis using a heating coil interface into which isopropyl alcohol was not introduced, and fig. 8C shows a mass spectrum generated from proteus mirabilis using a cold ball collision surface;

FIG. 9A shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.01mL/min, FIG. 9B shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.02mL/min, FIG. 9C shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.05mL/min, FIG. 9D shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.0.07mL/min, FIG. 9E shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.1mL/min, FIG. 9F shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.13mL/min, FIG. 9G shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.15 mL/min, FIG. 9H shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.2mL/min, FIG. 9I shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.25 mL/min;

FIG. 10A shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.01mL/min, FIG. 10B shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.02mL/min, FIG. 10C shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.05mL/min, FIG. 10D shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.0.07mL/min, FIG. 10E shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.1mL/min, FIG. 10F shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.13mL/min, FIG. 10G shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.15mL/min, FIG. 10H shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.2mL/min, FIG. 10I shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.25 mL/min;

FIG. 11 shows a desorption electrospray ionization ("DESI") device according to another embodiment;

fig. 12A shows a plot of intensity versus inlet capillary temperature for analysis of fatty acids using a Waters (Waters) synapt (rtm) mass spectrometer, fig. 12B shows a plot of intensity versus inlet capillary temperature for analysis of fatty acids using a Waters (Waters) xevo (rtm) mass spectrometer, fig. 12C shows a plot of intensity versus inlet capillary temperature for analysis of phospholipids using a Waters (Waters) synapt (rtm) mass spectrometer and fig. 12D shows a plot of intensity versus inlet capillary temperature for analysis of phospholipids using a Waters (Waters) xevo (rtm) mass spectrometer;

FIG. 13A shows an apparatus for performing a surgical procedure, FIG. 13B shows an embodiment of an apparatus that may be used in the apparatuses of FIG. 13A, and FIG. 13C shows an embodiment of a laparoscopic apparatus that may be used in the apparatuses of FIGS. 13A and 13B;

fig. 14A shows an embodiment of an electrosurgical tool for use in the various embodiments and methods disclosed herein, and fig. 14B shows an embodiment of an electrosurgical tool for use in the various embodiments and methods disclosed herein:

fig. 15A shows a portion of an apparatus for performing a surgical procedure in which a surgeon may use a hand-held manipulator to control a robotic device remote from the hand-held manipulator, and fig. 15B shows an embodiment of such a robotic device;

FIG. 16 illustrates an embodiment of a surgical tool for use in the various embodiments and methods disclosed herein;

FIG. 17 illustrates an embodiment of a surgical tool for use in the various embodiments and methods disclosed herein;

FIG. 18 illustrates an apparatus that may be used in a surgical operating room for controlling the use and distribution of the surgical tools disclosed herein;

FIG. 19 illustrates a method including analysis of a build classification library, in accordance with various embodiments;

FIG. 20 shows a set of reference sample spectra obtained from two class-known reference samples;

FIG. 21 shows a multivariate space having three dimensions defined by intensity axes, wherein the multivariate space comprises a plurality of reference points, each reference point corresponding to a set of three maximum intensity values derived from a reference sample spectrum;

FIG. 22 shows a general relationship between the cumulative variance and the number of PCA model components;

FIG. 23 shows a PCA space having two dimensions defined by principal component axes, wherein the PCA space includes a plurality of transformed reference points or scores, each transformed reference point or score corresponding to the reference point of FIG. 21;

FIG. 24 illustrates a PCA-LDA space having a single dimension or axis, wherein the LDA is performed based on the PCA space of FIG. 23, the PCA-LDA space comprising a plurality of further transformed reference points or category scores, each further transformed reference point or category score corresponding to the transformed reference points or scores of FIG. 23;

FIG. 25 illustrates a method including analysis using a classification library, in accordance with various embodiments;

FIG. 26 shows a sample spectrum obtained from an unknown sample;

FIG. 27 shows the PCA-LDA space of FIG. 24, wherein the PCA-LDA space further includes sample points derived from a PCA-LDA projection of the maximum intensity values of the sample spectrum of FIG. 26;

FIG. 28 illustrates a method including analysis to build a classification library according to various embodiments; and

FIG. 29 illustrates a method including analysis using a classification library, in accordance with various embodiments.

Detailed Description

Various embodiments are described below that relate to apparatus and methods for chemical analysis of aerosol and gaseous samples containing analytes using mass spectrometry and/or ion mobility spectrometry or other gas phase ion analysis modalities.

The embodiments disclosed herein may relate to the use of an electrosurgical tool, such as a device or probe (e.g., a rapid evaporative ionization mass spectrometry ("REIMS") device or a probe that may be provided in the form of a surgical diathermy probe). The rapid evaporative ionization mass spectrometry apparatus or probe can include one or more electrodes configured to vaporize or evaporate biological tissue to form an aerosol, surgical smoke, or vapor including particles of the biological tissue. The rapid evaporative ionization mass spectrometry apparatus or probe may further comprise a tube or other mechanism for transporting the particles to a mass analyzer and/or an ion mobility analyzer and/or a mass spectrometer and/or an ion mobility spectrometer. Various configurations of such devices or probes are possible.

Embodiments are disclosed in which alternative mechanisms are provided for generating aerosols, surgical smoke, or vapors. For example, an ultrasound device or probe is described with respect to fig. 16, and a laser device or probe is described with respect to fig. 17.

Various embodiments disclosed herein relate to the use of these probes in surgery or other situations (e.g., a surgical operating room or battlefield). Further embodiments disclosed herein relate to devices that can or benefit from the use of such probes, for example surgical robots that can be guided using information provided by the devices and probes disclosed herein.

Further embodiments are disclosed wherein the probes are incorporated into surgical devices (e.g., endoscopes and laparoscopes).

Other embodiments are more generally directed to ambient ionization ion sources.

Various other embodiments are contemplated and disclosed herein.

Open type ionization ion source

Although the various embodiments described herein are described in the context of using a rapid evaporative ionization mass spectrometry ("REIMS") ion source that includes an electrosurgical surgical tool, other embodiments are contemplated in which other devices may be used to generate aerosols, smoke, or vapors from one or more regions of a target (e.g., in vivo tissue).

Ambient ionization is a form of ionization in which ions are formed in an ion source outside the mass spectrum without the need for sample preparation or separation. Ions may be formed from droplets extracted into an electrospray, may be thermally desorbed and ionized via chemical ionization or laser desorption or ablation, and post-ionized before the ions enter the mass spectrometer.

These devices or ion sources may include ambient ionisation ion sources characterised by the ability to produce an analyte aerosol, smoke or vapour from a natural or unmodified target. In contrast, other types of ionization ion sources, such as matrix-assisted laser desorption ionization ("MALDI") ion sources, require the addition of a matrix, solvent or reagent to the sample prior to ionization. Ionization ion sources, such as matrix-assisted laser desorption ionization ("MALDI") ion sources, are not used to ionize native or unmodified samples because the sample (e.g., a tissue sample) needs to be prepared by adding a matrix, solvent, or reagent to the sample prior to ionization.

It is clear that: the requirement to add a matrix or reagent to the sample prevents both in vivo analysis of tissue and rapid and simple analysis of many other types of target materials. Thus, it has been recognized that: the ability of an ambient ionizing ion source to ionize a sample without the need for, for example, adding a solvent to the sample is particularly advantageous.

Many different ambient ionization techniques are known and are intended to fall within the scope of the present invention. As a historical record, desorption electrospray ionization ("DESI") was the first open ionization technique developed and disclosed in 2004. Since 2004, many other ambient ionization techniques have been developed. The exact ionization methods of these ambient ionization techniques differ, but these ambient ionization techniques have the same general ability to generate gas phase ions directly from a natural (i.e., untreated or unmodified) sample. A particular advantage of these various ambient ionization techniques, which are intended to fall within the scope of the present invention, is that the various ambient ionization techniques do not require any prior sample preparation. Thus, various ambient ionization techniques enable analysis of both in vivo and ex vivo tissue samples without the time and expense of adding matrices or reagents to the tissue sample or other target material.

A list of ambient ionization techniques intended to fall within the scope of the present invention is given in the following table:

according to an embodiment, the ambient ionization ion source may comprise a rapid evaporative ionization mass spectrometry ("REIMS") ion source, wherein an RF voltage is applied to one or more electrodes in order to generate an aerosol or plume of surgical smoke from joule heating.

However, it should be understood that: other ambient ion sources including those described above may also be used. For example, according to another embodiment, the ambient ionization ion source may comprise a laser ionization ion source. According to an embodiment, the laser ionization ion source may comprise a mid-infrared laser ionization ion source. For example, there are several lasers that emit radiation close to 2.94 μm or 2.94 μm, where 2.94 μm corresponds to a peak in the water absorption spectrum. According to various embodiments, the ambient ionization ion source may comprise a laser ablation ion source having a wavelength close to 2.94 μm based on a high absorption coefficient of 2.94 μm water. According to an embodiment, the laser ablation ion source may comprise an Er: YAG laser emitting 2.94 μm radiation.

Other embodiments are contemplated in which an intermediate infrared optical parametric oscillator ("OPO") may be used to generate a laser ablation ion source having a wavelength longer than 2.94 μm. YAG pumped ZGP-OPO may be used, for example, to generate laser radiation having a wavelength of, for example, 6.1 μm, 6.45 μm or 6.73 μm. In some cases, it may be possible to use a laser ablation ion source having a wavelength shorter or longer than 2.94 μm Is advantageous because only the surface layer will be ablated and less thermal damage may result. MgF Co according to the examples₂A laser may be used as a laser ablation ion source, wherein the laser may be tuned from 1.75 μm to 2.5 μm. According to another embodiment, an optical parametric oscillator ("OPO") system pumped by a Nd: YAG laser can be used for generating a laser ablation ion source having a wavelength between 2.9 μm and 3.1 μm. According to another embodiment, the CO has a wavelength of 10.6 μm₂Lasers may be used to generate aerosols, fumes, or vapors.

According to other embodiments, the ambient ionization ion source may comprise an ultrasonic ablation ion source that generates a liquid sample that is then inhaled as an aerosol. The ultrasonic ablation ion source may comprise a focused or unfocused source.

According to an embodiment, the first means for generating aerosol, smoke or vapor from one or more regions of a target may comprise an electrosurgical tool utilizing a continuous RF waveform. According to other embodiments, a radio frequency tissue cutting system may be used, which is arranged to provide pulsed plasma RF energy to the tool. The tool may include, for example, a plasma knife (RTM). Pulsed plasma RF tools operate at lower temperatures (e.g., 40-170 c versus 200-350 c) than conventional electrosurgical tools, thereby reducing the depth of thermal damage. The pulse shape and duty cycle may be used for both cutting and coagulation modes by introducing an electrical plasma along one or more cutting edges of a thin insulated electrode.

However, it should be understood that: many other ambient ion sources may be utilized. For example, according to another embodiment, the ambient ionization ion source may comprise a laser ionization ion source. A laser probe is disclosed herein and with reference to fig. 17. According to an embodiment, the laser ionization ion source may comprise a mid-infrared laser ionization ion source. For example, there are several lasers in the water absorption spectrum that emit radiation near the 2.94 μm or 2.94 μm peak. According to various embodiments, the ambient ionization ion source may comprise a laser ablation ion source having a wavelength close to 2.94 μm (e.g. between 2.84 μm and 3.04 μm) based on a high absorption coefficient of 2.94 μm water, or the laser source described in relation to fig. 17 may comprise a laser arranged and adapted to emit light having a wavelength close to 2.94 μm (e.g. between 2.84 μm and 3.04 μm) based on a high absorption water coefficient of 2.94 μm. According to an embodiment, the laser ablation ion source may comprise an Er: YAG laser emitting 2.94 μm radiation.

According to another embodiment, the laser ablation ion source may comprise a laser (e.g., a carbon dioxide laser) and may emit radiation between 10 μm to 11 μm or 10.4 μm to 10.8 μm (e.g., about 10.6 μm).

According to other embodiments, the ambient ionization ion source may comprise an ultrasonic ablation ion source. The ultrasonic ablation ion source may comprise a focused or unfocused source. An example of an ultrasound probe is described herein and with reference to figure 16.

(ii) fast evaporative ionization Mass Spectrometry (“REIMS”)

Fig. 1 illustrates a method of rapid evaporative ionization mass spectrometry ("REIMS") in which bipolar forceps 1 may be brought into contact with in vivo tissue 2 of a patient 3. In the example shown in fig. 1, the bipolar forceps 1 may be brought into contact with brain tissue 2 of a patient 3 during a surgical procedure on the brain of the patient. RF voltage from the RF voltage generator 4 may be applied to the bipolar forceps 1, which results in local joule or diathermic heating of the tissue 2. As a result, an aerosol or surgical plume 5 is generated.

The aerosol or surgical plume 5 may then be captured or otherwise inhaled via the irrigation ports of the bipolar forceps 1. Thus, the flushing port of the bipolar forceps 1 is used again as a suction port. The aerosol or surgical feathers 5 can then be transferred from the irrigation (suction) port of the bipolar forceps 1 to a tube 6 (e.g. 1/8 "or a 3.2mm diameter teflon (RTM) tube). The tube 6 is arranged for conveying the aerosol or surgical plume 5 to an atmospheric pressure interface 7 of an ion analyzer or mass spectrometer 8.

The ion analyser or mass spectrometer 8 may comprise a mass spectrometer and/or a mass to charge ratio spectrometer and/or an ion mobility spectrometer. The ion analyzer may include a tandem mass spectrometer and an ion mobility spectrometer system.

According to various embodiments, a substrate comprising an organic solvent (e.g., isopropyl alcohol) may be added to the aerosol or surgical plume 5 at the atmospheric pressure interface 7. The mixture of aerosol 3 and organic solvent may then be arranged to impinge on an impingement surface within a vacuum chamber of an ion analyzer or spectrometer 8.

According to one embodiment, the collision surface may be heated. Causing ionization of the aerosol when it impacts the collision surface resulting in the generation of analyte ions. Ionization efficiency for generating analyte ions can be improved via the addition of an organic solvent. However, the addition of an organic solvent is not essential.

The analyte ions generated by the collision of the aerosol, smoke or vapour 5 against the collision surface then pass through a subsequent stage of an ion analyser or spectrometer and may be mass analysed in the mass analyser and/or ion mobility analysed in the ion mobility analyser. The mass analyzer may comprise, for example, a quadrupole mass analyzer or a time-of-flight mass analyzer.

One embodiment of a suitable bipolar forceps 1400 is shown in fig. 14A, and this will be discussed in more detail below. Fig. 14B shows an alternative embodiment in which an RF voltage is applied to the monopole device 1450.

To form the path for the current, these devices used in connection with monopolar devices may include a counter electrode placed in a suitable position on the sample. This will also be discussed in more detail below.

Inlet instrument

Various embodiments relate to introducing an aerosol, smoke or vapor or other gaseous sample containing an analyte into an enclosed space, where the sample may be mixed with a low molecular weight matrix compound. According to an embodiment, the sample may be mixed with an organic solvent (e.g., isopropanol). This homogeneous or heterogeneous mixture may then be introduced into the atmospheric interface of an ion analyzer or mass spectrometer and/or ion mobility spectrometer.

The ion analyser or mass spectrometer may comprise a mass spectrometer and/or a mass to charge ratio spectrometer and/or an ion mobility spectrometer. The ion analyzer may include a tandem mass spectrometer and an ion mobility spectrometer system.

When the mixture is introduced into the low pressure system of the analytical instrument, aerosol particles containing the molecular components of the sample and the matrix compound (if present) are formed. The mixed composition aerosol particles can then dissociate via collisions with the solid collision surface. According to an embodiment, the aerosol particles may be ionized via collisions with a collision surface located within a vacuum chamber of an ion analyzer or mass spectrometer. These dissociation processes produce neutral and charged species that include molecular ions of the chemical composition of the sample. These molecular ions are then subjected to mass or mobility analysis.

A simple solution for analyzing the molecular components of an aerosol in an online manner, e.g. without the application of a voltage or a laser, is provided here.

Inlet set # 1-venturi pump

Fig. 2A to 2C show an inlet arrangement according to an embodiment.

Fig. 2A shows an inlet arrangement or apparatus comprising a venturi pump 11. The venturi pump 11 optionally includes a tube 21 that can be connected to a device or probe (e.g., a rapid evaporative ionization mass spectrometry device or a probe described herein) and can be configured to convey aerosol particles from a sample (e.g., biological tissue) to the venturi pump 11. The venturi pump 11 may comprise a gas inlet 13 which may be arranged and adapted to introduce gas (e.g. venturi gas) into the flow path of aerosol particles which are conveyed by the tube 21 to the venturi pump 11. The venturi pump 11 may comprise a sample transfer tube 15 in the form of an elongate member or portion which may be arranged and adapted to transfer a sample and gas mixture from a tube 21 to a sampling device 25 via an outlet end 23 of the sample transfer tube 15.

The sampling device 25 can broadly include a hollow tube or whistle 12, a matrix introduction conduit 30 and an inlet tube 40. The hollow tube or whistle 12 may be referred to as a deflecting means.

The substrate introduction conduit 30 may be arranged and adapted to introduce the substrate in liquid form into the substrate introduction conduit 30 via the channel 34 (fig. 2B). The end 34 of the substrate disposed or located within the whistle 12 exits the substrate introduction conduit 30 and the substrate can be atomized by the gas drawn into the inlet tube 40. As described in more detail below, the quality of the atomization of the substrate may be controlled and influenced by the size and/or relative distance between various portions of the sampling device 10.

The inlet tube 40 opens into the inlet of an ion analyser or mass spectrometer and may be arranged and adapted such that the mixture of sample, gas and matrix is conveyed into the ion analyser or mass spectrometer through the end 42 of the inlet tube 40 disposed or located within the whistle 12 and through the passage 44.

Fig. 2B shows a close-up view of the sampling device 10.

The whistle 12 may be provided in the form of a hollow tube optionally having a first side 22 which may be arranged so as to face the outlet end 23 of the sample delivery tube 15, and an opposite second side 24 which optionally faces away from the outlet end 23 of the sample delivery tube 15.

The squeaker 12 may include a first end 18, which first end 18 may be positioned coaxially about the inlet tube 40 and may be in sealing engagement therewith. The whistle may include the second end 20, the second end 20 may be positioned coaxially around the substrate introduction tube 30 and may be in sealing engagement therewith. The axial passage may extend from a first axial end 18 to a second axial end 20.

Voids, apertures, or openings 14 may be provided on the second side 24 of the whistle 12, and the openings 14 may form an inlet so that a sample and gas mixture flowing through the whistle 12 from the outlet end 23 of the sample transfer tube 15 may be transferred to the interior of the whistle 12 (e.g., an axial passage therein). The void, aperture or opening 14 may form the entrance to a radial channel that fluidly connects the axial channel to the area adjacent the second side 24 of the squeaker 12.

The mixture of sample and gas exiting the outlet end 23 of the sample transfer tube 15 can collide with the first side 22 of the whistle 12 and then travel around the outer surface and enter the aperture 14. Once inside the whistle, the mixture of sample, gas and matrix can be mixed with the nebulised matrix coming out of the matrix introduction conduit 30, optionally before being conveyed through the end 42 of the inlet tube 40 to the inlet tube 40. The mixture of sample, gas and matrix can then be transported to an ion analyzer or mass spectrometer via channel 44.

Positioning the opening 14 on the second side 24 of the whistle 12 means that the initial collision of the sample and gas mixture is on a surface that is not directly exposed to the vacuum (or reduced pressure region) of the ion analyzer or mass spectrometer. Thus, in various embodiments, the sampling device 25 may be arranged and adapted such that the initial collision of the sample and gas mixture is on a surface that is not directly exposed to the vacuum (or reduced pressure region) of the ion analyzer or mass spectrometer.

The opening 14 may have a semi-circular profile when the whistle 12 is viewed in cross-section (as shown, for example, in fig. 2A and 2B). This will mean that the edge 17 of the opening 14 is oval when viewed from the direction facing the second side 24 (see figure 2C) of the whistle 12. Alternatively, the opening 14 may have a different shape profile (e.g., square, triangular, or irregular) when the whistle 12 is viewed in cross-section. The edges 17 of the opening 14 may then also be square, triangular or irregular when viewing the whistle 12 from a direction facing the second side 24 (see figure 2C) of the whistle 12.

The position and orientation of the whistle 12 can affect the quantity and quality of the sample delivered to the mass spectrometer. The aperture 14 may include a center point 16, which may be aligned with a longitudinal centerline 19 of the sample delivery tube 15. Fig. 2C shows a view of the second side 24 of the whistle 12 (the whistle 12 is shown separately in fig. 2C), and the center point 16 can be considered to be the center point of the ellipse.

The whistle 12 can be oriented such that the longitudinal axis 26 of the whistle coincides with the axis of symmetry of the opening 14. The center point 16 can be located on the longitudinal axis 26 of the squeaker 12 and/or the axis of symmetry of the opening. The axis of symmetry of the aperture may include a longitudinal axis of symmetry, wherein a longitudinal direction may be defined as a direction along the longitudinal axis 26.

The location of the various parts of the sampling device 25 can also affect the quantity and quality of the sample transferred into the mass spectrometer.

Referring now to FIG. 2B, the distance x is defined as the distance (e.g., shortest distance) between the end 32 of the substrate introduction tube 30 and the end 42 of the inlet tube 40.

The distance y is defined as the distance (e.g., shortest distance) between the center point 16 of the aperture 14 and the end 42 of the inlet tube 40.

The distance z is defined as the distance (e.g., shortest distance) between the outlet end 23 of the sample delivery tube 15 and the whistle 12 (e.g., the first side 22 of the whistle 12).

The diameter a of the substrate introduction tube 30 can also affect the quantity and mass of sample delivered to the mass spectrometer and can also affect the atomization of the substrate as it exits the end of the substrate introduction tube 30.

The diameter b of the inlet tube 40 and the diameter c of the sample transfer tube 15 can also affect the quantity and quality of the sample transferred into the mass spectrometer.

The diameters a, b and c may correspond to the diameters of the end 32 of the substrate introduction tube 30, the end 42 of the inlet tube and the outlet end 23 of the sample transfer tube 15, respectively.

Any or all of the diameters a, b, and c may be greater than, less than, or substantially equal to (i) about 0.01mm to 0.02 mm; (ii) about 0.02mm to 0.03 mm; (iii) about 0.03mm to 0.04 mm; (iv) about 0.04mm to 0.05 mm; (v) about 0.05mm to 0.06 mm; (vi) about 0.06mm to 0.07 mm; (vii) about 0.07mm to 0.08 mm; (viii) about 0.08mm to 0.09 mm; (ix) about 0.1mm to 0.2 mm; (x) About 0.2mm to 0.3 mm; (xi) About 0.3mm to 0.4 mm; (xii) About 0.5mm to 0.6 mm; (xiii) About 0.6mm to 0.7 mm; (xiv) About 0.7mm to 0.8 mm; (xv) About 0.8mm to 0.9 mm; (xvi) About 0.9mm to 1 mm; (xvii) About 1mm to 2 mm; (xviii) About 2mm to 3 mm; (xix) About 3mm to 4 mm; (xx) About 4mm to 5mm or (xxi) > 5 mm.

Any or all of the diameters/distances a, b, c, x, y and z may be varied to optimize the quantity and mass of the sample delivered to the ion analyzer or mass spectrometer.

The matrix introduction conduit (30) and/or inlet tube (40) and/or axial channel may have (i) about 0.01mm to 0.02 mm; (ii) about 0.02mm to 0.03 mm; (iii) about 0.03mm to 0.04 mm; (iv) about 0.04mm to 0.05 mm; (v) about 0.05mm to 0.06 mm; (vi) about 0.06mm to 0.07 mm; (vii) about 0.07mm to 0.08 mm; (viii) about 0.08mm to 0.09 mm; (ix) about 0.1mm to 0.2 mm; (x) About 0.2mm to 0.3 mm; (xi) About 0.3mm to 0.4 mm; (xii) About 0.5mm to 0.6 mm; (xiii) About 0.6mm to 0.7 mm; (xiv) About 0.7mm to 0.8 mm; (xv) About 0.8mm to 0.9 mm; (xvi) About 0.9mm to 1 mm; (xvii) About 1mm to 2 mm; (xviii) About 2mm to 3 mm; (xix) About 3mm to 4 mm; (xx) An inner and/or outer diameter of about 4mm to 5mm or (xxi) > 5 mm.

Aspects of the present disclosure may extend to a method of optimizing the sampling device 10, the method comprising identifying one or more parameters (e.g., ion abundance or ion signal intensity) associated with the sampling device, and varying one or more of the distances a, b, c, x, y, and z until the one or more parameters are optimized or at a maximum or minimum value.

The venturi pump 11 may be used to introduce aerosol particles into the sample delivery tube 15. The sampling device 25 may be provided for sampling aerosols. The substrate introduction conduit 30 may be arranged to introduce a substrate (e.g. isopropanol) into the sampling device 25, and the inlet tube 40 may be arranged to forward the mixture of aerosol particles and substrate into an ion analyser or mass spectrometer.

The venturi pump 11 may facilitate the aspiration of an aerosol or other gaseous sample containing the analyte, and may be driven by nitrogen or standard medical air. Aerosol sampling may be arranged to occur perpendicular to the outlet end 23 from the venturi pump 11 as shown in fig. 2A and 2B. The outlet 32 of the matrix introduction conduit 30 can be spaced from the inlet tube 40 by a distance x from the ion analyzer or mass spectrometer. The distance x may be modified as needed to achieve optimal ion signal intensity.

Varying the value of the distance x may vary the velocity of the gas drawn into the inlet tube 40 and may have an effect on the atomization conditions. Then, if the nebulizing conditions are less favorable, the substrate droplets may not be of the correct size to interact with the analyte aerosol and/or will not break up efficiently when the aerosol collides with the collision surface.

The matrix may comprise a polar molecule, water, one or more alcohols, methanol, ethanol, isopropanol, acetone or acetonitrile. Isopropanol has been found to be particularly advantageous.

According to other embodiments, the inlet arrangement as shown in fig. 2A-2C may be used without introducing a substrate. For example, according to an embodiment, the matrix introduction conduit 30 may be removed or plugged. This may provide for direct introduction of the aerosol into the ion analyzer or mass spectrometer.

However, it has been found that the introduction of a matrix (e.g. isopropanol) aids ionization via partial or complete desolventization of analyte molecules and also via reducing intermolecular forces, which would otherwise negatively affect ionization and thus reduce sensitivity.

Figure 3 shows in more detail the inlet arrangement shown in the apparatus of figures 2A to 2C and connected to an ion analyser or mass spectrometer 50. In the illustrated example, the ion analyzer or mass spectrometer 50 includes an ion guide 52 (e.g., a stepwave (rtm) ion guide), although any type of ion analyzer or mass spectrometer may be suitably provided.

The device may comprise a housing 60 arranged and adapted to accommodate the venturi pump 11. A substrate inlet 36 may be provided for connection to a supply of substrate (e.g. isopropanol), and this may be in fluid communication with the substrate introduction conduit 3.

A gas connection 62 may be provided that may be in fluid communication with a source of inspired gas (e.g., nitrogen or standard medical air) via a gas line 64. The gas connection 62 may be in fluid communication with the gas line 3.

The apparatus may include a vent 66 for collecting larger sample particles that are not passed into the squeaker 12. A filter, such as a high efficiency particulate air ("HEPA") filter, may be arranged and adapted to filter gases and other substances passing through the exhaust 66.

As described above, the mixture of sample, gas, and substrate may be transported from sampling device 25 and through inlet tube 40, and may exit inlet tube 40 and impinge on collision surface 70. The impingement surface 70 may be heated, for example, by an inductive or resistive heater. Further heaters 72 may be provided for heating the mixture of sample, gas and substrate ("mixed composition") as it travels along the inlet tube 40. Heating the mixture may ensure that the matrix is in the form of droplets, which may effectively bind the sample. The heater 72 may be an inductive or resistive heater and may comprise a conductive metal (e.g., tungsten) wrapped around the inlet tube 40.

The mixed composition aerosol particles or analytes may be arranged to be ionized via the collision surface 70. The resulting analyte ions may then enter ion guide 52. The ion guide 52 may be arranged to separate analyte ions from neutral flux or background gas in a known manner.

The inlet is provided with a #2-T type three-way pipe

Fig. 4A and 4B illustrate an apparatus for introducing an aerosol mixture into an ion analyzer or mass spectrometer 110 having a T-tee fitting. In contrast to the devices shown in fig. 2A-2C, the tee device may employ a direct mixing approach (i.e., without the use of a venturi pump) using a tee or device 100.

The apparatus may include an ion analyzer or mass spectrometer 110. The ion analyser or mass spectrometer may comprise a mass spectrometer and/or a mass to charge ratio spectrometer and/or an ion mobility spectrometer. The ion analyzer may include a tandem mass spectrometer and an ion mobility spectrometer system.

The ion analyzer or mass spectrometer 110 can include an inlet 112 and a reduced pressure region 114 (e.g., a first vacuum region). A collision surface 116 (e.g., a solid collision surface) and optionally ion optics 118 may be arranged within the depressed region 114. The ion optics 118 may include an ion guide, such as a stepwave (rtm) ion guide.

The apparatus may include a sample delivery tube 120 that may be connected to a device or probe (e.g., a rapid evaporative ionization mass spectrometry device or probe as described herein) and may be configured to deliver aerosol particles 122 (fig. 4B) from a sample (e.g., biological tissue) to the T-tee 100.

The sample transfer tube 120 may be fluidly sealed to the tee 100. For example, the sample transfer tube 120 may be fluidly sealed to the first conduit 102 of the tee 100, optionally at a sample connection 125 at the end of the first arm 102. Any mechanism for fluidly sealing sample transfer tube 120 and tee 100 may be used, such as a clamp 126, which may be positioned around sample transfer tube 120 at sample connection 125, and which clamp 126 may seal against the wall of sample connection 125, for example, using an interference fit. The sample transfer tube 120 may be detachable from the tee 100 and/or replaceable with the tee.

In an alternative embodiment, the sample transfer tube 120 may be contiguous with the tee 100 (e.g., the first conduit 102 of the tee).

The apparatus may comprise a substrate introduction conduit 130 arranged and adapted for introducing a substrate or substrate compound 132 into the tee 100. The substrate introduction conduit 130 can be connected to a source (not shown) of substrate (e.g., isopropyl alcohol).

The substrate introduction conduit 130 may be fluidly sealed to the tee 100. For example, the substrate introduction conduit 130 may be fluidly sealed to the second conduit 103 of the tee 100, optionally at a substrate connection 135 located at the end of the second conduit 103. Any mechanism for fluidly sealing the substrate introduction conduit 130 and the tee 100 may be used, such as a clamp 136, which may be positioned around the substrate introduction conduit 130 at the substrate connection 135, and the clamp 136 may be sealed against the wall of the substrate connection 135, for example, using an interference fit. The substrate introduction conduit 130 may be detachable from and/or replaceable with the tee 100.

In an alternative embodiment, the matrix introduction conduit 130 may be contiguous with the tee 100 (e.g., the second conduit 103 of the tee).

The apparatus may include an inlet tube or capillary 140 that may be in fluid communication with mass spectrometer 110 (e.g., its depressurization region 114). The connection between the inlet tube 140 and the mass spectrometer 110 is schematically drawn and may take any form. In some embodiments, the inlet tube 140 is removable from the mass spectrometer 110 (e.g., its depressurization region 114) and/or replaceable with the mass spectrometer.

The inlet tube 140 may be fluidly sealed to the tee 100. For example, the inlet tube 140 may be fluidly sealed to the third conduit 104 of the tee 100, optionally at a mass spectrometer connection 145 at the end of the third arm 104. Any mechanism for fluidly sealing inlet tube 140 and tee 100 may be used, such as a clamp 146, which may be located around inlet tube 140 at mass spectrometer connection 145, and which clamp 146 may be sealed against the wall of mass spectrometer connection 146, for example, using an interference fit. The inlet tube 140 may be detachable from the tee 100 and/or replaceable with the tee.

In an alternative embodiment, the inlet tube 140 may be contiguous with the tee 100 (e.g., the third conduit 104 of the tee).

The tee 100 may comprise a single piece of material, such as plastic, polyethylene, polycarbonate, polyvinyl chloride ("PVC"), or polytetrafluoroethylene ("PTFE"). Tee 100 includes a first conduit 102, a second conduit 103, and a third conduit 104, all intersecting at a central junction 101.

As shown in fig. 4B, the substrate introduction tube 130 may be inserted into the second tube 103 by any amount desired. Optionally, the substrate introduction conduit 130 is inserted such that the substrate introduction conduit travels through the junction 101, e.g., into the third conduit 104.

It is contemplated that the matrix introduction conduit 130 may be further inserted into the third conduit 104, and may even be inserted into the inlet tube 140. In order to be inserted into the inlet tube 140, the substrate-introducing guide 130 should have an outer diameter (or maximum dimension) smaller than the inner diameter of the inlet tube 140.

Aerosol particles 122 may travel along the first conduit 102 and may encounter particles of substrate 132 at the junction 101 or the third conduit 104 (depending on the location of the outlet end 133 of the substrate introduction conduit 130). At this point, the aerosol particles 122 may mix with the substrate 132 and may form substrate molecules 142, where both the molecular components of the aerosol particles 122 and the substrate 132 may be present. The substrate 132 may be in excess compared to the molecular components of the aerosol particles 122.

The outer diameter or dimension of the matrix introduction catheter 130 may be such that a gap 131 exists between the outer surface of the matrix introduction catheter 130 and the surface of the second catheter 103 and/or the junction 101 and/or the third catheter 104. In use, aerosol particles 122 may travel around the gap 131 and exit the gap 131 so as to surround the substrate 132 emerging from the end 133 of the substrate introduction conduit 130. This may facilitate atomization of the substrate as it emerges from the substrate introduction conduit 130.

The gap 131 may be less than, greater than, or equal to about 0.01mm, 0.02mm, 0.03mm, 0.04mm, 0.05mm, 0.06mm, 0.07mm, 0.08mm, 0.09mm, 0.1mm, 0.5mm, 1mm, 2mm, 3mm, 4mm, or 5 mm.

The first conduit 102 and/or the second conduit 103 and/or the third conduit 104 may have an inner diameter or inner diameter (e.g., inner diameter 121 of the first conduit 102) that is less than, greater than, and/or equal to about 0.5mm, 1mm, 2mm, 3mm, 4mm, or 5 mm.

The substrate introduction conduit 130 and/or inlet tube 140 can have an inner diameter or bore of less than, greater than, and/or equal to about 0.01mm, 0.02mm, 0.03mm, 0.04mm, 0.05mm, 0.06mm, 0.07mm, 0.08mm, 0.09mm, 0.1mm, 0.5mm, 1mm, 2mm, 3mm, 4mm, or 5 mm. The inner diameter or inner diameter of the substrate introduction conduit 130 and/or inlet tube 140 may correspond to the diameter of the passage through which the substrate or substrate molecules (including both the molecular components of aerosol particles 122 and substrate 132) are to be used.

The tee fitting and apparatus shown with respect to fig. 4A and 4B may provide a particularly effective manner in which analyte aerosol particles are intermixed directly with the substrate without the further aid of a gas, such as a venturi gas.

The substrate (e.g., isopropyl alcohol) can help clean the portions of the equipment that come into contact with it. In this case, a substrate introduction conduit 130, second and

third conduits

103, 104 of the tee 100, and an inlet pipe 140 are included. For this reason it may be desirable to have a further connection at the central joint 101 connecting the first conduit 102 to the central joint 101. The first conduit 102 and sample delivery tube 120 may then be disposable and/or replaceable such that any portion of the device not in contact with the substrate may be disposable and/or replaceable.

The sample delivery tube 120 may have an inlet for receiving an aerosol sample 122 from a sample under investigation.

The tee 100 may be connected directly to the inlet pipe 140. The inlet tube or capillary 140 may form an inlet capillary of the ion analyzer or mass spectrometer 110.

It is apparent that an inlet arrangement according to the embodiment shown and described above with reference to fig. 4A and 4B may not require a gas (e.g. nitrogen or standard medical air). In addition, the apparatus shown and described above with reference to fig. 4A and 4B may utilize the inherent vacuum of the ion analyzer or mass spectrometer 110 to draw in an aerosol or other gaseous sample containing the analyte. Such a device may help to avoid analyte in the diluted aerosol and has been found to result in an increase in sensitivity to ion signals.

The aerosol particles 122 may be introduced into the tee 100 by the sample transfer tube 120. A matrix compound 132 (e.g., isopropyl alcohol) may be introduced into the T-tee by the matrix introduction conduit 130. Aerosol particles 122 and substrate compounds 132 may be drawn into inlet 112 of ion analyzer or mass spectrometer 110 by a pressure differential caused by reduced pressure region 114 being at a lower pressure than the pressure of sample delivery tube 120 and the inlet of substrate introduction conduit 130.

The substrate molecules 142 (which may be present in both the molecular components of the aerosol particles 122 and the substrate 132) may be arranged to enter the reduced pressure or reduced pressure region 114, so that the substrate molecules 142 may attain a significant linear velocity, for example, due to adiabatic expansion of the gas entering the reduced pressure region 114 from the sample transport portion 120 and/or due to associated free jet formation.

The accelerating matrix molecules 142 may be arranged to collide with the collision surface 9 such that the collision process breaks up the matrix molecules 142. This may result in the formation of gas phase ions 149 comprising the molecular components of the aerosol sample 122, and may also result in the formation of matrix molecules 148.

The impingement surface 116 may be heated and/or controlled and maintained at a temperature significantly above room temperature, for example, by an inductive or resistive heater.

The matrix molecules 148 can diffuse freely into the vacuum. In contrast, gas phase ions 149 of the molecular components of the aerosol sample 122 may be transported by the ion optics 118 to an analysis region of the ion analyzer or mass spectrometer 110. The analyte ions 149 may be directed to an analysis region by applying a voltage to the ion optics 118. The analyte ions 149 may then be analyzed by an ion analyzer or mass spectrometer 110.

According to an embodiment, the ion analyzer or mass spectrometer 110 may comprise an ion mobility spectrometer. According to an embodiment, the ion or mass analyzer 110 may comprise a mass spectrometer. According to further embodiments, the ion analyzer or mass spectrometer 110 may comprise a combination of an ion mobility spectrometer and a mass spectrometer.

As a result of the analysis, chemical information about the sample 122 may be obtained.

The portion of the tee fitting may be arranged to form part of a disposable inlet arrangement of a rapid evaporative ionisation mass spectrometry apparatus. For example, the sample delivery tube 120 may be disposable and form part of a disposable rapid evaporative ionization mass spectrometry apparatus. In this way, only the portion of the device exposed to the aerosol (and not both the aerosol and the substrate) may be disposable after each use. The disposal of this part of the apparatus may reduce contamination in subsequent experiments. To accomplish this, the T-tee may include a connection at the point where the sample delivery tube 120 and substrate introduction conduit 130 intersect.

According to another embodiment, the entire tee 100 may form part of a disposable rapid evaporative ionization mass spectrometry apparatus. According to this embodiment, the sample delivery tube 120, matrix introduction conduit 130 may be disposable and form part of a disposable rapid evaporative ionization mass spectrometry apparatus. A connector may be provided at the inlet 112 of the ion analyzer or mass spectrometer 110. According to an embodiment, the connector may be arranged at the inlet 112 of the first vacuum chamber 114. In this manner, portions of the device that do not form part of the vacuum region of ion analyzer or mass spectrometer 110 may be disposable after each use.

Inlet arrangement # 3-substrate in Venturi gas

Fig. 5A shows an apparatus for introducing an aerosol mixture into an ion analyzer or mass spectrometer 180 having a venturi pump 150. The ion analyzer or mass spectrometer 180 may include an inlet or inlet portion 182 and a reduced pressure region 184 (e.g., a first vacuum region). A collision surface 186 (e.g., a solid collision surface) and optionally ion optics 188 can be arranged within the depressed region 184. The ion optics 188 may include an ion guide, such as a stepwave (rtm) ion guide.

The venturi pump 150 can include an inlet tube 152 that can be connected to a device or probe (e.g., a rapid evaporative ionization mass spectrometry device or probe described herein) and can be configured to transport aerosol particles 160 from a sample (e.g., biological tissue) to the venturi pump 150.

The venturi pump 150 may include a gas and substrate inlet 154 that may be arranged and adapted to introduce a gas (e.g., nitrogen or standard medical air) and a substrate or substrate compound 162 into the flow path of aerosol particles 160 conveyed to the venturi pump 150 by the inlet tube 152. The venturi pump 150 may facilitate the aspiration of aerosol particles 160 or other gaseous sample containing an analyte, and may be driven by nitrogen or standard medical air.

The venturi pump 150 may include a sample transfer portion or capillary 156, which sample transfer portion or capillary 156 may be arranged and adapted to transfer a sample and gas mixture from the tube 152 and direct the mixture through the inlet 158, which may form an inlet of a channel 159 into the ion analyzer or mass spectrometer 180. The end 157 of the channel 159 may be located within and fluidly sealed from an inlet or inlet port 182 of an ion analyzer or mass spectrometer 180.

Aerosol particles 160 may be drawn into the channel 159 through the inlet 158 by a pressure differential between the ion analyzer or mass spectrometer and the inlet 158 adjacent the channel 159.

Some (and sometimes most) of the substrate and larger aerosol particles 161 may travel through the inlet to the channel 159 and exit the apparatus through the exhaust 151. A filter, such as a high efficiency particulate air ("HEPA") filter, may be arranged and adapted to filter gases and other substances passing through the exhaust 151.

The aerosol particles 160 and the substrate 162 may mix within the sample transfer portion or capillary 156 and the channel 159, and substrate molecules 164 may form, wherein both the molecular components of the aerosol particles 160 and the substrate 162 are present within the substrate molecules 164.

To ensure adequate mixing of the sample, the substrate flow rate or the venturi gas and substrate flow rate may be greater than 1 ml/min, 1.5ml/min, 2ml/min, 2.5ml/min, or 3 ml/min. This may be higher than the venturi gas flow rate described in connection with the embodiment of fig. 2A-2C.

The substrate molecules 164 (where both molecular components of the aerosol particles 160 and the substrate 162 may be present) may be arranged to enter the reduced pressure or reduced pressure region 184, so that the substrate molecules 164 may attain a significant linear velocity, for example, due to adiabatic expansion of gas entering the reduced pressure region 184 from the sample transfer portion 156 and/or due to associated free jet formation.

The accelerating matrix molecules 164 may be arranged to collide with the collision surface 186 such that the collision process breaks up the matrix molecules 164. This may result in the formation of gas phase ions 190 comprising the molecular components of the aerosol sample 160, and may also result in the formation of matrix molecules 189.

The impingement surface 186 may be heated and/or controlled and maintained at a temperature significantly above room temperature, for example, by an inductive or resistive heater.

The matrix molecules 189 may freely diffuse into the vacuum. In contrast, gas phase ions 190 of the molecular components of the aerosol sample 160 may be transported by the ion optics 188 to an analysis region of the ion analyzer or mass spectrometer 180. The analyte ions 190 may be directed to an analysis region by applying a voltage to the ion optics 188. The analyte ions 190 may then be analyzed by an ion analyzer or mass spectrometer 180.

According to an embodiment, the ion analyzer or mass spectrometer 180 may comprise an ion mobility spectrometer. According to an embodiment, the ion or mass analyzer 180 may comprise a mass spectrometer. According to further embodiments, the ion analyzer or mass spectrometer 180 may comprise a combination of an ion mobility spectrometer and a mass spectrometer (e.g., a tandem mass spectrometer and an ion mobility spectrometer).

As a result of the analysis, chemical information about the sample 160 may be obtained.

Inlet set # 4-matrix Dispersion to Venturi gas

Figure 5B shows an apparatus similar to figure 5A except that the substrate is introduced via a dedicated substrate introduction conduit as described below (more similar to figures 2A to 2C).

The apparatus comprises a venturi pump 200 for introducing the aerosol mixture to an ion analyzer or mass spectrometer 210. The ion analyzer or mass spectrometer 210 may include an inlet or inlet portion 212 and a reduced pressure region 214 (e.g., a first vacuum region). A collision surface 216 (e.g., a solid collision surface) and optionally ion optics 218 may be arranged within the depressed region 214. The ion optics 218 may include an ion guide, such as a stepwave (rtm) ion guide.

The venturi pump 200 can include an inlet tube 202 that can be connected to a device or probe (e.g., a rapid evaporative ionization mass spectrometry device or probe described herein) and can be configured to transport aerosol particles 222 from a sample (e.g., biological tissue) to the venturi pump 200.

The venturi pump 200 may comprise a gas inlet 204 which may be arranged and adapted to introduce a gas (e.g. nitrogen or standard medical air) into the flow path of aerosol particles conveyed by the tube 202 to the venturi pump 200. The venturi pump 200 may facilitate the aspiration of aerosol particles 222 or other gaseous sample containing an analyte, and may be driven by nitrogen or standard medical grade air.

The venturi pump 200 may comprise a sample transfer portion or capillary 220 which may be arranged and adapted to direct a sample and gas mixture produced by the venturi pump 200 to the junction 206. The substrate introduction conduit 230 is arranged and adapted to introduce a substrate or substrate compound 232 into the junction 206 and direct the flow of the substrate compound 232 to the inlet tube 240.

The aerosol particles 222 and the substrate 232 may mix at the junction 206 or as they pass through the inlet tube 240. Due to the pressure differential between the region adjacent to venturi pump 200 (which may be substantially at atmospheric or ambient pressure) and the reduced pressure region 214 of mass spectrometer 210, the smaller aerosol particles may have momentum such that they may be carried by the gas stream entering the inlet tube of the ion analyzer or mass spectrometer 210.

The larger aerosol particles 223 may have a relatively high momentum such that they are not carried by the airflow entering the inlet tube 240, but rather travel through the junction 206 and exit the device through the exhaust 208. A filter, such as a high efficiency particulate air ("HEPA") filter, may be arranged and adapted to filter gases and other substances passing through the exhaust 208. Although shown as continuous in fig. 5B, the sample transfer portion 220 may be a separate component from the junction 206 and the inlet tube 240. The junction 206 may include a connector or connection (not shown) for connecting to a separate sample transfer portion 220. The connection between the junction 206 and the sample transfer portion 220 may be fluidly sealed and/or may include an annular clamp.

The end 157 of the inlet tube 240 may be located within and fluidly sealed from the inlet or entrance portion 212 of the ion analyzer or mass spectrometer 210.

The aerosol particles 222 and the substrate 232 may mix within the inlet tube 240 and substrate molecules 242 may be formed, wherein both the molecular components of the aerosol particles 222 and the substrate 232 are present within the substrate molecules 242.

The substrate molecules 242 (where both the molecular components of the aerosol particles 222 and the substrate 232 may be present) may be arranged to enter the reduced pressure or reduced pressure region 214, so that the substrate molecules 242 may attain significant linear velocities, for example, due to adiabatic expansion of the gas entering the reduced pressure region 214 from the inlet tube 240 and/or due to associated free jet formation.

The accelerating matrix molecules 242 may be arranged to collide with the collision surface 216 such that the collision process breaks up the matrix molecules 242. This may result in the formation of gas phase ions 245 comprising the molecular components of the aerosol sample 222 and may also result in the formation of matrix molecules 244.

The impingement surface 216 may be heated and/or controlled and maintained at a temperature significantly above room temperature, such as by an inductive or resistive heater.

The matrix molecules 244 are free to diffuse into the vacuum. In contrast, gas phase ions 245 of the molecular components of the aerosol sample 222 may be transported by the ion optics 218 to an analysis region of the ion analyzer or mass spectrometer 210. The analyte ions 245 may be directed to an analysis region by applying a voltage to ion optics 218. The analyte ions 245 can then be analyzed by an ion analyzer or mass spectrometer 210.

According to an embodiment, the ion analyzer or mass spectrometer 210 may comprise an ion mobility spectrometer. According to an embodiment, the ion or mass analyzer 210 may comprise a mass spectrometer. According to further embodiments, the ion analyzer or mass spectrometer 210 may comprise a combination of an ion mobility spectrometer and a mass spectrometer.

As a result of the analysis, chemical information about the sample 222 may be obtained.

In any of the inlet arrangements disclosed above, the

substrate introduction conduit

30, 130, 230 may have a diameter greater than, less than or substantially equal to 0.2mm, 0.4mm, 0.6mm, 0.8mm, 1mm, 1.2mm, 1.4mm, 1.6mm, 1.8mm, 2mm, 2.2mm, 2.4mm, 2.6mm, 2.8mm, 3mm, 3.2mm, 3.4mm, 3.6mm, 3.8mm, 4mm, 4.2mm, 4.4mm, 4.6mm, 4.8mm or 5 mm.

The matrix may comprise a polar molecule, water, one or more alcohols, methanol, ethanol, isopropanol, acetone or acetonitrile. Isopropanol has been found to be particularly advantageous. The matrix may comprise a blocking substance or a calibration compound.

Analysis Using isopropanol as matrix

When operating an ion analyzer or mass spectrometer using the inlet set-up disclosed above, isopropanol was used to aid ionization. As mentioned above, ionization is assisted because the isopropanol partially or completely dissolves the analyte molecules and thus reduces intermolecular forces, which would otherwise be negatively affected and thus reduce sensitivity.

The introduction of isopropanol was first tested using inlet set-up #1 for transport of the aerosol to the inlet capillary of the ion analyzer or mass spectrometer 7. The hot impact surface according to various embodiments was found to eliminate certain spectral features (e.g., ceramides in the experimental data for bacteroides fragilis as shown in fig. 6A-6C) compared to skimmer atmospheric pressure ionization ("API") ion sources or at cold surface impacts.

Fig. 6A shows a mass spectrum generated from bacteroides fragilis using a skimmer atmospheric pressure inlet ("API") involving collision at a cold surface. Fig. 6B shows a mass spectrum generated from bacteroides fragilis using a cold collision ball 9 according to the embodiment shown in fig. 3 and 4.

FIG. 6C shows a mass spectrum generated from Bacteroides fragilis using a thermal collision ball according to the embodiment shown in FIGS. 3 and 4.

Introduction of isopropanol into the sampled aerosol before introduction into the ion analyser or mass spectrometer 7 was found to restore these spectral features and produce a mass spectral fingerprint similar to an atmospheric pressure interface with a non-heated collision surface.

The effect on the spectral appearance of candida albicans as shown in fig. 7A to 7C and proteus as shown in fig. 8A to 8C was also proposed.

As will be discussed in more detail below, it is apparent from the experimental results shown in fig. 7A-7C and 8A-8C that the use of a heated impingement surface (as opposed to a cold impingement surface) results in a significant beneficial change in the appearance of the spectrum.

Fig. 7A and 8A show mass spectra generated from candida albicans and proteus mirabilis, respectively, using a heating coil interface incorporating isopropyl alcohol.

Fig. 7B and 8B show mass spectra generated from candida albicans and proteus mirabilis, respectively, using a heating coil interface without the introduction of isopropyl alcohol.

Fig. 7C and 8C show mass spectra generated from candida albicans and proteus mirabilis, respectively, using the cold solid ball collision surface 9 according to the embodiments described above with reference to fig. 4 and 5.

As can be seen in fig. 7A to 7C, many of the spectral features in candida albicans significantly decreased in relative intensity or disappeared completely. The introduction of isopropanol as a matrix helps to circumvent this problem and create a spectrum more similar to the cold collision surface interface. However, one observed drawback is that the observation of an ascending baseline near lower quality effectively reduces the signal-to-noise ratio.

The use of isopropanol was observed to result in a loss of mass spectral information above m/z 1000 as evident in the case of proteus mirabilis (fig. 8A to 8C).

An increase in sensitivity can be achieved via introduction of the introduced isopropyl alcohol into the ion analyzer or mass spectrometer in combination with the introduced aerosol sample (containing the analyte). For this reason, an entry setting similar to entry setting #2 was tested. The inlet arrangement comprises a T-tee as shown in fig. 4A and 4B.

Means are provided in the form of a T-tube for connecting the sample transfer tube 21 and substrate introduction conduit 3 with the extended mass spectrometer inlet capillary. The increasing isopropanol flow rate was tested between 0 and 0.25mL/min and the optimum flow rate was determined to be 0.1 mL/min.

The effect of different isopropanol flow rates on the spectral appearance of bacteroides fragilis was determined and is shown in fig. 9A-I and fig. 10A-I.

FIG. 9A shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.1mL/min, FIG. 9B shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.02mL/min, FIG. 9C shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.05mL/min, FIG. 9D shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.0.07mL/min, FIG. 9E shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.1mL/min, FIG. 9F shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.13mL/min, FIG. 9G shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.15 mL/min, FIG. 9H shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.2mL/min, FIG. 9I shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.25 mL/min.

FIG. 10A shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.1mL/min, FIG. 10B shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.02mL/min, FIG. 10C shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.05mL/min, FIG. 10D shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.0.07mL/min, FIG. 10E shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.1mL/min, FIG. 10F shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.13mL/min, FIG. 10G shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.15mL/min, FIG. 10H shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.2mL/min, FIG. 10I shows a mass spectrum generated from Bacteroides fragilis at an isopropanol flow rate of 0.25 mL/min.

As is clear from the above, the effect of the presence of isopropanol can be detected from 0.02mL/min based on the appearance of m/z590 (ceramide species) and m/z 752(α -galactosylceramide). It was found that the relative abundance of these species increased with further increase in the isopropanol flow rate. Once the appearance of m/z590 and 752 is set, the peaks of the very high quality region m/z >2000 are found to disappear (see FIG. 9), and this indicates a negative impact on the heavier spectral features.

DESI atomizer with heat transfer capillary

Fig. 11 shows another embodiment and includes a desorption electrospray ionization ("DESI") nebulizer 300, in which a solvent capillary 302 may be arranged to direct charged particles 304 of a solvent at a sample surface 310. A sample 311 may be located on the sample surface 310, which may include analyte particles. Charging the solvent particles may be accomplished through the use of a power source, such as a high voltage power source 306 contacting the capillary 302. The high voltage power supply 306 may include an electrode 307, wherein the electrode may contact any portion of the capillary 302 such that it is operable to charge solvent particles as they exit the outlet end 303 of the capillary 302. The outlet end 303 of the capillary may be directed towards the sample surface 310.

A cladding gas 308 (e.g., nitrogen) may be arranged to surround the capillary 302 to atomize the solvent as it exits the capillary 302 and to direct the charged solvent particles 304 to the surface 310. The sheath gas may be introduced via a tube 312, which may be coaxial with the solvent capillary 302, having an inlet 314 at the distal end of the sample surface 310 and an outlet 316 at the end facing the sample surface 310.

The outlet 316 of the clad gas tube 312 may be concentric with the outlet end 303 of the capillary tube, which may help atomize the solvent as it exits the capillary tube 302. Solvent emerging from the outlet end 303 of the solvent capillary 302 may be atomized by the cladding gas 308. Connector 318 may connect tube 312 to a source of gas suitable for use as a blanket gas. The blanket gas 308 may comprise nitrogen or standard medical air and the blanket gas source may be a source of nitrogen or standard medical air.

When the solvent droplets 304 contact the sample, analyte particles on the sample can desorb and the charged droplets and analyte mixture 320 can be transported into a transport capillary 330, which can lead to a mass analyzer and/or ion mobility analyzer and/or mass spectrometer 340. The charged droplet and analyte mixture may be transported through the inlet 332 of the transport capillary 330. This may be accomplished by placing the opposite end 333 of the transfer capillary 330 in the low pressure region 352 (e.g., the vacuum stage of the ion analyzer or mass spectrometer 340).

The charged droplets and analyte mixture (including, for example, analyte ions) may be transported by ion optics 352 to an analysis region of an ion analyzer or mass spectrometer 340. The ion optics 352 may include an ion guide, such as a stepwave (rtm) ion guide.

The analyte ions may be directed to an analysis region by applying a voltage to ion optics 352. The analyte ions can then be analyzed by an ion analyzer and/or an ion mobility analyzer or mass spectrometer 340.

According to an embodiment, the ion analyzer or mass spectrometer 340 may comprise an ion mobility spectrometer. According to further embodiments, the ion analyzer or mass spectrometer 340 may comprise a combination of an ion mobility spectrometer and a mass spectrometer.

As a result of the analysis, chemical information about the sample 311 can be obtained.

One or more heaters may be provided for heating various portions of the apparatus shown in fig. 11. For example, a heater may be provided for heating one or more of the solvent capillary 302, the cladding gas tube 312, the sample surface 310, and a transfer or inlet capillary 330.

The one or more heaters may include a wire heater (e.g., tungsten wrap) and/or may be configured to heat the respective component above ambient temperature, and/or at least 30 ℃, 50 ℃, 100 ℃, 200 ℃, 300 ℃, 400 ℃, 500 ℃, or greater than 500 ℃. However, any type of heater having a function of heating the respective components may be used, such as a blower or an induction or resistance heater.

Fig. 11 shows a first heater 342 that may be arranged and adapted to heat the transfer or inlet capillary 330 so that the solvent and analyte mixture 320 may be heated prior to onward passage to, for example, a mass analyzer and/or ion mobility analyzer or mass spectrometer 340.

The first heater 348 can be located anywhere along the solvent capillary 330, such as adjacent to or at the inlet 341 of a mass analyzer and/or ion mobility analyzer or mass spectrometer. Alternatively, the first heater 342 may be located adjacent to or at the inlet 332 of the solvent capillary 330. The first heater 342 may include a filament heater (e.g., a tungsten filament winding) and/or may be configured to heat the inlet capillary above ambient temperature, and/or a temperature of at least 30 ℃, 50 ℃, 100 ℃, 200 ℃, 300 ℃, 400 ℃, 500 ℃, or greater than 500 ℃.

The second heater 344 may be arranged and adapted to heat the envelope gas tube 312 such that the solvent and/or envelope gas may be heated.

The second heater 344 may be located at the end of the tube 312 closest to the sample surface 310 so that the solvent and/or cladding gas may be heated before being directed to the sample surface 310. The second heater 344 may include a wire heater (e.g., a tungsten wire wrap) and/or may be configured to heat the tube 312 and/or the solvent and/or cladding gas above ambient temperature, and/or a temperature of at least 30 ℃, 50 ℃, 100 ℃, 200 ℃, 300 ℃, 400 ℃, 500 ℃, or greater than 500 ℃. The third heater 346 may be arranged and adapted to heat the solvent capillary 302 such that the solvent may be heated.

The third heater 346 may be located anywhere along the solvent capillary 302 (e.g., closest to the end 305 located away from the sample surface 310) so that the solvent may be heated before it is surrounded by the gas-clad tube 312. The third heater 346 may include a wire heater (e.g., a tungsten wire wrap) and/or may be configured to heat the solvent capillary 302 and/or the solvent above ambient temperature, and/or a temperature of at least 30 ℃, 50 ℃, 100 ℃, 200 ℃, 300 ℃, 400 ℃, 500 ℃, or greater than 500 ℃. The fourth heater 348 may be arranged and adapted to heat the sample surface 310 such that the sample 311 and/or the sample surface 310 may be heated. The fourth heater 348 can be located below a portion of the sample surface 310 that is arranged and adapted to hold or contain the sample 311. The fourth heater 348 may include a wire heater (e.g., a tungsten wire wrap) and/or may be configured to heat the sample 311 and/or sample surface 310 and/or the solvent above ambient temperature, and/or a temperature of at least 30 ℃, 50 ℃, 100 ℃, 200 ℃, 300 ℃, 400 ℃, 500 ℃, or greater than 500 ℃. The effect of heating the ion inlet transfer capillary (transfer capillary 120 as shown in figure 11) was tested on a Xevo G2-xs (rtm) quadrupole time-of-flight mass spectrometer and a Synapt G2-si (rtm) quadrupole ion time-of-flight migration mass spectrometer.

The ion transport capillary was heated to 100 ℃ to 490 ℃ using a nickel wire heater. Pig liver sections were used and compared for intensity of selected fatty acids and phospholipids. Inlet capillary heating was found to have some effect on fatty acid intensity using a xevo (rtm) mass spectrometer and no effect on fatty acid intensity using a synapt (rtm) mass spectrometer. However, monitoring the intensity of phospholipids can improve by nearly two orders of magnitude.

Fig. 12A to 12D show the effect of inlet capillary heating on absolute intensity. Fig. 12A and 12C relate to a wott synapse G2-si (rtm) mass spectrometer and fig. 12B and 12D relate to a wott Xevo G2-xs (rtm) mass spectrometer. The mean intensity of selected Fatty Acids (FA), Phosphatidylethanolamine (PE) and most enriched Phosphatidylinositol (PI) from porcine liver sections is shown.

It is apparent from fig. 12A to 12D that increasing the temperature of the ion-transport capillary can increase the observed phospholipid strength by nearly two orders of magnitude.

The embodiment described with respect to fig. 11 may be used in applications (e.g., medical swabs) where the sample surface 310 forms the surface of a swab. In this case, the swab itself may be heated in order to heat the sample 311 located on the swab. For example, the fourth heater may be a wire heater located within the swab and may be arranged and adapted to heat an end of the swab configured to preserve and/or retain a biological sample for analysis.

System for use in an operating room

Fig. 13A illustrates a device 1300, such as a portable device 1300, which can be provided according to one embodiment.

Device 1300 may include a surgical stack 1301 that includes a camera monitor 1303 operably connected to an instrument stack 1305. The instrument cluster 1305 includes a camera unit 1307 that is operably connected to an endoscope 1310. Surgical stack 1301 may include one or more surgical instruments, such as an endoscope 1310. Embodiments are contemplated in which the camera monitor 1303 is, or forms part of, a mobile device (e.g., a mobile tablet device).

In various embodiments, endoscope 1310 may be referred to as a laparoscope and include the same features and is arranged and adapted in the same manner as described with respect to endoscope 1310.

Endoscope 1310 may include a conduit that houses one or more endoscopic devices, such as one or more optical fibers and/or data cables. Endoscope 1310 may include a bundle of fiber optic and/or data line cables. The endoscope may take the form of an electrosurgical tool as described in any of the embodiments disclosed herein, for example the endoscope may be a laparoscope as described herein, or include a rapid evaporative ionization mass spectrometry apparatus or probe as described below with reference to figures 14A and 14B.

One of the optical fibers may feed light from a light source in the camera unit 1307 to the distal end 1312 of the endoscope 1310. One of the optical fibers may be arranged and adapted to feed light from the distal end 1312 to a camera or charge coupled device ("CCD") located in the camera unit 1307. Alternatively, a camera or charge coupled device ("CCD") may be located at the distal end 1312 of the endoscope 1310 and may be operatively connected to the camera unit 1307 via one or more data cables.

Instrument stack 1305 may be portable. For example, instrument stack 1305 may be positioned on a plurality of wheels 1309 and/or on a track such that the instrument stack may be moved between different positions, such as between different operating rooms. Instrument set 1301 may weigh less than 500kg, 400kg, 300kg, 200kg, 150kg, 100kg, 50kg, 40kg, 30 kg, 20kg, 10kg, or 5 kg.

Portable device 1300 may include an analysis stack 1330. Analysis stack 1330 can include one or more ion analyzers or mass spectrometers 1332. The ion analyser or mass spectrometer 1332 may comprise an ion inlet arrangement 1334 for introducing ions into the ion analyser for analysis, for example mass analysis and/or ion mobility analysis.

The ion inlet arrangement 1334 may include any of the inlet arrangements numbered #1 through #4 and discussed above with respect to fig. 2A through 5B. For example, the tissue sampling device 1336 may correspond to (i) the tube 21 referenced in portal setting #1 and shown in fig. 2A and 3, (ii) the sample delivery tube 120 referenced in portal setting #2 and shown in fig. 4A and 4B, (iii) the inlet tube 152 referenced in portal setting #3 and shown in fig. 5A, and (iv) the inlet tube 202 referenced in portal setting #4 and shown in fig. 5B.

Analysis stack 1330 may be portable. For example, analysis stack 1330 can be positioned on a plurality of wheels 1338 and/or on a track such that the instrument stack can be moved between different locations, e.g., between different operating rooms. Analysis stack 1336 may weigh less than 500kg, 400kg, 300kg, 200kg, 150kg, 100kg, 50kg, 40kg, 30 kg, 20kg, 10kg, or 5 kg.

The tissue sampling device 1336 may be connected to or form part of the endoscope 1310. The tissue sampling device 1336 may be incorporated into the endoscope 1310 at a junction 1325. At junction 1325, endoscope 1310 and tissue sampling device 1336 can be disconnected while endoscope 1310 continues to be connected to surgical stack 1301 and tissue sampling device 1336 continues to be connected to analysis stack 1330.

At junction 1325, endoscope 1310 and tissue sampling device 1336 may be combined and disposed in a larger tube. This may facilitate insertion of the endoscope 1310 and tissue sampling device 1336 into a human or animal body. The distal end 1312 of the endoscope 1310 may also correspond to, or form, the distal end 1312 of the tissue sampling device 1336.

Tissue sampling device 1336 may include one or more tubes and/or cables that may house one or more devices or tools, such as one or more electrodes and/or gas conduits. Tissue sampling device 1336 may comprise a tool, such as an electrosurgical tool (e.g., a rapid evaporative ionization mass spectrometry device or probe), wherein the electrosurgical tool may comprise one or more electrodes, and analysis stack 1330 may comprise a voltage source arranged and adapted to apply a voltage to the one or more electrodes.

The tool (and including therein an electrosurgical tool, a rapid evaporative ionization mass spectrometry device or probe, and/or one or more electrodes) may be located at the distal end 1312 of the tissue sampling device 1336. The tool and/or one or more electrodes may be arranged and adapted to protrude from the distal end 1312 of the tissue sampling device 1336 and arranged and adapted to contact biological tissue within the field of view of a camera or charge coupled device ("CCD") as discussed above.

The electrosurgical tool may be a monopolar device, in which case a counter electrode may be provided, and the counter electrode may be arranged and adapted to contact different portions of biological tissue, one or more electrodes located at the distal end 1312 of the tissue sampling device 1336. For example, the counter electrode may comprise a pad or pad on which a sample of biological tissue is placed.

The electrosurgical tool may comprise a bi-polar device (such as a bipolar forceps as described herein), in which case at least two electrodes may be disposed at the distal end of the tool, such that a potential difference may be generated between the two electrodes, which may vaporize tissue in contact with the electrodes.

One or more electrodes may be arranged and adapted to contact or surround a portion of biological tissue or a biological tissue sample and vaporize or vaporize the portion of biological tissue or the biological tissue sample to form an aerosol, smoke, or vapor. One or more gas conduits may be provided for drawing aerosol, smoke, or vapor through tissue sampling device 1336 and into ion inlet device 1334 through tissue sampling device 1336.

The portable device 1300 may include a filter, such as a high efficiency particulate air ("HEPA") filter, which may be arranged and adapted to filter gases and other substances expelled from the tissue sampling apparatus 1336, the ion inlet apparatus 1334, or the ion analyzer or mass spectrometer 1332.

Ion inlet arrangement 1334 may be arranged and adapted to ionize particles in aerosol, smoke or vapor and convey the ionized particles to an ion analyzer or mass spectrometer 1332.

According to one embodiment, ion analyzer or mass spectrometer 1332 may comprise an ion mobility spectrometer. According to an embodiment, the ion or mass analyzer 1332 may comprise a mass spectrometer. According to further embodiments, the ion analyzer or mass spectrometer 1332 may comprise a combination ion mobility spectrometer and mass spectrometer.

As a result of the analysis, chemical information about the aerosol, smoke or vapour may be obtained, and thus chemical information of a portion of biological tissue or a biological tissue sample may be obtained.

Portable device 1300 may include a single stack or unit that includes instrument stack 1301 and analysis stack 1330, as well as their components. In this manner, instrument stack 1301 and analysis stack 1330 may move as an integral unit.

The entire stack or unit may be portable. For example, the entire stack or unit may be located on a plurality of wheels and/or on a track such that the single stack or unit may be moved between different locations, such as between different operating rooms. The overall stack or unit weight may be less than 500kg, 400kg, 300kg, 200kg, 150kg, 100kg, 50kg, 40 kg, 30kg, 20kg, 10kg or 5 kg.

In various embodiments, an operating room may be provided that includes a portable device 1300. The operating room may comprise a track arranged and adapted such that the portable device 1300 can move along the track.

In various embodiments, a suite of operating rooms may be provided, wherein portable devices may be moved between operating rooms. The track may be arranged and adapted such that the portable device 1300 may move along the track between different operating rooms.

The camera monitor 1303 may be arranged and adapted to relay multiple images or image data output from the camera unit 1307 to display a field of view from the distal end 1312 of the endoscope 1310.

An analysis monitor 1333 may be provided that is operatively connected to analysis stack 1330. The analysis monitor 1333 may be arranged and adapted to display data output from the ion analyzer or mass spectrometer 1332, for example mass spectral data or chemical information about a portion of biological tissue or a biological tissue sample being analyzed. Embodiments are envisaged in which the analysis monitor is, or forms part of, a mobile device, such as a mobile tablet device.

In some embodiments, the camera monitor 1303 may be connected to an ion analyzer or mass spectrometer via an interface. The interface may include a serial interface such as an RJ45 connector, an ethernet connector, an RS232 connector, a USB connector, or the like. The interface may also or instead be provided by a wireless interface such as a Wi-Fi connection, Bluetooth (Bluetooth) connection, ZigBee connection, or the like.

The camera monitor 1303 may be arranged and adapted to display data output from the ion analyzer or mass spectrometer 1332, such as mass spectral data or chemical information about a portion of a biological tissue or biological tissue sample being analyzed. The processor or other processing unit may be arranged and adapted to superimpose mass spectral data or chemical information on the image of the biological tissue sample shown on the camera monitor 1303.

In some embodiments, the analysis monitor 1333 may be connected to the camera unit 1307 via an interface. The interface may include a serial interface such as an RJ45 connector, an ethernet connector, an RS232 connector, a USB connector, or the like. The interface may also or instead be provided by a wireless interface such as a Wi-Fi connection, Bluetooth (Bluetooth) connection, ZigBee connection, or the like.

The analysis monitor 1333 may be arranged and adapted to display a plurality of images or image data output from the camera unit 1307, e.g. mass spectral data or chemical information about a portion of the biological tissue or a biological tissue sample being analyzed. The processor or other processing unit may be arranged and adapted to superimpose these images or image data on the mass spectral data or chemical information shown on the camera monitor 1333.

In embodiments, the camera monitor 1303 and the analysis monitor 1333 may be the same component, and the processor or other processing unit may be arranged and adapted to display multiple images or image data on the same screen, e.g., side-by-side or superimposed on each other.

In various embodiments, analysis stack 1330 may be provided separately, such that tissue sampling device 1336 may not be connected to an endoscope. Analysis stack 1330 can also include one or more surgical instruments, such as a rapid evaporative ionization mass spectrometry device or probe as described herein that can be connected to or form part or all of a tissue sampling device.

In a particular example, gastrointestinal ("GI") cancer accounts for 23% of cancer-related deaths worldwide. Despite increasing morbidity, cancer mortality has declined over the last forty years. However, it is estimated that 30% to 40% of these deaths may still be prevented. Accurate disease diagnosis and early treatment are key factors in improving cancer outcomes.

Early cancers and premalignant lesions can be successfully treated using endoscopic techniques based on electrocautery, while the gold standard diagnostic method remains a tissue biopsy for white light endoscopic examination of the gastrointestinal tract.

It has recently been reported that in endoscopy, up to 7.8% of gastrointestinal cancers in patients subsequently diagnosed with cancer may be overlooked. The main advantage of current endoscopic surgery is that if the patient's lesion is completely removed, the patient can avoid the need for major surgery. However, as many as 41% of patients require re-intervention due to incomplete resection.

It will be apparent that a particular advantage of the devices disclosed herein is that they enable accurate real-time mass spectral data to be obtained and utilized to reduce the rate of misdiagnosis and improve the rate of complete ablation.

Enhanced imaging techniques are being developed to improve diagnostic accuracy within the gastrointestinal tract, with particular emphasis on spectral characterization using elastic scattering spectroscopy, optical coherence tomography, multimodal imaging combined raman spectroscopy, autofluorescence, and narrow band imaging.

However, none of these approaches are currently used in mainstream clinical practice.

Mass spectrometry ("MS") based tissue identification is known as a tissue analysis study using imaging techniques, sampling probe/electrospray systems and direct ambient ionization mass spectrometry.

Rapid evaporative ionization mass spectrometry ("REIMS"), which allows real-time analysis in situ using an electrosurgical tool as a mass spectrometry ion source, has emerged as a useful technology from this group of technologies.

Endoscope with ferrule

According to one aspect of the present disclosure, an apparatus is provided that includes an endoscope and an electrosurgical probe, such as a rapid evaporative ionization mass spectrometry probe. The rapid evaporative ionization mass spectrometry probe can include a ferrule arranged and used to surround a portion of biological tissue and vaporize or vaporize the portion of biological tissue to form an aerosol.

FIG. 13B illustrates one embodiment of a device 1350 located at the distal end 1312 of the endoscope 1310 of FIG. 13A. The device 1350 may be or form part of a tissue sampling device 1336 as shown in fig. 13A, and may take the form of a hollow tube having one or more electrodes therethrough, as will be described in more detail below.

The device 1350 may take the form of a rapid evaporative ionization mass spectrometry device or probe 1350, which may include an elongated tube 1352 and an electrode 1354 that may protrude from a distal end 1356 of the tube 1352. The electrodes 1354 may take the form of rings or collars as shown, or may take the form of pointed or straight members protruding from the distal end 1312 of the endoscope 1310. In various embodiments, the electrodes 1354 may take the form of a bipolar forceps as shown with reference to fig. 14A, or the electrodes 1354 may take the form of a monopolar device as shown with reference to fig. 14B.

In the embodiment of fig. 13B, the two strands of the electrode located within the rapid evaporation ionization mass spectrometry device or probe 1350 may not be in contact with each other. For example, the strands may be held apart by being held in respective sheaths or otherwise.

A rapid evaporative ionization mass spectrometry device or probe 1350 can be held in a channel 1358 in the endoscope, which channel 1358 can be referred to as an instrument channel. Channel 1358 may begin at junction 1325 (see fig. 13A, if provided) and may be arranged and adapted to receive a component from analysis stack 1330, such as a tissue sampling device 1336 in the form of a rapid evaporative ionization mass spectrometry device or probe 1350 in the illustrated embodiment.

Endoscope 1310 may further include one or more optical fibers 1360. As discussed above with reference to fig. 13A, the optical fibers may be arranged and adapted to transmit light from the light source to the distal end 1312 of the endoscope 1310. The one or more optical fibers 1360 may be arranged and adapted to transmit light from the distal end 1312 of the endoscope 1310 to a camera or charge coupled device ("CCD").

Multiple data cables or other conduits may be provided in place of the optical fibers, depending on the application at hand. If it is desired to deliver gas to the distal end 1312 of the endoscope 1310, a gas tube may be provided in place of one of the optical fibers, which may be connected to a gas source, such as an insufflation source. The outlet (or additional outlets) of the airway tube may be located anywhere along the endoscope 1310.

The apparatus 1350 may be arranged and adapted to apply a voltage to a portion 1370 of the sample to generate an aerosol (or surgical smoke) 1372. The aerosol (or surgical smoke) 1372 may then be drawn or otherwise drawn into the device 1350, and may then be conveyed to the ion analyzer or mass spectrometer 1332 via the gas path 1374 (fig. 13A). A plurality of apertures 1365 may be provided on the outer surface of the device 1350 to provide more opportunity for aerosol to pass into the device 1350.

In some embodiments, device 1350 may include multiple channels, where a first channel may house electrode 1354 (or multiple electrodes) and a second channel may be a gas channel arranged and adapted to convey aerosol to an ion analyzer or mass spectrometer 1332. The second channel may be located coaxially around the first channel.

A tool or electrode deployment opening 1362 is provided at the distal end 1356 of the device 1350 and the electrode (or other tool) can be arranged and adapted so that it can be retracted and extended from the opening 1362.

In the example shown, the electrodes 1354 can be deployed around a neoplasm or "polyp" 1370, and the neoplasm 1370 can be located on the membrane 1342 of the stomach 1340.

If desired, ablation may be performed using an electrode as shown in FIG. 13B. In use, the snare 1354 can be extended and deployed over the wart 1370 to surround the wart. The snare 1354 can then be retracted to form a tight seal around the lower portion of the wart 1370. In doing so, as shown in fig. 2B, wart 1370 can at least partially or completely block tool deployment opening 1362 of tube 1352 during resection.

When a voltage is applied to the electrodes 1354, aerosol 1372 generated by the ablation may be drawn through the openings 1365 that may be provided on the outer surface of the device 1350.

Apertures 1365 located on an outer surface of the device 1350 and spaced apart from the opening 1362 can be beneficial because these apertures or suction ports 1365 allow surgical smoke and/or aerosol to be drawn when the tool deployment opening 1362 is at least partially or fully blocked.

The aerosol particles entering the device 1350 via the apertures or suction ports 1365 are then transported to an ion analyzer or mass spectrometer 1332 via the tube 1352 and/or tissue sampling device 1336 (both of which may also be the same component as described above).

The illustrated device 1350 may also be attached to, or form part of, the proximal end 1312 of the endoscope 1310. The tube 1352 may be directly connected to an ion inlet device 1334 (e.g., its inlet capillary or ion sampling port) of an ion analyzer or mass spectrometer 1332. It will be appreciated that the ion analyser or mass spectrometer may be spaced from the evaporation point. One or more aerosol or gas channels may be located within tube or conduit 1352 to convey the aerosol to an ion analyzer or mass spectrometer 1332.

Laparoscopy and laparoscopy tool

As described above, the endoscope described with respect to the embodiment of FIGS. 13A and 13B may be used for laparoscopy. In this case, the endoscope (or laparoscope) or its tip may be rigid (e.g., the endoscope may be constructed of metal or rigid plastic), and/or may be arranged and adapted to perform laparoscopic procedures (keyhole surgery).

Figure 13C illustrates a laparoscope 1310 that may include a rigid end 1380 that may be attached to a flexible portion 1382. The distal end 1312 may include the same features as discussed above with respect to fig. 13B, for example, a rapid evaporative ionization mass spectrometry device 1350 may be arranged and adapted to protrude from the distal end 1312 to generate an aerosol or surgical smoke, which may then be transported back to the ion analyzer or mass spectrometer by openings in the device 1350.

The end 1380 of the laparoscope 1310 may include an elongated portion 1381 that may have a width 1384 (or thickness, diameter, etc.) and a length 1386. The width 1384 may be uniform or substantially uniform over the length 1386 of the elongated portion 1381. The elongated portion 1381 may be arranged and adapted for insertion into a small incision in a human or animal body, such as an incision having a length of less than 20mm, 15mm, 10mm, or 5 mm.

The width 1384 may be less than 20mm, 15mm, 10mm, or 5 mm.

The length may be greater than 5mm, 10mm, 15mm, 20mm, 25mm, 30mm, 35mm, 40mm, 50mm, 60mm, 70mm, 80mm, 90mm, 100mm, 150mm, 200mm, 300mm, 400mm or 500 mm.

End 1380 may include a handle to assist in holding and moving laparoscope 1310. The handle may be located at or near the junction 1396 between the flexible portion 1382 and the rigid end 1380. The handle may be rigid and may form part of the same rigid element as rigid end 1380. The handle may be arranged and adapted to move or guide the rigid end 1380 and/or the elongated portion 1381 (e.g., during a surgical procedure (e.g., laparoscopy)).

The apparatus may include various surgical devices disclosed herein, such as a laparoscope as described above with respect to fig. 13A, 13B and 13C, a surgical robot as described above with respect to fig. 15A and 15B, an electrosurgical probe (e.g., a rapid evaporative ionization mass spectrometry device or probe), or an electrosurgical tool. The surgical procedure may be laparoscopy.

According to one aspect of the present disclosure, a tool for use in laparoscopy is provided that includes an endoscope or laparoscope (e.g., endoscope or laparoscope 1310 as described above with reference to fig. 13C) and a rapid evaporative ionization mass spectrometry probe (e.g., rapid evaporative ionization mass spectrometry probe 1350 as described above with respect to fig. 13B).

The rapid evaporative ionization mass spectrometry probe 1350 can be located at the distal end 1312 of the endoscope 1310. The tool (e.g., the elongate portion 1381 thereof) may be inserted through a small incision (e.g., less than 5cm, 4cm, 3cm, 2cm, or 1cm) in human or animal tissue. The tool may comprise an elongate tube or conduit and the endoscope and the rapid evaporative ionisation mass spectrometry probe may form part of the elongate tube or conduit.

₂Blowing (e.g. using carbon dioxide (CO))

According to one aspect of the present disclosure, an apparatus is provided that includes an electrosurgical device (e.g., a rapid evaporative ionization mass spectrometry device or probe) and an insufflator. The apparatus may comprise a surgical instrument, such as an endoscope or laparoscope as discussed herein with reference to fig. 13C, which may comprise a rapid evaporative ionization mass spectrometry device or probe.

Referring to fig. 13C, the surgical instrument (e.g., laparoscope 1310) may include a gas channel for delivering gas from an insufflator into a cavity (e.g., a body cavity). The insufflator may include a gas source and a mechanism (e.g., a pump) for fluidly communicating the gas source to the gas channel.

Insufflator airway 1390 is provided to deliver insufflation gas from a gas source to laparoscope 1310, such as its tip 1380. The airway tube 1390 may be in fluid communication with the internal gas passageway 1394 of the laparoscope 1310 and may be connected thereto via a connector 1391.

Laparoscope 1310 may include one or more insufflation gas outlets 1392 located in a portion of the laparoscope that are configured to be inserted into a body cavity.

Internal gas passageway 1394 can extend at least partially along the length of laparoscope 1310. One or more outlets 1392 of internal gas passageway 1394 may be located at distal end 1312, elongated portion 1381, or end 1380 of the laparoscope, for example within 10mm, 15mm, 20mm, 25mm, 30 mm, 35mm, 40mm, 45mm, 50mm, 60mm, 70mm, 80mm, 90mm, 100mm, 200mm, or 300mm of distal end 1312 (i.e., the end configured for insertion into a human or animal sample). The internal gas passageway 1394 may be adjacent to or connected to an optical fiber, such as the one or more optical fibers 1360 discussed above, that may be connected to a camera at the distal end of the laparoscope. The gas source may include carbon dioxide ("CO₂") a source of gas.

The laparoscope may be an endoscope or laparoscope as described above with respect to fig. 13A and 13B.

Surgical instrument and optimized probe for intra-operative diagnosis

According to one embodiment, a surgical instrument is provided that includes a rapid evaporative ionization mass spectrometry apparatus or probe. The surgical instrument may form part of a surgical stack 1301 as described above with respect to fig. 13A. The surgical instrument may comprise an endoscope or a laparoscope and the rapid evaporative ionization mass spectrometry apparatus or probe may comprise a surgical diathermic probe. The rapid evaporative ionization mass spectrometry probe can include one or more electrodes configured to vaporize or vaporize biological tissue to form an aerosol including particles of the biological tissue. The rapid evaporative ionization mass spectrometry probe may further comprise a tube or other mechanism for transporting the particles to a mass analyzer and/or an ion mobility analyzer or mass spectrometer.

According to one embodiment, a rapid evaporative ionization mass spectrometry apparatus or probe for use in intraoperative diagnostics is provided. The rapid evaporative ionization mass spectrometry apparatus or probe may form part of a surgical instrument, such as an endoscope or laparoscope, and the rapid evaporation ionization mass spectrometry apparatus or probe may comprise a surgical diathermic probe.

According to one embodiment, a surgical method is provided that includes intraoperative diagnostic use of a rapid evaporative ionization mass spectrometry apparatus or probe. The method may include identifying tissue for analysis, generating an aerosol comprising particles of the identified tissue using a rapid evaporative ionization mass spectrometry device or probe, and analyzing the particles. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The method may include identifying a plurality of tissue samples for analysis, generating an aerosol comprising particles of each identified tissue sample using a rapid evaporative ionization mass spectrometry device or probe, and analyzing and/or ion mobility analyzing the particles of each identified tissue sample. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis. These particles of each identified tissue sample may be mass analyzed separately. The method may comprise outputting one or more mass spectra and/or ion mobility data (or data derived therefrom) from each tissue sample, and optionally comparing the mass spectra and/or ion mobility data (or data derived therefrom) from each tissue sample, and optionally identifying differences between different tissue samples.

The method may comprise searching for one or more specific compounds in the tissue using a rapid evaporative ionization mass spectrometry apparatus or probe, and may comprise searching for or identifying one or more compounds in a mass spectrum produced by the tissue or tissue samples.

Each tissue sample may be taken from the same part of the body or the same organ. Alternatively, each tissue sample may be taken from a different part of the body or a different organ.

The rapid evaporative ionization mass spectrometry apparatus or probe may be optimized for surgical use. For example, the rapid evaporative ionization mass spectrometry apparatus or probe or one or more electrodes thereof may be miniaturized and/or one or more of the maximum size, maximum length, maximum width and maximum depth of the rapid evaporative ionization mass spectrometry apparatus or probe may be less than 5cm, 2cm, 1cm or 5 mm. One or more of the electrodes may have a surface area, for example less than 200mm²、100mm²、50mm²、40mm²、30mm²、 20mm²Or 10mm²、2mm²、1mm²、0.5mm²、0.4mm²、0.3mm²、0.2mm²Or 0.1mm²Exposed surface area of (a).

The rapid evaporative ionization mass spectrometry apparatus or probe may be shaped such that it can be surgically inserted into the human or animal body. For example, the rapid evaporative ionization mass spectrometry device or probe may be elongate, or form part of an elongate tube or conduit, and/or form part of a surgical instrument such as an endoscope or laparoscope.

Figure 14A illustrates one embodiment of a probe 1400 that may be optimized for surgical use. The probe may be a rapid evaporative ionization mass spectrometry device or probe, and/or a surgical instrument operatively connected to those surgical instruments described above. Probe 1400 is similar (or identical) to the bipolar forceps described above with respect to fig. 1, and may include a small tip 1402 to assist in the surgical procedure.

The illustrated probe includes a bipolar arrangement and may include two electrodes 1404 located at a tip 1402. Tip 1402 may include two arms or forceps 1410, which may be flexible and/or articulated such that electrodes 1404 at tip 1402 may be brought closer to (or in contact with) each other.

One or more apertures 1406 may be located at tip 1402 (e.g., on one of the electrodes 1404) to convey aerosol particles generated by the probe to an ion analyzer or mass spectrometer 8 (see also fig. 1) via internal passage 1408 and conduit 6. Alternatively or additionally, one or more apertures 1406 may be located anywhere on the probe and may be arranged and adapted to deliver aerosol particles as described above. For example, one or more apertures 1406 may be provided along arm 1410 and/or outside of tip 1402.

The electrodes 1404 located at the tip portion 1402 may be sharpened and may have a diameter of less than 2mm²、1mm²、0.5 mm²、0.4mm²、0.3mm²、0.2mm²Or 0.1mm²A contact area (e.g., surface area). The contact area may be defined as the area of the distal portion 1402, such as the exterior or exposed surface area of the distal portions of the electrodes 1404.

Alternatively (or additionally), the contact area of tip 1402 may be defined as the area of the tip within a distance d from an end of the tip, where d may be 10mm, 5mm, 4mm, 3mm, 2mm, 1mm, 0.8mm, 0.6mm, 0.5mm, 0.4mm, 0.3mm, 0.2mm, or 0.1 mm.

Since the electrical contact area is minimized, a smaller contact area (or increased sharpness) may facilitate minimally invasive or non-invasive surgical procedures. In addition to (or alternatively to) providing a relatively small contact area, a lower voltage may also be used.

The surgical instrument may comprise a voltage source arranged and adapted to apply a voltage to the electrodes 1404 located at the end portion 1402. The applied voltage may be less than 3kV, 2.5kV, 2kV, 1.5kV, 1kV, 500V, 400V, 350V, 300V, 250V, 200V, 150V, 100V, 50V, 20V, or 10V. One or more wires 9 may be provided to apply a voltage, and these wires may be connected to the probe 1400 at the connection portion thereof. One or more internal leads 1412 or other mechanisms may be provided for applying voltages to the electrodes 1404.

This may be distinguished from invasive surgery using electrosurgical tools, which may typically involve an applied voltage of 1kV and greater than 10mm²The contact area of (a). Thus, the probe 1400 described with respect to fig. 14 may be considered optimized for minimally invasive or non-invasive surgical procedures. For example, when the probe 1400 is operated, the probe may not have a high enough voltage or surface area to cut or score tissue.

A voltage or current limiter may be provided in, for example, the surgical instrument, voltage source, or probe 1400, which may be arranged and adapted to limit the current passing through or the voltage applied to the electrodes 1404. The voltage or current limiter can be arranged and adapted to limit the voltage applied to the electrodes 1404 to a peak or RMS of 3kV, 2.5kV, 2 kV, 1.5kV, 1kV, 500V, 400V, 350V, 300V, 250V, 200V, 150V, 100V, 50V, 20V, or 10V. The voltage or current limiter is arranged and adapted to limit the current supplied to the electrodes 1404 to a peak or RMS of 0.02mA, 0.04mA, 0.06mA, 0.08mA, 0.1mA, 0.2mA, 0.3mA, 0.4 mA, 0.5mA, 0.6mA, 0.7mA, 0.8mA, 0.9mA, or 1 mA.

Alternatively or additionally, the voltage or current limiter may be arranged and adapted to limit the power supplied to the electrodes 1404. The voltage or current limiter may be arranged and adapted to limit the power supplied to the electrodes 1404 to a peak value or RMS of 1W, 5W, 10W, 20W, 30W, 40W, 50W, 60W, 70W, 80W, 90W, 100W, 120W, 140W, 160W, 180W or 200W.

The probe 1400 may be operably connected to an ion analyzer or mass spectrometer, such as the ion analyzer or mass spectrometer forming a portion of the analysis stack 1330 described above with respect to fig. 13A. The probe 1400 may be connected to the ion analyzer or mass spectrometer via a tissue sampling device or conduit (e.g., tissue sampling device 1336 as described above with respect to fig. 13A or conduit 6 shown in fig. 1).

The tissue sampling device or tubing or other connection mechanism connecting the probe 1400 to the ion analyzer or mass spectrometer (e.g., the first vacuum stage thereof) can have a maximum diameter of less than 1mm, 0.9mm, 0.8mm, 0.7mm, 0.6mm, 0.5mm, 0.4mm, 0.3mm, 250 μm, 200 μm, 150 μm, 100 μm, 50 μm, 40 μm, 30 μm, 20 μm, or 10 μm. The small diameter tube can help to quickly transport the aerosol generated by the probe 1400 to an ion analyzer or mass spectrometer. A tissue sampling device or conduit may connect the probe 1400 to an ion inlet device or first vacuum stage of an ion analyzer or mass spectrometer.

An alternative to the probe shown in fig. 14A is shown in fig. 14B. The probe 1450 of fig. 14B has the same features as the probe of fig. 14A, but instead of two arms 1410, a single arm 1460 is equipped with a single electrode 1454 at a tip 1452. In such "monopolar" embodiments, instead of creating a potential difference between the electrodes of the probe (and the tissue located therebetween), a potential difference may be created between the contact point of the electrodes and a counter electrode placed in contact with the sample being analyzed.

The features and its various features and arrangements described above with respect to the probe 1400 of FIG. 14A are equally applicable to the probe 1450 shown in FIG. 14B. Similar features have been provided with reference numerals increased by "50", for example the tip of the probe in figure 14B is denoted by reference numeral 1452, and these features may be interchanged with those described above with reference to figure 14A.

As“Point type probe”Fast evaporation ionization mass spectrum device and beam diagnosis

According to one aspect, there is provided an apparatus comprising a surgical instrument comprising an electrosurgical tool, such as a rapid evaporative ionisation mass spectrometry device or probe, an ion analyser or mass spectrometer, and a control system. The surgical instrument may form part of an analysis stack 1301 and/or apparatus 1300 as described above with respect to fig. 13A, for example, including a camera monitor 1303 and/or an analysis monitor 1333 (which may also be the same component). The rapid evaporative ionization mass spectrometry apparatus or probe may form part of an endoscope or laparoscope as described herein.

The electrosurgical tool or the rapid evaporative ionisation mass spectrometry probe may be a rapid evaporative ionisation mass spectrometry probe as described herein with reference to figures 14A to 14B or a bipolar forceps probe as described herein with reference to figure 1.

The electrosurgical tool or the rapid evaporative ionisation mass spectrometry probe may comprise one or more electrodes configured to vaporise or vaporise biological tissue to form an aerosol comprising particles of the biological tissue, and the ion analyser or mass spectrometer may be arranged and adapted to mass analyse or ion mobility analyse the particles, and the data may comprise a mass spectrum resulting from the mass analysis.

The control system may be arranged and adapted to process data from the ion analyser or mass spectrometer and output analyte information for use in surgery. The analyte information may include mass spectral data or chemical data associated with a particular portion of the biological tissue or other sample being analyzed.

The control system may be arranged and adapted to display the analyte information on a monitor, e.g. a camera monitor 1303 or an analysis monitor 1333 or a mobile device, e.g. a mobile tablet device. Analyte information may be displayed or recorded according to another variable, such as location (e.g., distance, or coordinates, for example, in a three-dimensional environment), time, etc. In this way, analyte information (e.g., mass spectral data and/or ion mobility data, or data derived from mass spectral and/or ion mobility data, or chemical data) may be displayed or recorded with another variable, and this may improve the surgical procedure.

For example, during a surgical procedure, a surgeon may use information provided by the control system and/or displayed on a monitor to help guide the surgical procedure. If cancerous tissue is found using the probe, the voltage may be increased to remove or vaporize the cancerous tissue. After vaporization of the cancerous tissue, the control system may make the surgeon aware that the tissue is not cancerous and may lower the voltage.

It is contemplated that such functions may be performed automatically. For example, the control system may be arranged and adapted to monitor information output from the ion analyser or mass spectrometer and to alter, adjust or alter operating parameters in response.

For example, the control system may be arranged and adapted to alter, adjust or alter the voltage applied to the electrosurgical tool in response to information output from the ion analyser or mass spectrometer (e.g. by a voltage source). If cancerous tissue is found using the probe, the voltage applied to the electrosurgical tool may be automatically increased to remove or vaporize this cancerous tissue. After vaporization of the cancerous tissue, the control system may automatically reduce the voltage applied to the electrosurgical tool.

Such a surgical procedure may be referred to as a chemically guided surgery procedure, in which the surgeon may be provided (e.g., via a monitor as described above) with real-time information about the tissue in contact with the probe.

According to one embodiment, a method, such as a method of chemically guided surgery, is provided that includes analyzing a sample (e.g., a biological tissue, a biological substance, a bacterial colony, or a fungal colony) using a rapid evaporative ionization mass spectrometry probe and providing real-time analysis (e.g., mass spectrometry or ion mobility analysis) of the sample using an ion analyzer or mass spectrometer.

The rapid evaporative ionisation mass spectrometry probe may be a rapid evaporative ionisation mass spectrometry probe as described herein with reference to figures 14A to 14B, or a bipolar clamp probe as described herein with reference to figure 1.

The method may comprise guiding or scanning the rapid evaporative ionization mass spectrometry probe over the sample (e.g. using a robot, such as a surgical robot as described below), and optionally using real-time analysis to assist or provide guidance of the rapid evaporative ionization mass spectrometry probe.

The method may comprise using a rapid evaporative ionization mass spectrometry probe to search for, identify or scan one or more specific compounds. The method can include changing the orientation of the fast evaporative ionization mass spectrometry probe based on the real-time analysis.

If one or more compounds are identified, the method may include continuing to guide or scan the fast evaporative ionization mass spectrometry probe in the same direction. If one or more compounds are not identified, the method can include changing the orientation of the rapid evaporation ionization mass spectrometry probe. The method may include performing different types of guidance or scanning patterns if one or more specific compounds are identified.

For example, once one or more particular compounds are identified, the method may include switching from a first scan pattern to a second, different scan pattern. The first scanning pattern may be linear, for example scanning is performed over a plurality of points of a line, wherein the points are separated by a distance. The second scan pattern may comprise a spiral scan pattern. In this manner, if one or more compounds of interest are identified at a linear scan point, the method may include switching to a helical scan pattern centered at the scan point of interest.

The above method may be performed by a control system, for example, a rapid evaporative ionisation mass spectrometry probe may form part of a robotic instrument (e.g. a surgical robotic instrument or apparatus for performing a surgical procedure including a hand-held manipulator as described below). The rapid evaporative ionization mass spectrometry probe, or the control system or processing unit thereof, can be programmed to perform these guidance or scanning procedures described above. Alternatively or additionally, the rapid evaporation ionization mass spectrometry probe may be controlled or controllable using a user interface.

Teleoperated instrument for surgical use

In accordance with various embodiments, robotic surgical methods are disclosed in which a control device (e.g., a hand-held manipulator) may be used to remotely control a surgical robot. Fig. 15A and 15B illustrate an apparatus and includes a hand-held manipulator 1500 (fig. 15A) and a surgical robot or robotic probe 1550 (fig. 15B).

Robotic surgical techniques have been developed in which hand-held manipulator 1500 may be used to remotely control surgical robot 1550. Generally, in such procedures, the surgeon's hand movements may be computer-translated into smaller and more precise movements of the robotic instrument within the patient, as described in more detail below.

Other procedures outside of the hospital environment are contemplated. For example, on a battlefield, it is sometimes difficult or impossible to cure an injured soldier. It is envisaged that the surgical robot may form part of a battlefield medical unit (e.g. part of a larger robot that may be moved across battlefield terrain) and be arranged and adapted to perform a surgical procedure (e.g. amputation) on the battlefield.

Surgical robot 1550 may include one or more arms, such as right arm 1570 and left arm 1560 as shown in fig. 15B. Each arm may include one or more joints or sub-sections to allow movement of the arm in various directions.

In the illustrated example, the right arm 1560 includes a first rotational member 1561 that can be arranged and adapted to rotate about a first rotational axis 1591. First rotational member 1561 may be connected to first arm 1562, which may be in the form of an elongated member.

At the distal end of the first arm 1562 may be a rotating cup 1564 that is operatively connected to the first arm 1562. The rotating cup 1564 may be arranged and adapted to rotate independently of the first arm 1562 in the direction indicated by arrow 1592. The rotating cup 1564 may be connected to the second arm 1566, and the second arm 1566 may be arranged and adapted to rotate with the rotating cup 1564 in the direction shown by arrow 1592.

At the distal end of the second arm 1566 may be a hand unit 1568. The hand unit may be operably connected to one or more actuators or instruments 1569 and may be arranged and adapted to control movement of one or more instruments 1555 and/or surgical device 1580.

It should be noted that the left arm 1570 includes the same components as the right arm. These components are indicated in fig. 15B with reference numerals increased by "10", for example the rotating cup of the left arm is indicated by reference numeral 1574.

Fig. 15B schematically illustrates these instruments in the form of fingers or

forceps

1569 and 1579, for example. These simple instruments are given for example purposes only, and these instruments may (alternatively or additionally) contain fingers, forceps, graspers, knives, scalpels, drills, or any other tools that may be useful during a surgical procedure.

One or more of

instruments

1569 and 1579 may be moved in any direction using suitable bearings and motors. One or

more instruments

1569 and 1579 may rotate about any axis of rotation and may translate toward and away from their respective hand unit 1568. These

instruments

1569 and 1579 may themselves include additional instruments at their distal ends. For example, the forceps 1569 itself may include a drill at its distal end, meaning that the instrument may additionally be used to drill into a specimen held between the forceps.

The size of the one or

more instruments

1569 and 1579 may vary and be adapted for any particular surgical procedure. For example, the instruments may have a maximum dimension of less than or greater than 10cm, 5cm, 4cm, 3cm, 2cm, 10mm, 5mm, 4mm, 3mm, 2mm, 1mm, 0.8mm, 0.6mm, 0.5mm, 0.4mm, 0.3mm, 0.2mm, or 0.1 mm. The maximum dimension may be defined as the maximum linear distance between any two points located on the instrument. For example, in the case of a simple elongated rod, the maximum distance would be equal to the length of the rod.

It should be understood that more or fewer arms may be provided on the surgical robot, and the arms themselves may include more or fewer components as needed for a particular surgical procedure. More complex processes typically require multiple arms, each arm being arranged and adapted to perform a particular process or being provided for a particular purpose. Alternatively, the surgical robot may be used to perform a relatively simple procedure (e.g., amputation), in which case a single arm may be provided.

The

hand units

1568 and 1578 may include one or more cameras 1582 (only one shown in the illustrated embodiment, but more may be provided as desired). The cameras 1582 can be arranged and adapted to capture multiple images or image data of a specimen manipulated by the surgical robot 1550.

One or more electrosurgical devices 1580 (e.g., rapid evaporative ionization mass spectrometry devices or probes) may be located on one or both of the

hand units

1568 and 1578. One or more electrosurgical devices 1508 may be arranged and adapted to apply a voltage (e.g., via one or more electrodes located at a distal end thereof) to a sample held or manipulated by surgical robot 1550.

One or more electrosurgical devices 1580 may be arranged and adapted to generate an aerosol, for example, electrodes may be arranged and adapted to generate an analyte, smoke, liquid, gas, surgical smoke, aerosol, or vapor when the probe contacts a sample being manipulated by surgical robot 1550.

The one or more electrosurgical devices 1580 may be or include a rapid evaporative ionization mass spectrometry probe as described herein with reference to fig. 14A-14B, or a bipolar forceps probe as described herein with reference to fig. 1.

The apparatus may comprise a hand-held manipulator 1500 as shown in fig. 15A.

The hand-held manipulator 1500 may be operably connected to the surgical robot via an interface (or communication mechanism). The interface may include a serial interface, such as an RJ45 connector, an Ethernet (Ethernet) connector, an RS232 connector, a USB connector, or the like. The interface may also or instead be provided by a wireless interface such as a Wi-Fi connection, a bluetooth connection, a ZigBee connection, etc. The interface may be via satellite or other long-range wireless connection.

Hand-held manipulator 1500 may be arranged and adapted to control movement of various portions of a surgical robot. The control system may be provided within the surgical robot and may be arranged and adapted to relay a plurality of commands sent by the hand-held manipulator into movement of various parts of the surgical robot.

The hand-held manipulator may comprise a monitor 1502, which may be in the form of a mobile device, such as a mobile tablet device, and which is arranged and adapted to display information related to the surgical procedure and/or other information. One or more control devices, such as joysticks 1504, may be provided, and the hand-held manipulator may be configured such that movement of these control devices 1504 in particular directions (or other types of activation of the control devices) causes corresponding movement of the surgical robot 1550 or particular components thereof in the respective directions.

In the illustrated example, the type of movement caused by the joysticks 1504 may be changed or altered. For example, one or more buttons 1506 may be located on each joystick 1504, and activation or depression of these buttons 1506 may change the direction of movement of the controlled component or the controlled component.

The control device 1504 may be arranged and adapted to operate one or more electrosurgical devices 1580. For example, the control devices 1504 may be arranged and adapted to send signals to a voltage source such that the voltage source applies voltages to the electrodes to generate an aerosol.

These actuators or

instruments

1569 and 1579 may be configured to move in accordance with commands from a hand-held manipulator user (e.g., a surgeon). Similarly, as described above, the electrodes may be controlled by a hand-held manipulator such that the generation of the analyte, smoke, liquid, gas, surgical smoke, aerosol or vapour may be controlled by the user.

Embodiments may provide a rapid evaporative ionization mass spectrometry probe as part of a robotic control device. Movement and/or actuation of the device may be caused by movement of a hand-held manipulator.

The surgical robot may take other forms than that shown in fig. 15B. For example, the surgical robot may include an endoscopic or laparoscopic device, wherein an endoscope or laparoscope is provided in place of the arms. One or more actuators or instruments may be located at the distal end of the laparoscope or endoscope, which may be controlled by movement of the hand-held manipulator.

The endoscopic or laparoscopic device may include a camera, such as a charge coupled device ("CCD"), at the distal end of the endoscope. The camera may be configured to transmit the plurality of images or image data to a video monitor or a mobile device, such as a mobile tablet device (e.g., monitor 1502 shown in fig. 15A), via a transmission cable and/or wireless transmission.

The endoscopic device may include one or more instrument channels at least partially along the endoscope. One or more electrosurgical devices (e.g., rapid evaporative ionization mass spectrometry devices or probes) may be located at the distal end of the endoscope or laparoscope.

The probe and/or endoscopic or laparoscopic device may be part of a robotically controlled laparoscopic device. An endoscopic or laparoscopic device may include one or more arms that are movable in response to movement of a hand-held manipulator.

The probe or endoscopic or laparoscopic device may include a rapid evaporative ionization mass spectrometry ("REIMS") electrosurgical tool including one or more electrodes. The apparatus may comprise a device arranged and adapted to aspirate an analyte, smoke, fumes, liquid, gas, surgical smoke, aerosol or vapour.

The apparatus may include a mass spectrometer comprising: (i) a substantially cylindrical crash assembly having a first longitudinal axis; (ii) a heater for heating the impingement assembly; (iii) a first device arranged and adapted to direct an analyte, smoke, fume, liquid, gas, surgical smoke, aerosol or vapour onto the heated collision assembly along a second axis substantially orthogonal to the first axis to form analyte ions; and (iv) a mass analyser and/or an ion mobility analyser for analysing and/or ion mobility analysing the analyte ions. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

According to various embodiments, the control device (for remotely controlling the surgical robot described above) may not be in the form of a hand-held manipulator. Certain surgical techniques may be loaded into memory on the surgical robot in the form of a set of movement instructions. This may be applicable to simple medical procedures such as amputation, and may be referred to as an automated method.

Whether these surgical procedures are performed automatically using a set of instructions loaded onto the surgical robot, or using a hand-held manipulator as described above, a rapid evaporative ionization mass spectrometry apparatus or probe that can be incorporated into the surgical robot can be used to guide the surgical procedure.

For example, a rapid evaporative ionization mass spectrometry apparatus or probe may be used to locate a particular tissue, such as bone or muscle tissue. Further steps in the surgical procedure may be to provide for rapid evaporative ionization mass spectrometry apparatus or probes to locate specific tissue in this manner.

This can be used in particular in the case of automated methods. Information from the rapid evaporative ionization mass spectrometry apparatus or probe can be used to decide where to perform a particular process that has been loaded into the memory of the surgical robot. The set of movement instructions that may be loaded onto the surgical robot memory may be a set of conditional instructions, where the conditions may relate to data or information generated using a rapid evaporative ionization mass spectrometry apparatus or probe.

Alternatively or additionally, an alarm system may be incorporated into the surgical robot and/or hand-held manipulator, wherein the alarm system is arranged or adapted to output an alarm based on data or information generated using the rapid evaporative ionization mass spectrometry apparatus or probe. For example, if a certain compound is found in an aerosol analyzed by a rapid evaporative ionization mass spectrometry device or a probe device, an alarm may be issued on a surgical robot, or an alarm message may be popped up on a monitor.

Miniature fast evaporation ionization mass spectrum device

According to one aspect of the present disclosure, there is provided an apparatus comprising a rapid evaporative ionization mass spectrometry device or probe, wherein the apparatus is miniaturized. For example, the apparatus (containing the rapid evaporative ionization mass spectrometry device or probe) is sized such that it cannot be controlled or manipulated by a human.

The apparatus may comprise a robot arranged and adapted to control a miniature rapid evaporative ionisation mass spectrometry apparatus or probe. The maximum dimension of the apparatus (rapid evaporative ionisation mass spectrometry apparatus or probe or electrode or electrodes thereof) may be less than 5 cm, 2cm, 1cm, 5mm, 2mm, 1mm, 0.5mm or 0.1 mm.

The mass spectrometry apparatus or probe may be substantially the same as the probe shown in any of figures 14A, 14B, 16 or 17, but with corresponding size reductions. The microprobe may be incorporated into a laparoscope or endoscope as described herein, for example, with reference to figures 13A and 13B.

The microprobe may form part of a surgical robot as described herein, for example a surgical robot or other device as described with reference to fig. 15A and 15B. For example, the hand-held manipulator may be operatively coupled to the microprobe via one or more actuators.

The surgical robot may be arranged and adapted to perform small scale surgery, such as brain surgery. Small scale surgery may be defined as surgery involving manipulation or tissue destruction on a scale of less than 10mm, 5mm, 4mm, 3mm, 2mm, 1mm, 0.5mm, 0.4mm, 0.3mm, 0.2mm or 0.1 mm.

The surgical robot may be arranged and adapted to move the probe in a stepwise manner, wherein each step corresponds to a movement (e.g. in three-dimensional space) of less than 10mm, 5mm, 4mm, 3mm, 2mm, 1mm, 0.5mm, 0.4mm, 0.3mm, 0.2mm or 0.1 mm.

Alternatively, the surgical robot may be arranged and adapted to move the probe in a continuous manner. The surgical robot may be arranged and adapted to move the probe (e.g. in three-dimensional space and/or in one direction in three-dimensional space) in a single movement less than 10mm, 5mm, 4mm, 3mm, 2mm, 1mm, 0.5mm, 0.4mm, 0.3mm, 0.2mm or 0.1mm in length.

The use of such micro-devices may be useful in surgical situations that require moving tools over very small distances (e.g., rapid evaporative ionization mass spectrometry devices or probes), such as during brain surgery.

Ion optical component

According to one embodiment, a method is provided that includes analyzing a sample using a rapid evaporative ionization mass spectrometry probe, analyzing the sample, and adjusting ion optics based on the mass analysis. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis. The analysis may be performed using any of the apparatus disclosed herein, including an ion analyzer or a mass spectrometer, which may include ion optics as discussed with respect to the embodiments. For example, the analysis can be performed using the mass spectrometers disclosed with respect to fig. 1, 2A-2C, 3, 4, 5A-5B, 11, or 13A-13B.

The method may include adjusting the electrostatic lens in response to the analysis (e.g., if one or more particular compounds exceed or fall below a defined intensity limit, or if the total intensity exceeds or falls below a specified intensity limit). The method may be performed in real time, for example during intra-operative diagnosis. The method may include adjusting an ion optical component (e.g., an electrostatic lens) based on one or more specific compounds located in the tissue sample being analyzed. The tuning of the ion optics (e.g., electrostatic lens) may include tuning the transmission of ions through the ion optics.

Alternative energy source-ultrasonic probe

Embodiments are contemplated in which the various electrosurgical tools disclosed herein (e.g., rapid evaporative ionization mass spectrometry devices or probes) may be replaced or combined with other forms of energy generation. One example of this is ultrasound, which, as described below, can be used in a variety of surgical procedures in addition to or as an alternative to electrosurgery or rapid evaporative ionization mass spectrometry techniques.

According to one embodiment, a surgical instrument is provided that includes an ultrasound device, a probe, an aspirator, a vaporizer, or a dissector. The ultrasonic device may be referred to as an ultrasonic ablation instrument or an ion source, and may correspond to the ultrasonic ablation ion source described above. The surgical instrument may form part of a surgical stack 1301 as described above with respect to fig. 13A. The surgical instrument may comprise an endoscope or a laparoscope. The ultrasound device may be configured to aspirate or break up biological tissue and form a sample fluid comprising particles of the biological tissue. The rapid evaporation ionization mass spectrometry probe can further include a tube or other mechanism for transporting the particles to a mass analyzer and/or an ion mobility analyzer and/or a mass spectrometer.

According to one embodiment, a surgical method is provided that includes intraoperative diagnostic use of an ultrasound device, probe, aspirator, or dissector. The method may include identifying tissue for analysis, generating a sampled fluid including identified tissue particles using an ultrasound device, probe, aspirator, or dissector, and analyzing the particles. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The method may include identifying a plurality of tissue samples for analysis, generating a sampling fluid including each identified tissue sample particle using an ultrasound device, probe, aspirator, or dissector, and analyzing each identified tissue sample particle. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis. The identified particles of each tissue sample may be mass analyzed or ion mobility analyzed, respectively. The method may comprise outputting one or more mass spectra from each tissue sample, and optionally comparing the mass spectra from each tissue sample and optionally identifying differences between different tissue samples.

The method may include searching for one or more specific compounds in the tissue using an ultrasound device, probe, aspirator or dissector, and may include searching for or identifying one or more compounds in a mass spectrum generated by the tissue or tissue samples.

The ultrasound device, probe, aspirator or dissector may be optimized for surgical use. For example, the ultrasound device, probe, aspirator, or dissector may be miniaturized and/or one or more of the maximum size, length, width, and depth of the ultrasound device, probe, aspirator, or dissector may be less than 5cm, 2cm, 1cm, or 5 mm. The ultrasound device, probe, aspirator or dissector may be shaped so as to be surgically insertable into the human or animal body. For example, the ultrasound device, probe, aspirator or dissector may be elongated or form part of an elongated tube or conduit, and/or form part of a surgical instrument such as an endoscope or laparoscope. For example, an ultrasound device, probe, aspirator, or dissector may be passed through a port or instrument channel of an endoscope or laparoscope.

According to one aspect of the present disclosure, an apparatus is provided that includes a rapid evaporative ionization mass spectrometry probe and a scalpel, wherein movement of the scalpel is assisted or caused by ultrasound. The apparatus may include an endoscope including the rapid evaporative ionization mass spectrometry probe and a scalpel at a distal end thereof.

Fig. 16 shows one embodiment of a probe 1600 that may be optimized for surgical use. The probe may be an ultrasound device, a probe, an aspirator or dissector, and/or a surgical instrument that may be operably connected to those surgical instruments as described above. Probe 1600 can include tip 1602 to assist in a surgical procedure.

Located at a distal end 1602 of the probe 1600 is an ultrasonic device 1604 that may be arranged and adapted to move and generate ultrasonic pulses. The ultrasonic device 1604 may be located at the distal end of an arm 1610, which arm 1610 may be elongated for ease of use.

The movement may be toward and away from the probe, as indicated by arrow 1620. This can control the ultrasound pulses at the tissue proximate to the probe 1600, which in turn can aspirate, dissect, or break up the tissue by the probe 1600.

The frequency and/or amplitude of the ultrasound waves can be altered to accommodate different tissues and/or surgical techniques. For example, relatively low amplitude and/or frequency pulses may be applied to dissect or break up tissue with low intracellular associations (e.g., fat), and high amplitude pulses may be used to dissect or break up tissue with high intracellular associations, such as tendons.

One or more holes 1606 may be located on tip 1602 (e.g., within ultrasonic device 1604) to convey tissue particles aspirated by the probe to an ion analyzer or mass spectrometer 8 (see also fig. 1) via internal passageway 1608 and conduit 6. Alternatively or additionally, one or more of the holes 1606 may be located anywhere on the probe and may be arranged and adapted to deliver particles as described above. For example, one or more apertures 1606 may be provided along arm 1610 and/or outside of tip portion 1602.

The end face 1605 of the ultrasonic device 1604 (facing away from the probe 1600 and toward the sample) may have a width of less than 2mm²、1 mm²、0.5mm²、0.4mm²、0.3mm²、0.2mm²Or 0.1mm²Surface area of (a). The end surface may be concave (or convex).

The length that ultrasonic device 1604 extends from arm 1610 varies as ultrasonic device 1604 moves into and out of arm 1610. However, the length of the extension of the ultrasonic device 1604 from the arm 1610 may not exceed 1mm, 800 μm, 600 μm, 500 μm, 400 μm, 300 μm, 200 μm, 100 μm, or 50 μm.

Because the pulse energy is minimized, the smaller surface area 1605 (or pulses of lower amplitude and/or frequency) of the ultrasonic device 1604 may facilitate performing minimally or non-invasive procedures.

The surgical instrument can include a voltage source arranged and adapted to drive movement of the ultrasonic device 1604. The applied voltage may be less than 3kV, 2.5kV, 2kV, 1.5kV, 1kV, 500V, 400V, 350V, 300V, 250V, 200V, 150V, 100V, 50V, 20V, 10V, 5V, or 2V. One or more wires 9 may be provided to apply a voltage, and these wires may be connected to the probe 1600 at a connection thereto. One or more internal wires or other mechanisms may be provided for applying a voltage to a transducer located within the probe 1600. The transducer may be arranged and adapted to convert a voltage into a movement of the ultrasonic device 1604.

The power supply may be arranged and adapted to apply variable voltages to the probe 1600, and these variable voltages may be used to vary the amplitude and/or frequency of the ultrasonic waves generated by the ultrasonic tip end 1604.

The probe 1600 may be operably connected to an ion analyzer or mass spectrometer, such as the ion analyzer or mass spectrometer forming a portion of analysis stack 1330 described above with respect to fig. 13A. The probe 1600 may be connected to the ion analyzer or mass spectrometer via a tissue sampling device or conduit (e.g., tissue sampling device 1336 as described above with respect to fig. 13A or conduit 6 shown in fig. 1).

The tissue sampling device or tubing or other connection mechanism connecting the probe 1600 to the ion analyzer or mass spectrometer (e.g., the first vacuum stage thereof) can have a maximum diameter of less than 1mm, 0.9mm, 0.8mm, 0.7mm, 0.6mm, 0.5mm, 0.4mm, 0.3mm, 250 μm, 200 μm, 150 μm, 100 μm, 50 μm, 40 μm, 30 μm, 20 μm, or 10 μm. The small diameter tubing can facilitate rapid transfer of the sample fluid generated by the probe 1600 to an ion analyzer or mass spectrometer. A tissue sampling device or conduit may connect the probe 1600 to an ion inlet device or first vacuum stage of an ion analyzer or mass spectrometer.

The ultrasonic probe 1600 can be used to liquefy or otherwise disrupt tissue in contact with the ultrasonic device 1604. This produces a liquid that can be delivered to the mass spectrometer.

Embodiments are contemplated in which the ultrasound probe 1600 forms part of a laparoscope or endoscope. In this case, the arm 1610 of the probe may be positioned laparoscopically or endoscopically and may be longer than the arm schematically depicted in FIG. 16. The ultrasonic device 1604 may be located at the distal end of a laparoscope or endoscope and may be arranged and adapted to aspirate or dissect tissue in contact with the distal end of the laparoscope or endoscope.

In various embodiments, a rapid evaporative ionization mass spectrometry apparatus or probe can be used in conjunction with the ultrasonic probe 1600. For example, probe 1600 may include an electrode, or ultrasonic device 1604 may also be an electrode, such that electrosurgical techniques may be combined with ultrasonic electrosurgical techniques.

In such embodiments, the ultrasound probe 1600 can be arranged and adapted to vaporize a sample fluid produced by contact of the ultrasound device 1604 with tissue. The ultrasonic device 1604 may be arranged and adapted to break up and/or liquefy tissue to produce a sample fluid in liquid form as described above.

A rapid evaporative ionisation mass spectrometry apparatus or probe may be arranged and adapted to vaporise these sample fluids to produce an aerosol which may then be passed to an ion analyser or mass spectrometer for analysis as described herein. Various methods may involve providing a surgical instrument that includes an ultrasonic probe 1600 as described above and a rapid evaporative ionization mass spectrometry device or probe (e.g., as described with respect to fig. 14A and 14B).

The method may include identifying a tissue sample for analysis, generating a sample fluid including particles of such tissue sample (of a portion of the tissue sample) using an ultrasound device, probe, aspirator, or dissector, and analyzing the tissue sample particles included in the sample fluid. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The method may further comprise using a rapid evaporative ionization mass spectrometry device or probe to generate an aerosol comprising particles of the same tissue sample (or portion of a tissue sample); and analyzing these particles included in the aerosol. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The method may comprise outputting one or more mass spectra from each tissue sample, and optionally comparing or combining the mass spectra generated using the rapid evaporative ionization mass spectrometry device or probe with the mass spectra generated using the ultrasound device, probe, aspirator or dissector.

Alternative energy source-laser probe

Further embodiments are contemplated wherein the electrosurgical tools disclosed herein (e.g., rapid evaporative ionization mass spectrometry devices or probes) may be replaced by or combined with laser technology.

According to one embodiment, a surgical instrument is provided that includes a laser device, a probe, a suction device, or a dissection device. The laser device may be or include a laser ablation ion source as described above. The surgical instrument may form part of a surgical stack 1301 as described above with respect to fig. 13A. The surgical instrument may comprise an endoscope or a laparoscope. The laser device may be configured to attract or break up biological tissue and form an aerosol comprising particles of the biological tissue. The laser probe may further comprise a tube or other mechanism for transporting particles to a mass analyser and/or ion mobility analyser and/or mass spectrometer.

According to one embodiment, a surgical method is provided that includes using a laser device, a probe, a suction device, or an dissecting device in an intra-operative diagnosis. The method may include identifying tissue for analysis; using the laser device, probe, suction device or dissecting device to generate an aerosol comprising particles of the identified tissue; and these particles were analyzed. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The method may include identifying a plurality of tissue samples for analysis; using the laser device, probe, suction device, or dissection device to generate a sample fluid comprising the identified particles of each tissue sample; and analyzing the identified particles of each tissue sample. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis. The identified particles of each tissue sample may be mass analyzed or ion mobility analyzed, respectively. The method may comprise outputting one or more mass spectra from each tissue sample, and optionally comparing the mass spectra from each tissue sample and optionally identifying differences between different tissue samples.

The method may include using a laser device, probe, suction device or dissection device to look for one or more specific compounds in the tissue, and may include looking for or identifying the compound or compounds in a mass spectrum generated from the tissue or tissue sample.

Each tissue sample may be taken from the same tissue or the same part of the body. Alternatively, each tissue sample may be taken from a different tissue or a different part of the body.

The laser device, probe, suction device or dissecting device may be optimized for surgical use. For example, the laser device, probe, suction device, or dissection device may be miniaturized, and/or one or more of the largest dimension, length, width, and depth of the laser device, probe, suction device, or dissection device may be less than 5cm, 2cm, 1cm, or 5 mm. The laser device, probe, suction device or dissection device may be shaped such that it can be inserted into a human or animal body during surgery. For example, the laser device, probe, suction device, or dissector device may be elongated or form part of an elongated tube or conduit, and/or form part of a surgical instrument (e.g., an endoscope or laparoscope). The laser device, probe, suction device or dissecting device may be passed through, for example, a port or instrument channel of an endoscope or laparoscope.

Fig. 17 illustrates one embodiment of a probe 1700 that may be optimized for surgical use. The probe may be a laser device, a probe, a suction device, or a dissection device, and/or may be operably connected to a surgical instrument, such as those surgical instruments described above. The probe 1700 may include a tip 1702 that aids in the surgical procedure.

Located at the end 1702 of the probe 1700 is an aperture 1704, which may be arranged and adapted to output a laser beam. The aperture 1704 may be located at the distal end of an arm 1710, which arm 1710 may be elongated for ease of use.

The laser beam may be directed away from the probe as indicated by arrow 1720. This can direct a laser pulse in tissue in close proximity to the probe 1700, which in turn can attract, dissect, or break up this tissue.

The frequency and/or amplitude and/or wavelength and/or pulse duration of the laser may be varied to suit different tissues and/or surgical techniques. For example, relatively low energy laser pulses may be applied to dissect or break up tissue with low intracellular associations (e.g., skin or fat), and relatively high energy pulses may be used to dissect or break up tissue with high intracellular associations (e.g., bone or tendon).

One or more apertures 1706 may be located at the end 1702 to convey tissue particles attracted by the laser to the ion analyzer and/or mass spectrometer 8 (see also fig. 1) via the internal passage 1708 and the tube 6. One or more apertures 1706 may alternatively or additionally be located anywhere on the probe and may be arranged and adapted to deliver particles as described above. For example, one or more apertures 1706 may be located on the arm 1710 and/or outside of the end 1702.

The end 1702 may have a diameter of less than 2mm²、1mm²、0.5mm²、0.4mm²、0.3mm²、0.2mm²Or 0.1mm²Surface area of (a). The end face may be concave (or convex).

A smaller energy of the laser beam (or lower amplitude and/or frequency of the pulses) may be helpful for minimally invasive surgery or non-invasive surgery.

The surgical instrument may include a voltage source arranged and adapted to power the laser source 1715. The laser source 1715 may be located within the probe 1700 or may be located external to the probe and connected to the probe via one or more optical fibers or fiber optic cables. One or more wires 9 may be provided to apply the voltage, and these wires may be connected to the probe 1700 at the connection of the probe. If the laser source is external to the probe 1700, the wire 9 would be replaced by an optical fiber.

The power supply may be arranged and adapted to apply varying amounts of voltage to the laser source 1715, and the varying voltage may be used to vary the applied energy of the laser pulse.

The probe 1700 may be operably connected to an ion analyzer or mass spectrometer, such as the ion analyzer or mass spectrometer forming a portion of the analysis stack 1330 described above with respect to fig. 13A. The probe 1700 may be connected to the ion analyzer or mass spectrometer via a tissue sampling device or conduit (e.g., a tissue sampling device 1336 as described above with respect to fig. 13A or a conduit 6 as shown in fig. 1).

The tissue sampling device or tubing or other connection mechanism connecting the probe 1700 to the ion analyzer or mass spectrometer (e.g., the first vacuum stage thereof) can have a maximum diameter of less than 1mm, 0.9mm, 0.8mm, 0.7mm, 0.6mm, 0.5mm, 0.4mm, 0.3mm, 250 μm, 200 μm, 150 μm, 100 μm, 50 μm, 40 μm, 30 μm, 20 μm, or 10 μm. The small diameter tube can help to quickly transport the sample fluid produced by the probe 1700 to the ion analyzer or mass spectrometer. A tissue sampling device or conduit may connect the probe 1700 to an ion inlet device, or a first vacuum stage of an ion analyzer or mass spectrometer.

The laser probe 1700 can be used to break up or destroy tissue in contact with the laser beam. This can produce an aerosol which can then be delivered to a mass spectrometer.

Embodiments are contemplated in which the laser probe 1700 forms part of a laparoscope or endoscope. In this case, the arm 1710 of the probe may be positioned laparoscopically or endoscopically and may be longer than the arm schematically depicted in FIG. 17. The laser aperture 1704 may be located at the distal end of the laparoscope or endoscope and may be arranged and adapted to break up or destroy tissue adjacent to the distal end of the laparoscope or endoscope.

In various embodiments, a rapid evaporative ionization mass spectrometry apparatus or probe may be used in conjunction with a laser probe. For example, probe 1700 may include electrodes so that electrosurgical techniques may be combined with the laser beam.

The rapid evaporative ionization mass spectrometry apparatus or probe may be arranged and adapted to vaporize the same portion of tissue in contact with the laser beam to produce an aerosol which may then be conveyed to an ion analyzer or mass spectrometer for analysis as described below.

The method may involve providing a surgical instrument that includes a laser probe 1700 and a rapid evaporative ionization mass spectrometry device or probe as described above (e.g., a rapid evaporative ionization mass spectrometry device or probe as described above with respect to fig. 14A and 14B).

The method may include identifying a tissue sample for analysis; using a laser device, a probe aspiration device, or a dissection device to generate an aerosol comprising particles of a tissue sample (or a portion of a tissue sample); and analyzing the particles of the tissue sample included in the sample fluid. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The method may include outputting one or more mass spectra from each tissue sample, and optionally comparing or combining the mass spectra generated using the rapid evaporative ionization mass spectrometry device or probe with the mass spectra generated using the laser device, probe attraction device, or dissection device.

The laser or laser source may be a surgical laser or surgical laser source, and/or may be arranged and adapted to disintegrate, vaporise or cut a sample, such as biological tissue. The apparatus may comprise an instrument, for example a surgical instrument comprising a laser probe. The laser source may be or include a carbon dioxide laser source, an argon laser source, a neodymium-doped yttrium aluminum garnet ("Nd: YAG") laser source, an erbium-doped yttrium aluminum garnet ("Er: YAG") laser source, or a titanyl potassium phosphate laser source.

Alternative energy-hydrotherapy operation

Further embodiments are contemplated wherein the electrosurgical tools disclosed herein, such as rapid evaporative ionization mass spectrometry devices or probes, may be replaced by or combined with hydrotherapy techniques.

According to one embodiment, a surgical instrument is provided that includes a hydrotherapy device. The hydrotherapy device may be or include a fluid source and a nozzle for directing fluid (e.g., from the fluid source) at a target (e.g., a sample of a biological sample, etc.) under high pressure (e.g., greater than 10000psi or 0.69 megapascals). The surgical instrument may form part of a surgical stack 1301 as described above with respect to fig. 13A. The surgical instrument may comprise an endoscope or a laparoscope. The hydrotherapy device can be configured to attract or break up biological tissue and form an aerosol that includes particles of the biological tissue. The rapid evaporation ionization mass spectrometry probe can further include a tube or other mechanism for transporting the particles to a mass analyzer and/or an ion mobility analyzer and/or a mass spectrometer.

According to one embodiment, a surgical method is provided that includes using an ultrasound device, probe, aspirator, or dissector, for example, in intraoperative diagnosis. The method may include identifying tissue for analysis, generating a sampled fluid including identified tissue particles using an ultrasound device, probe, aspirator, or dissector, and analyzing the particles. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The method may include identifying a plurality of tissue samples for analysis; using the hydrotherapy device, the probe, the suction device, or the dissection device to generate a sample fluid that includes the identified particles of each tissue sample; and analyzing the identified particles of each tissue sample. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The identified particles of each tissue sample may be mass analyzed or ion mobility analyzed, respectively. The method may comprise outputting one or more mass spectra from each tissue sample, and optionally comparing the mass spectra from each tissue sample and optionally identifying differences between different tissue samples.

The method may include using a hydrotherapy device, probe, suction device or dissection device to look for one or more specific compounds in the tissue, and may include looking for or identifying the compound or compounds in a mass spectrum generated from the tissue or tissue sample.

The hydrotherapy device, probe, aspirator or dissector may be optimized for surgical use. For example, the hydrotherapy device, probe, aspirator, or dissector may be miniaturized and/or one or more of the maximum size, length, width, and depth of the ultrasonic device, probe, aspirator, or dissector may be less than 5cm, 2cm, 1cm, or 5 mm. The hydrotherapy device, probe, aspirator or dissector may be shaped so as to be surgically insertable into the human or animal body. For example, the hydrotherapy device, probe, aspirator or dissector may be elongated or form part of an elongated tube or conduit, and/or form part of a surgical instrument such as an endoscope or laparoscope. The hydrotherapy device may be passed through, for example, an endoscopic or laparoscopic port or instrument channel.

In one embodiment, the probe may be optimized for surgical use. The probe may be a hydro-surgical device, a probe, an aspirator or dissector, and/or a surgical instrument that may be operably connected to those surgical instruments as described above. The probe may include a tip to assist in the surgical procedure.

Located at the end of the probe is a nozzle which may be arranged and adapted to output a fluid, such as water or a liquid like a saline solution. The nozzle may be arranged and adapted to output a small amount of fluid.

The apertures or nozzles may have an outlet end or orifice with a diameter or largest dimension in the range of about 0.05mm to about 1mm, 0.06mm to about 0.8mm, 0.07mm to about 0.7mm, about 0.08mm to about 0.6mm, about 0.09mm to about 0.5mm, about 0.1mm to about 0.4mm, about 0.1mm to about 0.3mm, about 0.1mm to about 0.2mm, about 0.1mm to about 0.15 mm.

The aperture or nozzle may have an outlet end or orifice with a cross-sectional area of about 50mm²To about 150mm²、60mm²To about 140mm²、70mm²To about 130mm²、80mm²To about 120mm²、90mm²To about 110mm²And 95mm²To about 105mm²。

The size of the output or exit orifice may affect the aggressiveness of the treatment. The larger the aperture, the less aggressive the treatment and vice versa.

The nozzle may be located at the distal end of an arm, which may be elongate for ease of use.

The fluid jet can be directed away from the probe. This can direct fluid in tissue in close proximity to the probe, which in turn can attract, dissect or break up this tissue. Embodiments are contemplated in which the fluid jet is directed through tissue, e.g., parallel to the tissue. The nozzle may be located along the arm at a distance from the tip and arranged and adapted to direct a fluid stream from an output end or outlet aperture substantially parallel to the arm. In this way, the arm can be used like a knife.

The pressure and/or flow rate and/or pulse duration of the fluid may be varied to suit different tissues and/or surgical techniques. For example, relatively low energy flow rates and/or pressures may be applied to dissect or break up tissue with low intracellular associations (e.g., skin or fat), and relatively high energy flow rates and/or pressures may be applied to dissect or break up tissue with high intracellular associations (e.g., bone or tendon).

One or more holes may be located at the distal end to convey tissue particles attracted by the laser to the ion analyzer and/or mass spectrometer 8 (see fig. 1) via the internal channels and conduits. The one or more apertures may alternatively or additionally be located anywhere on the probe and may be arranged and adapted to deliver particles as described above. For example, one or more apertures may be located on the arm and/or external to the tip.

The tip may have less than 2mm²、1mm²、0.5mm²、0.4mm²、0.3mm²、0.2mm²Or 0.1mm²Surface area of (a).

The less energy of the fluid flow (or lower pressure and/or flow rate of the fluid) may facilitate minimally invasive surgery or non-invasive surgery.

The surgical instrument may comprise a pump arranged and adapted to supply and/or pump fluid. A conduit may be provided to supply fluid to the surgical instrument. The pump may be located within the probe, or may be located external to the probe and connected to the probe via a conduit.

The pump may be arranged and adapted to apply a varying flow rate and/or pressure of the fluid to the nozzle, and the varying flow rate and/or pressure may be used to vary the applied energy of the fluid.

The pump and/or nozzle may be arranged and adapted to output fluid from the nozzle at a pressure between about 0.5MPa and about 1.5MPa, between about 0.6MPa and about 1.4MPa, between about 0.7MPa and about 1.3MPa, between about 0.8MPa and about 1.2MPa, between about 0.9MPa and about 1.1MPa, or between about 0.95MPa and about 1.05 MPa. In some applications, the pump and/or nozzle may be arranged and adapted to output fluid from the nozzle at a pressure greater than 2MPa or even 3 MPa.

The pump may be arranged and adapted to pump fluid at a flow rate of less than or greater than about 50 μ l/min, or a flow rate selected from the group consisting of: (i)50 to 100 mul/min; (ii) about 100 μ l/min to about 200 μ l/min; (iii) about 200. mu.l/min to 500. mu.l/min; (iv) about 500. mu.l/min to 1000. mu.l/min; (v) about 1 μ l/min to about 2 ml/min; (vi) about 2 μ l/min to about 3 ml/min; (vii) about 3 μ l/min to about 4 ml/min; (viii) about 4 μ l/min to about 5 ml/min; (ix) about 5 μ l/min to about 10 ml/min; (x) About 10 μ l/min to about 50 ml/min; (xi) About 50 μ l/min to about 100 ml/min; (xii) About 100. mu.l/min to about 200 ml/min; (xiii) About 200. mu.l/min to about 300 ml/min; (xiv) About 300. mu.l/min to about 400 ml/min; (xv) About 500. mu.l/min to about 600 ml/min; (xvi) from about 600 μ l/min to about 700 ml/min; (xvii) About 700. mu.l/min to about 800 ml/min; (xviii) About 800. mu.l/min to about 900 ml/min; (xix) From about 900. mu.l/min to about 1000ml/min or greater than about 1000 ml/min.

The probe may be operably connected to an ion analyzer or mass spectrometer, such as the one forming part of analysis stack 1330 described above with respect to fig. 13A. The probe may be connected to the ion analyzer or mass spectrometer via a tissue sampling device or conduit (e.g., tissue sampling device 1336 as described above with respect to fig. 13A or conduit 6 as shown in fig. 1).

The tissue sampling device or conduit or other connection mechanism connecting the probe to the ion analyser or mass spectrometer (e.g. its first vacuum stage) may have a maximum diameter of less than 1mm, 0.9mm, 0.8mm, 0.7mm, 0.6mm, 0.5mm, 0.4mm, 0.3 mm, 250 μm, 200 μm, 150 μm, 100 μm, 50 μm, 40 μm, 30 μm, 20 μm or 10 μm. The small diameter tube may help to rapidly transport the sample fluid produced by the probe to the ion analyzer or mass spectrometer. A tissue sampling device or conduit may connect the probe to the ion inlet device, or the first vacuum stage of the ion analyzer or mass spectrometer.

The hydrotherapy probe can be used to break up or destroy tissue in contact with the fluid. This can produce an aerosol or tissue particles which can then be transported to an ion analyzer or mass spectrometer via, for example, a conduit.

Embodiments are envisaged in which the hydrotherapy probe forms part of a laparoscope or endoscope. In this case, the arms of the probe may be positioned laparoscopically or endoscopically. The nozzle may be located at the distal end of a laparoscope or endoscope and may be arranged and adapted to break up or destroy tissue adjacent to the distal end of the laparoscope or endoscope.

In various embodiments, a rapid evaporative ionization mass spectrometry device or probe (or other electrosurgical device described herein) may be used in conjunction with a hydrotherapy probe. For example, the probe may include electrodes so that the electrosurgical technique may be combined with a jet of hydrotherapy fluid.

The rapid evaporative ionization mass spectrometry apparatus or probe may be arranged and adapted to vaporize the same portion of tissue in contact with the jet of hydrotherapy fluid to produce an aerosol which may then be passed to an ion analyzer or mass spectrometer for analysis as described below.

The method may involve providing a surgical instrument that includes a hydrotherapy probe and a rapid evaporative ionization mass spectrometry apparatus or probe as described above (e.g., a rapid evaporative ionization mass spectrometry apparatus or probe as described above with respect to fig. 14A and 14B).

The method may include identifying a tissue sample for analysis; using a hydrotherapy device, a probe aspiration device, or a dissection device to generate an aerosol comprising particles of a tissue sample (or a portion of a tissue sample); and analyzing the particles of the tissue sample included in the sample fluid. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The method may include outputting one or more mass spectra from each tissue sample, and optionally comparing or combining the mass spectra generated using the rapid evaporative ionization mass spectrometry device or probe with the mass spectra generated using the hydrotherapy device, probe attraction device, or dissection device.

The hydrotherapy probe may be arranged and adapted to disintegrate, vaporize or cut a sample, such as biological tissue. The apparatus may comprise an instrument, for example a surgical instrument comprising a hydrotherapy surgical probe.

Alternative energy source-argon plasma coagulation

Further embodiments are contemplated wherein the electrosurgical tools disclosed herein, such as rapid evaporative ionization mass spectrometry devices or probes, may be replaced by or combined with argon plasma coagulation ("APC") technology.

According to one embodiment, a surgical instrument is provided that includes an argon plasma coagulation ("APC") device. The argon plasma coagulation device may look similar to the device of the above described embodiment, but instead of e.g. water or saline solution, an argon jet may be directed or pumped through the supply tube and may exit the nozzle. Gases other than argon may be used. For example, the argon gas jet may be replaced with a non-combustible gas jet.

According to the tip of the above embodiments, the tip may be modified and may include an electrode arranged and adapted to apply a high voltage spark or discharge (e.g., in excess of about 1kV, 1.5kV, 2kV, 2.5kV, 3kV, 4kV, or 5kV) to argon, for example, adjacent to or at the nozzle. A high voltage spark or discharge may ionize the argon gas as it is ejected from the nozzle. A high voltage spark or discharge may be applied by an electrode (e.g., a tungsten wire) connected to a power source (e.g., making up a portion of analysis stack 1330 as described above with respect to fig. 13A).

Once the argon gas is ionized, the argon gas then seeks the ground and this ground can be found in the tissue adjacent to the end 1702 of the device. Thermal energy can be delivered, typically with a penetration depth of about 2mm to 3 mm. The probe may be placed separately from the tissue to be attracted or destroyed. As discussed above, argon gas may be emitted, followed by ionization by a high voltage discharge. Then, through the gas jet, an electric current can be conducted, causing coagulation of the tissue at the other end of the jet. Since the device may not be in physical contact with tissue, the process may be considered relatively safe and may be used to treat delicate tissue with low intracellular junctions, such as skin or fat. The depth of coagulation is typically only a few millimeters.

The argon plasma coagulation device may include a gas source and a nozzle for directing a gas (e.g., from the gas source) at a target (e.g., a sample such as a biological sample) at a high pressure (e.g., greater than 6 kilopascals, 7 kilopascals, 8 kilopascals, 9 kilopascals, or 10 kilopascals). The surgical instrument may form part of a surgical stack 1301 as described above in connection with fig. 13A. The surgical instrument may comprise an endoscope or a laparoscope. The argon plasma coagulation device may be passed through, for example, a port or instrument channel of an endoscope or laparoscope.

The argon plasma coagulation device may be configured to attract or break up biological tissue and form an aerosol comprising particles of the biological tissue. The argon plasma coagulation device may further comprise a tube or other mechanism for transporting particles to a mass analyzer and/or an ion mobility analyzer and/or a mass spectrometer.

According to one embodiment, a surgical method is provided that includes using an argon plasma coagulation device, a probe, a suction device, or an dissection device, for example, in intraoperative diagnostics. The method may include identifying tissue for analysis; using the apc device, probe, aspiration device or dissection device to generate an aerosol comprising particles of the identified tissue; and these particles were analyzed. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The method may include identifying a plurality of tissue samples for analysis; using the apc device, probe, aspiration device or dissection device to produce a sample fluid comprising identified particles of each tissue sample; and analyzing the identified particles of each tissue sample. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The method may comprise using an argon plasma coagulation device, probe, suction device or dissection device to look for one or more specific compounds in the tissue, and may comprise looking for or identifying the compound or compounds in a mass spectrum generated from the tissue or tissue sample.

The argon plasma coagulation device, probe, suction device or dissection device may be optimized for surgical use. For example, the argon plasma coagulation device, probe, suction device, or dissection device may be miniaturized, and/or one or more of the largest dimension, length, width, and depth of the hydro-surgical device, probe, suction device, or dissection device may be less than 5cm, 2 cm, 1cm, or 5 mm. The argon plasma coagulation device, probe, suction device or dissection device may be shaped such that it can be inserted into a human or animal body during surgery. For example, the argon plasma coagulation device, probe, suction device or dissection device may be or constitute part of an elongate tube or conduit and/or part of a surgical instrument (e.g. an endoscope or laparoscope).

The argon plasma coagulation device may include structural features as described above with respect to the hydrotherapy device.

As discussed above, the aperture or nozzle may have an outlet end or orifice with a diameter or maximum dimension in the range of about 0.05mm to about 1mm, 0.06mm to about 0.8mm, 0.07mm to about 0.7mm, about 0.08 mm to about 0.6mm, about 0.09mm to about 0.5mm, about 0.1mm to about 0.4mm, about 0.1mm to about 0.3mm, about 0.1mm to about 0.2mm, about 0.1mm to about 0.15 mm.

The gas jet can be directed away from the probe. This can direct a gas or plasma in the tissue in close proximity to the probe, which in turn can attract, dissect, fragment or destroy the tissue. Embodiments are contemplated in which the gas or plasma is directed through the tissue, e.g., parallel to the tissue. The nozzle may be located along the arm at a distance from the tip and arranged and adapted to direct a gas or plasma stream from an output end or exit orifice substantially parallel to the arm.

The flow rate of the gas and/or the voltage of the high voltage spark or discharge may be varied to suit different tissues and/or surgical techniques. For example, relatively low energy flow rates and/or voltages may be applied to dissect or break up tissue with low intracellular associations (e.g., skin or fat), and relatively high energy flow rates and/or voltages may be applied to dissect or break up tissue with high intracellular associations (e.g., bone or tendon).

One or more apertures may be located at the distal end to convey tissue particles attracted by the apc device to the ion analyzer and/or mass spectrometer 8 (see fig. 1) via the internal channel and conduit(s). one or more apertures may alternatively or additionally be located anywhere on the probe and may be arranged and adapted to convey particles as described above. For example, one or more apertures may be located on the arm and/or external to the tip.

Lower voltage or airflow may be helpful for minimally invasive surgery or non-invasive surgery.

The surgical instrument may comprise a pump arranged and adapted to supply and/or pump gas. A conduit may be provided to supply gas to the surgical instrument. The pump may be located within the probe, or may be located external to the probe and connected to the probe via a conduit.

The pump may be arranged and adapted to apply a varying flow rate and/or pressure of the gas to the nozzle, and the varying flow rate and/or pressure may be used to vary the applied energy of the fluid.

The pump and/or nozzle may be arranged and adapted to output gas from the nozzle at a pressure greater than about 0.01MPa, for example between about 0.01MPa and about 1.5 MPa, between about 0.05MPa and about 1.4MPa, between about 0.1MPa and about 1.3MPa, between about 0.8MPa and about 1.2MPa, between about 0.9MPa and about 1.1MPa, or between about 0.95MPa and about 1.05 MPa.

The argon plasma coagulation device may be used to break up or destroy tissue in contact with the fluid. This can produce an aerosol or tissue particles which can then be transported to an ion analyzer or mass spectrometer via, for example, a conduit.

In various embodiments, a rapid evaporative ionization mass spectrometry device or probe (or other electrosurgical device described herein) may be used in conjunction with an argon plasma coagulation device. For example, the probe may comprise a further electrode arranged and adapted to be in contact with tissue adjacent the argon plasma coagulation device, so that the electrosurgical technique may be combined with the jet of hydrotherapy fluid.

The rapid evaporative ionization mass spectrometry device or probe may be arranged and adapted to vaporize the same portion of tissue adjacent the argon plasma coagulation device to produce an aerosol (or aerosols) which may then be passed to an ion analyzer or mass spectrometer for analysis as described below.

The method may involve providing a surgical instrument that includes an argon plasma coagulation device as described above and a rapid evaporative ionization mass spectrometry device or probe (e.g., a rapid evaporative ionization mass spectrometry device or probe as described above with respect to fig. 14A and 14B).

The method may include identifying a tissue sample for analysis; using an argon plasma coagulation device, a probe attraction device, or a dissection device to generate an aerosol comprising particles of a tissue sample (or a portion of a tissue sample); and analyzing the particles of the tissue sample included in the sample fluid. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The method may include outputting one or more mass spectra from each tissue sample, and optionally comparing or combining the mass spectra generated using the rapid evaporative ionization mass spectrometry device or probe with the mass spectra generated using the argon plasma coagulation device, probe attraction device or dissection device.

The argon plasma coagulation device may be arranged and adapted to decompose, vaporise or cut a sample, such as biological tissue. The apparatus may comprise an instrument, for example a surgical instrument comprising an argon plasma coagulation device.

Dermatology study

According to one embodiment, there is provided a method of processing a biological sample, the method comprising identifying a portion of the sample to be analyzed; vaporizing or generating an aerosol from the sample portion; analyzing the aerosol; and determining whether any compound of interest is contained in the aerosol. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

The biological sample and/or sample portion may comprise skin.

Any of the methods disclosed herein for vaporizing or generating an aerosol from a biological sample may be used. For example, a laser probe or an ultrasound probe may be used as discussed above. The method of processing a biological sample may comprise any of the methods disclosed herein, provided that the methods are compatible.

A surgical instrument may be used to perform a portion of the method, and the surgical instrument may include an electrosurgical tool, for example, a rapid evaporative ionization mass spectrometry device or probe, an ion analyzer or mass spectrometer, and a control system.

The present disclosure extends to an apparatus arranged and adapted to carry out the methods disclosed herein, and which may include a control system arranged and adapted to perform any of the method steps.

The surgical instrument may form part of an analysis stack 1301 and/or apparatus 1300 (e.g., including camera monitor 1303 and/or analysis monitor 1333 (which may also be the same components) as described above with respect to fig. 13A.

The electrosurgical tool or the rapid evaporative ionisation mass spectrometry probe may be a rapid evaporative ionisation mass spectrometry probe as described herein with reference to figure 14, or a bipolar forceps probe as described herein with reference to figure 1.

Non-invasive or minimally invasive methods may be used that do not penetrate deeply into tissue.

For example, the step of partially vaporizing or generating an aerosol from the sample may comprise penetrating the sample no more than (and/or less than) 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 10 μm, 20 μm, 25 μm, 30 μm, 35 μm, 50 μm, 100 μm, 200 μm, or 250 μm.

The method may further comprise making a dermatological decision based on the compound. For example, if the compound of interest is located within a sample portion, the method may comprise removing the sample portion, or removing a portion of the sample portion.

The method may then comprise checking whether the compounds of interest are still present (via vaporization or generation of an aerosol from the sample portion and analysis of the aerosol) and, if so, removing further material. The analysis may comprise mass analysis and/or ion mobility analysis and/or a combination of mass and ion mobility analysis.

If these compounds of interest are no longer present, the method may include stopping, or immediately stopping, the removal of material from the sample portion.

If the compound of interest is not in a sample portion, the invention may include the steps of moving to a different portion of the sample and performing the method again.

For example, cancerous tissue may be located on a portion of the skin and then broken up or removed using a suitable probe (e.g., a laser probe).

The aerosol generated during this process can be drawn through a tissue sample device or tube and can serve as a guide to interrupt the removal of tissue once cancerous tissue has been removed.

Electrosurgical tip/coating

According to one embodiment, an electrosurgical tool or probe is provided, for example comprising a rapid evaporative ionisation mass spectrometry probe. The electrosurgical tool or probe may be arranged and adapted to apply an electrical current to a sample (e.g. biological tissue) to cut, coagulate, dry or fulgure the sample or a portion thereof. The tool or probe may be arranged and adapted to capture particles from a portion of the sample that has been vaporised by the electrosurgical tool. The apparatus may comprise an electrosurgical tool and a mass analyser and/or ion mobility analyser and/or mass spectrometer, and the mass analyser and/or ion mobility analyser and/or mass spectrometer may be arranged and adapted for mass analysis and/or ion mobility analysis of the vaporised particles.

The electrosurgery may comprise an electrode arranged and adapted to evaporate or vaporise the sample. The electrosurgical tool may further comprise a counter or return electrode arranged and adapted to contact the sample. The pair of electrodes or the return electrode may be grounded.

Any of the embodiments disclosed herein that relate to electrosurgical tools can be operated in this manner, and the electrosurgical tools disclosed in those embodiments can be arranged and adapted in the manner described above.

Consumable material for rapid evaporation ionization mass spectrometry technology

Referring back to fig. 1, fig. 1 shows an apparatus comprising an electrosurgical tool 1 (e.g., a bipolar forceps) that can be connected to an ion analyzer or mass spectrometer 8 via a tube 6. The electrosurgical tool 1 may be connected to the power source 4 via a wire 9. As discussed herein, the tool may include one or more electrodes or other mechanisms (e.g., laser or ultrasound) that may be configured to vaporize, or break up the biological tissue 3 to form an aerosol.

Referring now to fig. 18, a surgical tool 1800 is shown in a packaged configuration. The surgical tool 1800 may be an electrosurgical tool (e.g., a rapid evaporative ionization mass spectrometry probe as described herein with reference to fig. 14A-14B, a bipolar forceps probe as described herein with reference to fig. 1), or the surgical tool 1800 may be an ultrasound probe 1600 as described herein with reference to fig. 16, or a laser probe 1700 as described herein with reference to fig. 17.

The surgical tool 1800 may be packaged in a pouch or capsule 1802, and the pouch or capsule 1802 may be transparent or translucent. The package may further contain supplemental items such as a mixing device 1804 and/or another conduit 1806. Alternatively, these supplemental items may be contained in separate cartridges.

The capsule 1802 may be one of a plurality of capsules 1802, which may be contained in a capsule support 1810. The capsule support 1810 may include compartments 1812a to 1812f arranged and adapted to receive or contain capsules (e.g., capsule 1802) containing surgical tools or other equipment for use with such tools. Each compartment 1812a to 1812f of capsule support 1810 may include a different type of surgical tool or other equipment associated with a different surgical procedure.

For example, compartment 1812B may support multiple cartridges 1802, each containing bipolar forceps as described with reference to fig. 1-14A, and a different compartment (e.g., 1812a) may support multiple cartridges 1802, each containing monopolar forceps as described with reference to fig. 14B.

Identification means 1808, 1809 (e.g., bar codes) may be provided on the capsule 1802 and/or on the tool 1800. The identification means may contain data or information relating to the type of tool or equipment in the capsule 1802, or a code that can be read by a scanner or reading mechanism (e.g., a bar code reader).

An apparatus 1850 may be provided that houses an analyzer 1860 that includes an inlet device 1862. The analyzer may be an ion analyzer or mass spectrometer as described herein (e.g., ion analyzer or mass spectrometer 8 disclosed with reference to fig. 1), and the inlet device 1862 may be an ion inlet device. The apparatus 1850 may form part of a surgical stack and/or an analytical stack as disclosed in fig. 13A and 13B.

The analyzer 1860 can include a connector 1864 that can constitute an entrance to the first vacuum stage of the analyzer 1860. The tool 1800 may include a corresponding connector 1816, which may be connected to the tool 1800 via tubing 1815. Alternatively, the mixing device 1804 may include a connector 1817 configured to connect to a connector 1834 located on the analyzer 1860. Alternatively, another conduit 1806 may include a connector 1807 configured to connect to a connector 1834 located on analyzer 1860.

The apparatus 1850 may further comprise a voltage supply 1852 which may be arranged and adapted to supply a voltage to the tool via an outlet 1854. A cord 1820 may be provided on the tool 1800 and may include a plug 1822 configured for insertion into a receptacle 1854 to power the tool 1800. In some embodiments, voltage supply 1852 can be replaced by a different energy source (e.g., a laser source).

The apparatus 1850 may comprise a scanner, reader, detector or other mechanism 1856 arranged and adapted to scan, read or detect identification means 1808, 1809 located on the capsule 1802 and/or on the tool 1800. The apparatus may include a memory containing data or a database associating codes or other data contained on the

identification devices

1808, 1809 with particular types of surgical procedures.

The memory may contain a statistical model or recognition algorithm or other algorithm, and the code or other data contained on the

recognition devices

1808, 1809 may constitute or include a portion of the parameters or inputs of the statistical model or algorithm. Other inputs (e.g., type of patient, patient condition, etc.) may be used for the statistical model or algorithm. The results of the model or algorithm may be used to determine operating parameters of the tool 1800, or instrument parameters of the analyzer 1860.

Apparatus 1850 may include a display 1857 for displaying information, for example, regarding the type of device that has been scanned, or the type of surgical procedure that is about to be performed. The display may be in the form of a mobile device (e.g., a mobile tablet device).

Apparatus 1850 can comprise a fluid outlet 1866 that can be in fluid communication with a fluid source (e.g., the substrate discussed herein). A tube may be connected to the fluid outlet 1866, and the tube may be connected to a corresponding port 1819 on the mixing device 1804.

An input device 1858 (e.g., a keyboard) may be provided on device 1850, which may be coupled to memory and display 1857 via a processor or other processing mechanism. It is contemplated that a user (e.g., a surgeon or other person) may enter a code into input device 1858, and a processor or other processing mechanism may be configured to find this code in memory and find the corresponding "correct" surgical procedure. The correct surgical procedure may then be displayed on the display 1857, along with a list of required equipment. The array of equipment may contain the type of surgical tool required.

When the user notices the type of surgical tool desired, the user can retrieve the desired tool from the capsule support 1810. Display 1857 may show, for example, which of bays 1812a through 1812f the tool is located. Once the capsule 1802 is retrieved from the capsule support 1810, the identifying

means

1808, 1809 may then be scanned, read or detected by a scanner, reader or detector 1856. If the correct (or incorrect) tool has been retrieved, the display 1857 may display the tool.

It is contemplated that the control mechanism of apparatus 1850 may be arranged and adapted to control activation of voltage supply 1852 and/or analyzer 1860. The control mechanism may be arranged and adapted to activate the voltage supply 1852 and/or the analyzer 1860 only when the capsule 1802 or tool 1800 corresponding to (or associated with) the correct surgical procedure is scanned, read or detected by the scanner, reader or detector 1856.

This may help the physician prevent the use of incorrect tools. In the case of a rapid evaporative ionisation mass spectrometry apparatus or probe, bipolar forceps (see figure 14A) may operate quite differently from monopolar apparatus (figure 14B) and depending on the type of surgical procedure required, it may be important to select the correct tool and so this may be important.

Alternatively or additionally, capsule support 1810 may include a precaution screen or other device configured to block access to each compartment 1812a to 1812f (and within the tool). The screens are movable such that access to a first location of each compartment is prevented or restricted and access to a second and different location of the compartment is permitted. Movement of the screen between the first position and the second position may be controlled by a control mechanism of device 1850.

The control mechanism may be arranged and adapted such that only codes corresponding to a particular compartment or tool therein are entered into the input device 1858, access to the compartment being permissible (e.g., movement of the screen between the first and second positions). This may provide an alternative or additional method of preventing the selection of an incorrect tool for a particular surgical procedure.

To prevent contamination between the tools, the package 1802 and its contents may be replaceable and/or disposable.

According to one embodiment, a kit is provided that includes an apparatus 1850, a capsule support 1810, and a plurality of capsules 1802. Located within each of the plurality of cartridges may be a surgical tool (e.g., bipolar forceps 1800) and optionally one or more supplemental items (e.g., 1804, 1806).

The articles and tools in the cartridges may correspond to any of the tools, devices, probes, and related equipment disclosed herein.

For example, referring to fig. 1, the surgical tool may be bipolar forceps 1 and the conduit 1815 may be an inlet tube 6. The bipolar forceps 1 and the inlet tube 6 may be replaceable and/or disposable. The bipolar forceps 1 and inlet tube 6 may be made of plastic, polyethylene, polycarbonate, polyvinyl chloride ("PVC") or polytetrafluoroethylene ("PTFE").

With reference to the embodiment of fig. 2A-2C, the surgical tool may be a device or probe (e.g., a rapid evaporative ionization mass spectrometry device or probe as disclosed with reference to fig. 14A and 14B), and the supplemental items may include a tube 21, a sample delivery tube 15, and a whistle 12. The surgical tool 1800, tube 21, sample delivery tube 15, and whistle 12 may be replaceable and/or disposable.

Any of the surgical tool 1800, tube 21, sample delivery tube 15, and whistle 12 can be made of plastic, polyethylene, polycarbonate, polyvinyl chloride ("PVC"), or polytetrafluoroethylene ("PTFE"). Making these components replaceable may mean that all components prior to the substrate (see substrate introduction conduit 30 of fig. 2A) are replaceable and/or disposable.

With reference to the embodiment of fig. 4A and 4B, the surgical tool may be a device or probe (e.g., a rapid evaporative ionization mass spectrometry device or probe as disclosed with reference to fig. 14A and 14B), and the supplemental items may include a tee 100 and a sample transfer tube 120 (which are the same components as the tube 1815/inlet tube 6). The substrate introduction conduit 130 may be included in the supplemental article for convenience, but may not be susceptible to contamination since it is not in contact with the flowing aerosol particles 122.

In some embodiments as described above, the inlet tube 140 (fig. 14A and 14B) may be removed from the ion analyzer or mass spectrometer and may also be included in the supplemental item. Any of surgical tool 1800, tee 100, substrate introduction tube 130, inlet tube 140, and sample delivery tube 120 may be replaceable and/or disposable. Any of surgical tool 1800, tee 100, substrate introduction tube 130, inlet tube 140, and sample transfer tube 120 may be made of plastic, polyethylene, polycarbonate, polyvinyl chloride ("PVC"), or polytetrafluoroethylene ("PTFE").

With reference to the embodiment of fig. 5A, the surgical tool may be a device or probe (e.g., a rapid evaporative ionization mass spectrometry device or probe as disclosed with reference to fig. 14A and 14B), and the supplemental item may comprise an inlet tube 152 (which is the same component as tube 1815/inlet tube 6). For convenience, the sample transport portion 156 may be included in a refill item.

Any of the device or probe, inlet tube 152 and sample transfer portion 156 may be replaceable and/or disposable. Any of the device or probe, inlet tube 152, and sample transfer portion 156 may be made of plastic, polyethylene, polycarbonate, polyvinyl chloride ("PVC"), or polytetrafluoroethylene ("PTFE").

With reference to the embodiment of fig. 5B, the surgical tool may be a device or probe (e.g., a rapid evaporative ionization mass spectrometry device or probe as disclosed with reference to fig. 14A and 14B), and the supplemental item may comprise inlet tube 202 (which is the same component as tube 1815/inlet tube 6). For convenience, any one of the sample-transferring part 220, the substrate-introducing conduit 230 and the inlet tube 240 may be contained in a supplementary article.

Any of the device or probe, inlet tube 202, sample transfer section 220, matrix introduction conduit 230, and inlet tube 240 may be replaceable and/or disposable. Any of the device or probe, inlet tube 202, sample transfer section 220, matrix introduction conduit 230, and inlet tube 240 may be made of plastic, polyethylene, polycarbonate, polyvinyl chloride ("PVC"), or polytetrafluoroethylene ("PTFE").

Referring to the embodiment of fig. 11, the surgical tool may be a desorption electrospray ionization ("DESI") nebulizer 300, such as a solvent capillary 302 and its blanket gas tube 312 (where the remaining components may not be items contained in the capsule) and/or a transport or inlet capillary 330, and supplemental items may be contained on the sample surface 310.

Any of desorption electrospray ionization ("DESI") nebulizer 300, solvent capillary 302 and cladding gas tube 312, and/or transport or inlet capillary 330 may be replaceable and/or disposable. Any of desorption electrospray ionization ("DESI") nebulizer 300, solvent capillary 302 and clad gas tube 312, and/or transport or inlet capillary 330 can be made of plastic, polyethylene, polycarbonate, polyvinyl chloride ("PVC"), or polytetrafluoroethylene ("PTFE").

Referring to the embodiment of fig. 13A-13C, the surgical tool may include an ion sampling device 1336 and/or an endoscope (or laparoscope) 1310. The ion analyzer or mass spectrometer 1332 of fig. 13A can be the same component as the analyzer 1850 of fig. 18. The ion inlet device 1334 of fig. 13A may be the same component as the inlet device 1862 of fig. 18.

Either the ion sampling apparatus 1336 and/or the endoscope (or laparoscope) 1310 can be replaceable and/or disposable. Either the ion sampling device 1336 and/or the endoscope (or laparoscope) 1310 may be made of plastic, polyethylene, polycarbonate, polyvinyl chloride ("PVC"), or polytetrafluoroethylene ("PTFE").

The surgical tool may comprise (or be) one of the

electrosurgical probes

1400, 1450 disclosed with reference to fig. 14A and 14B. In this case, the tube 1815 may correspond to the inlet tube 6, and the tube may be included as part of the surgical tool or as a supplemental item (e.g., not attached to the probe). The wire 9 may be included as a supplement or may simply be separately attached to the voltage supply 1852.

Any of the electrosurgical probe 1400, the inlet tube 6, or the electrical wire 9 may be replaceable and/or disposable.

The surgical tool may comprise (or be) one of the ultrasonic or

laser probes

1600, 1700 disclosed with reference to fig. 16 and 17, respectively. In this case, the tube 1815 may correspond to the inlet tube 6, and the tube may be included as part of the surgical tool or as a supplemental item (e.g., not attached to the probe). The wire 9 may be included as a supplement or may simply be separately attached to the voltage supply 1852.

Any of the ultrasound or laser probe 1600, the inlet tube 6, or the electrical wire 9 may be replaceable and/or disposable.

The surgical tool may comprise (or be) one of a hydrotherapy surgical device or an argon plasma coagulation ("APC") device. In this case, the tube 1815 may correspond to an inlet tube, and the tube may be included as part of a surgical tool or as a supplemental item (e.g., as attached to a probe). The wires may be included as a supplement or may simply be separately attached to the voltage supply 1852.

Any of the hydrotherapy device or argon plasma coagulation ("APC") device, the inlet tube, or the electrical wire may be replaceable and/or disposable.

According to one embodiment, a replaceable and/or disposable rapid evaporative ionization mass spectrometry ("REIMS") device or probe is provided, the rapid evaporative ionization mass spectrometry or probe comprising one or more electrodes arranged and adapted to vaporize or vaporize biological tissue to form an aerosol; and a transfer mechanism for transferring the aerosol into the mass spectrometer (e.g., a first vacuum stage thereof).

The transfer mechanism includes one or more tubes, which may be made of plastic, polyethylene, polycarbonate, polyvinyl chloride ("PVC"), or polytetrafluoroethylene ("PTFE").

According to one embodiment, an apparatus is provided that includes a mass spectrometer and a replaceable and/or disposable rapid evaporative ionization mass spectrometry ("REIMS") device or probe. The mass spectrometer may include a fixed or non-disposable connection that may be configured to mate with a connection located on the replaceable and/or disposable rapid evaporative ionization mass spectrometry ("REIMS") device or probe.

The fixed or non-disposable connection may be at the inlet of a first vacuum chamber of the mass spectrometer.

The apparatus may comprise a conduit arranged and adapted to introduce the substrate or solvent mixed with the flowing aerosol into the mass spectrometer. The fixed or non-disposable connection may be at a location where the substrate or solvent is mixed with the flowing aerosol.

Identification means (e.g. radio frequency identification (R))“RFID”) Label)

According to various embodiments, a surgical tool 1800 (and/or a cartridge 1802) as described with reference to fig. 18 may be provided, the surgical tool (and/or cartridge) comprising an

identification device

1808, 1809. The

identification devices

1808, 1809 may include RFID tags.

The controller or control system may interrogate or scan the RFID tag to identify or determine the intended use of the surgical tool 1800 (e.g., a rapid evaporative ionization mass spectrometry device or probe).

For example, the surgical tool 1800 may be intended for and/or may have obtained regulatory approval for use for only a particular surgical procedure. In this case, the controller or control system may set various operating parameters corresponding to interrogating or scanning the identification devices 1808, 1809 (e.g., RFID tags).

For example, it may be desirable that the surgical tool 1800 may perform a single surgical procedure for safety reasons only, in which case the controller or control system may block or prevent a second and subsequent attempted use of the surgical tool 1800. In various embodiments, the memory may include data regarding the number of surgical procedures that are permitted for a particular type of surgical tool 1800. The control system may be arranged and adapted to control the voltage supply 1852 (or other energy source), for example, such that only the allowed number of surgical procedures may be performed using a given surgical tool 1800. Prior to each surgical procedure, the surgeon (or other user) may scan the identification means 1808, 1809 of a given surgical tool 1800, and the control system may be arranged and adapted to switch on the voltage supply 1852 (or other energy source) only if the surgical tool 1800 is used for some surgical procedure equal to or less than the allowed amount stored in the memory.

The surgical tool 1800 (e.g., a rapid evaporative ionization mass spectrometry device or probe) may be intended for use in a particular surgical procedure, such as resecting lung cancer tissue as described above with respect to fig. 13A and 13B. In this case, the controller or control system is arranged and adapted to load a particular database and display this data on display 1857 (or another type of display, such as

monitors

1303 and 1333 described with respect to fig. 13A and 13B). The data may include, for example, identifying data about normal tissue and lung cancer tissue to help a surgeon distinguish between these types of tissue.

Moreover, according to various embodiments, subsequent multi-dimensional analysis of the mass spectral data by, for example, PCA analysis, may be customized according to the intended use of the surgical tool 1800 as indicated by the recognition device.

Embodiments are contemplated in which the limits imposed by the identification device and the controller or control device may be overridden in case of an emergency. For example, in an emergency or battlefield situation, the limitations that would normally be imposed on the intended use of the surgical tool 1800 may be overridden. According to one embodiment, override codes may be obtained that may unlock certain limits that would otherwise impose limitations on the intended use of the surgical tool 1800.

Analysing a sample spectrum

A list of analytical techniques intended to fall within the scope of the present invention is given in the following table:

combinations of the foregoing analytical approaches may also be used, such as PCA-LDA, PCA-MMC, PLS-LDA, and the like.

Analyzing the sample spectrum may include unsupervised analysis with reduced dimensions prior to classification-supervised analysis.

For example, several different analysis techniques will now be described in more detail.

Multivariate analysis-developing models for classification

For example, a method of constructing a classification model using multivariate analysis of multiple reference sample spectra will now be described.

FIG. 19 shows a method 1500 of constructing a classification model using multivariate analysis. In this example, the method includes step 1502: sets of intensity values of the reference sample spectrum are obtained. Then, the method includes step 1504: unmonitored Principal Component Analysis (PCA), followed by step 1506: linear Discriminant Analysis (LDA) was monitored. This approach may be referred to herein as PCA-LDA. Other multivariate analysis methods such as PCA-MMC may be used. The PCA-LDA model is then output, for example, to memory at step 1508.

Such multivariate analysis may provide a classification model that allows for classification of an aerosol, smoke, or vapor sample using one or more sample spectra obtained from the aerosol, smoke, or vapor sample. Multivariate analysis will now be described in more detail with reference to a simple example.

Fig. 20 shows a set of reference sample spectra obtained from two class-known reference samples. These categories may be any one or more of the categories of targets described herein. However, for simplicity, the two categories in this example will be referred to as the left-hand category and the right-hand category.

Each reference sample spectrum has been pre-processed to derive a set of three reference peak intensity values for each mass-to-charge ratio in the reference sample spectrum. Although only three reference peak intensity values are shown, it should be understood that more reference peak intensity values (e.g., about 100 reference peak intensity values) may be derived for a corresponding number of mass-to-charge ratios in each reference sample spectrum. In other embodiments, the reference peak intensity value may correspond to: quality; mass to charge ratio; ion migration (drift time); and/or operating parameters.

Fig. 21 shows a multivariate space with three dimensions defined by intensity axes. Each dimension or intensity axis corresponds to the peak intensity at a particular mass-to-charge ratio. It should also be understood that there may be more dimensions or intensity axes (e.g., about 100 dimensions or intensity axes) in the multivariate space. The multivariate space comprises a plurality of reference points, wherein each reference point corresponds to a reference sample spectrum, i.e. the peak intensity value of each reference sample spectrum provides the coordinates for the reference point in the multivariate space.

The set of reference sample spectra may be represented by a reference matrix D having rows associated with each reference sample spectrum, columns associated with each mass-to-charge ratio, the elements of the matrix being peak intensity values of the mass-to-charge ratios of each reference sample spectrum.

In many cases, the large number of dimensions in the multivariate space and the matrix D may make it difficult to classify the reference sample spectrum. The matrix D can be PCA accordingly, computing a PCA model having a PCA space with a small number of one or more dimensions defined by principal component axes. The principal component may be selected to include or "interpret" the largest variance in matrix D and cumulatively interpret a threshold amount of variance in matrix D.

Fig. 22 shows how the cumulative variance can increase with the number n of principal components in the PCA model. The threshold amount of variance may be selected as desired.

The PCA model may be calculated from the matrix D using a non-linear iterative partial least squares (NIPALS) algorithm or singular value decomposition, the details of which are known to those skilled in the art and therefore not described in detail herein. Other methods of calculating the PCA model may be used.

The resulting PCA model may be defined by a PCA score matrix S and a PCA orthogonal matrix L. The PCA model may also generate an error matrix E containing variances that are not accounted for by the PCA model. D. S, L and E may be:

D＝SL^T+E (1)

fig. 23 shows the resulting PCA scores for the reference sample spectra of fig. 20 and 21. In this example, the PCA model has two principal components PC₀And PC₁And thus the PCA space has two dimensions defined by two principal component axes. However, a lesser or greater number of principal components may be included in the PCA model, as desired. It is generally desirable that the number of principal components is at least one less than the number of dimensions in the multivariate space.

The PCA space includes a plurality of converted reference points or PCA scores, each corresponding to the reference sample spectrum of fig. 20 and thus to the reference points of fig. 21.

As shown in fig. 23, the reduced dimensionality of the PCA space enables easy classification of the reference sample spectra into two classes. Any outliers may also be identified and removed from the classification model at this stage.

Further monitoring multi-component analysis in PCA space, such as multi-class LDA or maximum edge criteria (MMC), may then be performed, defining classes, and optionally further reducing dimensionality.

As will be understood by those skilled in the art, multi-class LDAs seek to minimize the ratio of methods between classes to variance within classes (i.e., to give the greatest possible distance between the most compact classes as possible). The details of LDA are known to those skilled in the art and are therefore not described in detail herein.

The resulting PCA-LDA model may be defined by a transformation matrix U that may be derived from the PCA score matrix S and the class assignments of the individual transformed spectra contained therein via an analysis of a generalized eigenvalue problem.

Then, the conversion of the score S from the original PCA space to the new LDA space may be given by:

Z ＝ SU (2)

where the matrix Z contains scores that are converted into LDA space.

Fig. 24 shows a PCA-LDA space with a single dimension or axis, where LDA is performed in the PCA space of fig. 23. As shown in fig. 24, the LDA space includes a plurality of further transformed reference points or PCA-LDA scores, each of which corresponds to a transformed reference sample point or PCA score of fig. 23.

In this example, the further reduction in the dimensionality of the PCA-LDA space enables easy classification of the reference sample spectrum into two classes. Each class in the PCA-LDA model may be defined by its transformed class mean and covariance matrices or one or more hyperplanes (including points, lines, planes or higher order hyperplanes) or hypersurfaces or voronoi cells in the PCA-LDA space.

The PCA orthogonal matrix L, LDA matrix U and the transformed class mean and covariance matrices or hyperplane or hypersurface or voronoi cells may be output to a database for later use in classifying aerosol, smoke or vapor samples.

Covariance matrix V 'for conversion of class g in LDA space'_gCan be given by:

V’_g ＝ U^T V_g U (3)

wherein, V_gIs the category covariance matrix in the PCA space.

Transition class mean position z for classification g_gCan be given by:

s_gU＝z_g (4)

wherein s is_gIs the class mean position in PCA space.

Multivariate analysis-Using models for Classification

For example, a method of classifying aerosol, smoke or vapour using a classification model will now be described.

FIG. 25 illustrates a method 2100 of using a classification model. In this example, the method includes step 2102: a set of intensity values of a reference sample spectrum is obtained. Then, the method comprises step 2104: the set of intensity values of the reference sample spectrum is projected into a PCA-LDA model space. Other classification model spaces, such as PCA-MMC, may be used. Then, at step 2106, the sample spectra are classified based on the projection locations, and then the classifications are output at step 2108.

The classification of aerosol, smoke or vapour samples will now be described in detail with reference to the simple PCA-LDA model described above.

Fig. 26 shows a sample spectrum obtained from an unknown aerosol, smoke or vapor sample. The sample spectrum has been pre-processed to derive a set of three sample peak intensity values for each mass-to-charge ratio. As noted above, although only three sample peak intensity values are shown, it should be understood that more sample peak intensity values (e.g., about 100 sample peak intensity values) may be derived for a greater corresponding number of mass-to-charge ratios of the sample spectra. Also, as described above, in other embodiments, the sample peak intensity values may correspond to: quality; mass to charge ratio; ion migration (drift time); and/or operating parameters.

The sample spectrum may be represented by a sample vector d_xThe elements of the vector are the peak intensity values for each mass-to-charge ratio. Converted PCA vector s of a sample spectrum_XCan be obtained as follows:

d_xL＝s_x (5)

the converted PCA-LDA vector z of the sample spectrum is then_XCan be obtained as follows:

s_xU＝z_x (6)

fig. 27 again shows the PCA-LDA space of fig. 24. However, P of FIG. 27The CA-LDA space further includes projection sample points corresponding to the converted PCA-LDA vector z_xPeak intensity values derived from the sample spectrum of fig. 26.

In this example, the projected sample points are located on one side of the hyperplane between classes relating to the right-hand class, and thus the aerosol, smoke, or vapor sample may be classified as belonging to the right-hand class.

Alternatively, the Mahalanobis distance from the center of the class in LDA space, where the point z is from the center of the class g, can be used_xThe mahalanobis distance of (a) can be given by the square root of:

(z_x-z_g)^T(V’_g)^-1(z_x-z_g) (8)

and a data vector d_xThe category having the shortest distance to this point can be assigned.

In addition, considering each class as a multivariate Gaussian (Gaussian), the membership probability of the data vector to each class can be calculated.

Library-based analysis-developing libraries for classification

For example, a method of constructing a classification library using a plurality of input reference sample spectra will now be described.

FIG. 28 shows a method 2400 of building a classification library. In this example, the method includes step 2402: obtaining a plurality of input reference sample spectra, and step 2404: metadata is derived from a plurality of input reference sample spectra for each class sample. The method then comprises step 2406: the metadata for each class sample is stored as a separate library volume. The classification library is then output, for example, to electronic memory at step 2408.

Such classification libraries allow an aerosol, smoke or vapor sample to be classified using one or more sample spectra obtained from the aerosol, smoke or vapor sample. Library-based analysis will now be described in more detail with reference to one example.

In this example, entries in the classification library are created from a plurality of preprocessed reference sample spectra of the class. In this example, one class of reference sample spectra is preprocessed according to the following process:

first, a recombination method is performed. In this embodiment, the data is resampled onto a logarithmic grid with abscissa:

wherein N is_chanIs a selected value and

indicating the nearest integer below x. In one example, N_chanIs 2¹²Or 4096.

Then, a background subtraction method is performed. In this embodiment, a cubic spline with k knots is then constructed such that the p% data between pairs of knots lies below the curve. This curve is then subtracted from the data. In one example, k is 32. In one example, p is 5. A constant value corresponding to the intensity minus the q% quantile of the data is then subtracted from each intensity. Positive and negative values are retained. In one example, q is 45.

Then, a normalization method is performed. In this implementation, it is the data that is normalized to have an average value

In one example of the above-described method,

the entries in the library are then represented by each N in the spectrum_chanMedian spectral value mu of a point_iAnd deriving the value D_iThe metadata of the form.

The possibility of the ith channel is given by:

wherein 1/2 ≦ C < ∞ and wherein Γ (C) is the gamma function.

The above equation is a generalized Cauchy (Cauchy) distribution, reduced to a standard Cauchy distribution where C ═ 1 and changed to a gaussian (conventional) distribution where C → ∞. Parameter D_iControlling the width of the distribution (in the Gaussian limit, D)_i＝σ_iJust the standard deviation) and the global value C controls the size of the tail.

In one example, C is 3/2, located between the cauchy distribution and the gaussian distribution, so the probability becomes:

for each library, the parameter μ_iSet as the median of the list of values in the ith channel in the input reference sample spectrum, and the derivative D_iThese values are considered to be divided by a quarter of the range of √ 2. This choice ensures that the ith channel has the same quarter range as the input data, and the use of quantiles provides some protection against peripheral data.

Library-based analysis-Using libraries for Classification

For example, a method of classifying aerosol, smoke or vapour using a classification library will now be described.

FIG. 29 illustrates a method 2500 of using a classification library. In this example, the method includes step 2502: a set of multiple sample spectra is obtained. Then, the method includes step 2504: a classification probability or score is calculated for the set of multiple sample spectra for each class sample using the metadata for the class terms in the classification library. Then, at step 2506, the sample spectrum is classified, and then the classification is output at step 2508.

The classification of aerosol, smoke or vapour samples will now be described in detail with reference to the classification libraries described above.

In this example, the unknown sample spectrum y is the median spectrum of a set of multiple sample spectra. Taking the median spectrum y may include protecting against peripheral data on a channel-by-channel basis.

Then, the likelihood L of the input data given in the library s_sGiven by:

wherein, mu_iAnd D_iThe bin median value and the derived value of channel i are separated. Possibility L_sCan be calculated as a numerically safe logarithmic probability.

Then, the likelihood L of all candidate classes's' is normalized_sTo give a probability, assuming a uniform prior probability over the classes. Categories

The results of (a) are given by:

the exponent (1/F) may weaken the probability otherwise the probability may be too definite. In one example, F is 100. These probabilities may be expressed as percentages, for example, in a user interface.

Or, RMS classification score R_sThe same median sample value and derived value from the library may be used to calculate:

also, the scores R for all candidate classes's' are normalized_s。

The aerosol, smoke or vapor may then be classified as belonging to the category with the highest probability and/or highest RMS classification score.

Methods of drug therapy, surgical and diagnostic and non-drug therapy

Various sets of different embodiments are contemplated. According to some embodiments, the methods disclosed above may be performed on tissue in vivo, in vitro, or ex vivo. The tissue may comprise human tissue or non-human animal tissue. Embodiments are envisaged in which the target may comprise biological tissue, bacterial or fungal colonies or more generally organic targets such as plastics).

Various embodiments are contemplated in which analyte ions are generated by an ambient ionization ion source, followed by: (i) mass analysis by a mass analyser such as a quadrupole mass analyser or a time-of-flight mass analyser; (ii) ion mobility analysis (IMS) and/or differential ion mobility analysis (DMA) and/or asymmetric field ion mobility spectrometry (FAIMS) analysis; and/or (iii) a combination of first (or second) performing ion mobility analysis (IMS) and/or differential ion mobility analysis (DMA) and/or asymmetric field ion mobility spectrometry (FAIMS) analysis, and second (or first) performing mass analysis by a mass analyser such as a quadrupole mass analyser or a time of flight mass analyser. Various embodiments also relate to ion mobility spectrometers and/or mass analyzers and methods of ion mobility mass spectrometry and/or mass analysis. Ion mobility analysis may be performed before or after mass to charge ratio analysis.

Throughout this application, various references are made to mass analysis, mass analyzers, ion analyzers, mass analysis, mass spectrometry data, mass spectrometers, and other related terms (e.g., analyte ions) relating to devices and methods for determining the mass or mass of an ion. It should be understood that it is also contemplated that the present invention may extend to other related terms of ion mobility analysis, ion mobility analyzer, ion mobility analysis, ion mobility data, ion mobility spectrometer, ion mobility separator, and apparatus and methods for determining ion mobility, differential ion mobility, collision cross-section, or interaction cross-section of molecular ions. Furthermore, it should also be understood that embodiments may be envisaged in which analyte ions may be subjected to a combination of ion mobility analysis and mass analysis, namely (a) determining the ion mobility, differential ion mobility, collision cross-section or interaction cross-section of the analyte ions and (b) determining the mass-to-charge ratio of the analyte ions. Thus, embodiments of mixed ion mobility-mass spectrometry (IMS-MS) and mass-ion mobility (MS-IMS) are envisaged in which both the ion mobility and mass-to-charge ratio of the analyte ions are generated, for example, by an ambient ion source. Ion mobility analysis may be performed before or after mass to charge ratio analysis. Further, it should be understood that embodiments are contemplated wherein reference to mass spectral data and databases including mass spectral data should also be understood to encompass ion mobility data and differential ion mobility data, and the like, as well as databases including ion mobility data and differential ion mobility data, and the like (alone or in combination with mass spectral data).

In any aspect or embodiment disclosed herein, the disclosed ion analyzer or mass spectrometer (and/or ion mobility spectrometer) can obtain data in only negative ion mode, only positive ion mode, or in both positive and negative ion mode. The positive ion mode spectral data may be combined with the negative ion mode spectral data.

Ion mobility spectrum data may be obtained using different ion mobility drift gases. These data can then be combined.

Various surgical, therapeutic, pharmacotherapeutic and diagnostic methods are contemplated.

However, other embodiments of non-surgical and non-therapeutic methods involving mass spectrometry not performed on in vivo tissue are contemplated. Other related embodiments are contemplated that are performed in an in vitro manner such that they are performed outside of the human or animal body.

Further embodiments are contemplated wherein the method is performed on a non-living human or animal, for example as part of an autopsy procedure.

While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as set forth in the following claims.

Claims

1. A device comprising:

first means arranged and adapted to, in use, emit a stream of charged droplets at a target;

a delivery capillary, arranged and adapted to deliver ions generated by the target to an ion analyzer or mass spectrometer; and

a heating device arranged and adapted to heat: (i) the capillary of the first device; (ii) the stream of charged droplets emitted by the first device; (iii) the target; or (iv) the transfer capillary.

2. The apparatus of claim 1, wherein the first device comprises a desorption electrospray ionization ("DESI") device.

3. The ion inlet device of claim 1 or 2, wherein the heating device comprises a heater.

4. The ion inlet device of claim 3, wherein the heating device comprises a filament heater.

5. An ion inlet device as claimed in claim 1 or 2, wherein the heating device is arranged and adapted to heat the capillary of the first device, the charged droplets emitted by the first device The flow, the target or the transfer capillary is heated to a temperature above ambient temperature, and/or to a temperature of at least 30°C, 50°C, 100°C, 200°C, 300°C, 400°C, 500°C or above 500°C .

6. The ion inlet device of claim 1 or 2, wherein the heating device is located adjacent to the inlet of the ion analyzer or mass spectrometer.

7. The ion inlet device of claim 6, wherein the inlet forms an inlet to a first vacuum stage of the ion analyzer or mass spectrometer.

8. An ion inlet device as claimed in claim 1 or 2, wherein the heating device comprises a first heater arranged and adapted to heat the transfer capillary so that the ions pass onward to the ions The analyzer or mass spectrometer is heated before.

9. The ion inlet device of claim 1 or 2, wherein the first device comprises a cladding gas tube, and wherein the heating means comprises a second heater arranged and adapted to heat the cladding gas tube , so that the solvent and/or the cladding gas is heated.

10. The ion inlet device of claim 9, wherein the second heater is located at the end of the cladding gas tube closest to the target such that the solvent and/or cladding gas is directed to the The target was heated before.

11. The ion inlet device of claim 1 or 2, wherein the first device comprises a solvent capillary, and wherein the heating device comprises a third heater arranged and adapted to heat the solvent capillary such that The solvent is heated.

12. The ion inlet device of claim 11, wherein the third heater is located adjacent to the solvent capillary near the end located away from the target.

13. The ion inlet device of claim 12, wherein the third heater is located adjacent the solvent capillary so that the solvent is heated before it is surrounded by the cladding gas tube.

14. An ion inlet device as claimed in claim 1 or 2, wherein the heating device comprises a fourth heater arranged and adapted to heat the target such that the target is heated.

15. The ion inlet device of claim 14, wherein the fourth heater is located below the target.

16. The ion inlet device of claim 14, wherein the target comprises a swab, and wherein the fourth heater is arranged and adapted to heat the swab.

17. A method of introducing ions into an ion analyzer or mass spectrometer, comprising:

generating ions by desorption electrospray ionization ("DESI"); and

The ions are transported through a heated capillary into an ion analyzer or mass spectrometer.

18. The method of claim 17, further comprising heating the capillary to a temperature above ambient temperature, and/or to at least 30°C, 50°C, 100°C, 200°C, 300°C, 400°C, 500°C or temperatures higher than 500°C.

19. The method of claim 17 or 18, wherein the step of generating ions comprises desorbing ions from a biological sample, wherein the sample comprises lipids.

20. The method of claim 19, wherein the sample comprises phospholipids.

21. An apparatus comprising:

first means for generating aerosol, smoke or vapor from one or more regions of the target;

A device arranged and adapted to mix said aerosol, smoke or vapor with a substrate or solvent to produce a mixture of particles of said aerosol, smoke or vapor and said substrate, wherein said device comprises:

a first conduit arranged and adapted to receive said aerosol, smoke or vapour from said first device;

a second conduit arranged and adapted to receive a matrix conduit or tube, wherein the matrix conduit is arranged and adapted to supply the device with matrix or solvent from a source of matrix or solvent; and

A third conduit, arranged and adapted to receive an inlet tube for delivering said matrix or mixture of solvent and said aerosol, smoke or vapour to an ion analyzer or mass spectrometer.

22. An apparatus comprising:

Inlet conduit connected to an ion analyzer or mass spectrometer;

an aerosol, smoke or vapour introduction conduit arranged and adapted to introduce said aerosol, smoke or vapour into said inlet conduit; and

A matrix introduction conduit arranged and adapted to introduce the matrix into the inlet conduit.

23. An apparatus comprising:

Venturi pump means arranged and adapted to direct said aerosol, smoke or vapour to the junction;

a matrix introduction catheter arranged and adapted to introduce a matrix or solvent into said junction; and

An inlet conduit having an inlet at said junction and arranged and adapted to deliver said aerosol, smoke or vapor and said matrix to an ion analyzer or mass spectrometer.

24. An apparatus comprising:

A portable device comprising one or more instrument sets, wherein each of the one or more instrument sets includes one or more wheels or tracks for facilitating movement of the instrument set; and

An ion analyzer or mass spectrometer carried by one of the one or more instrument sets and connected in use to the first device.

25. A method of robotic surgery comprising:

providing a hand-held manipulator operably coupled to the probe via one or more actuators;

manually moving the hand-held manipulator;

automatically causing the one or more actuators to move the probe in response to movement of the handheld manipulator;

energizing the probe to generate an aerosol, smoke or vapor; and

Mass analysis and/or ion mobility analysis are performed on the aerosol, smoke or vapor.

26. An apparatus comprising:

User Interface;

a robotic probe, responsive to or controlled by the user interface, wherein the robotic probe is arranged to generate an aerosol, smoke or vapor; and

Mass analyzer and/or ion mobility analyzer for performing mass analysis and/or ion mobility analysis on the aerosol, smoke or vapor.

27. A laparoscopic tool comprising:

an extension arranged and adapted to be inserted into the human or animal body through an incision in the human or animal body; and

A first device, located at the distal end of the extension, wherein the first device is arranged and adapted to generate an aerosol, smoke or vapor from tissue located within the human or animal body.

28. An apparatus comprising:

Ultrasonic knife, probe, aspirator or dissector for use in surgery and arranged and adapted to liquefy, destroy or otherwise liquefy tissue in contact with said ultrasonic knife, probe, aspirator or dissector way broken; and

An analysis device, arranged and adapted to analyze particles of said tissue, eg using open ionization techniques.

29. An apparatus comprising:

surgical lasers, arranged and adapted to generate aerosols, fumes or vapours from a sample; and

An ion analyser or mass spectrometer, arranged and adapted to analyse said aerosol, smoke or vapour.

30. A method comprising:

provide surgical lasers arranged and adapted to generate aerosols, fumes or vapours from a sample;

scanning the surgical laser across one or more regions of the sample to generate an aerosol, smoke or vapor;

The aerosol, smoke or vapor generated at the one or more regions of the sample is conveyed to an ion analyzer or mass spectrometer.

31. An electrosurgical tool or probe arranged and adapted to:

applying an electrical current to the sample to cut, coagulate, dry or electrocauterize the sample or a portion of the sample; and

Particles from a portion of the sample that have been vaporized are captured by the electrosurgical tool and delivered to an analysis device.

32. An apparatus comprising:

a laparoscope including a first device for generating an aerosol, smoke or vapor from one or more regions of a target; and

One or more insufflation gas outlets for delivering insufflation gas from a gas source into a human or animal body.

33. An apparatus comprising:

a first device arranged and adapted to generate aerosol, smoke or vapor from one or more areas of the target;

an ion analyser or mass spectrometer, arranged and adapted to analyse said aerosol, smoke or vapour; and

delivery means arranged and adapted to deliver said aerosol, smoke or vapour to an inlet portion of said ion analyser or mass spectrometer, wherein said inlet portion comprises a first vacuum to said ion analyser or mass spectrometer the entrance to the room;

wherein the first device and the transfer device are removable and/or replaceable from the ion analyzer or mass spectrometer.

34. An apparatus comprising:

first means arranged and adapted to generate an aerosol, smoke or vapour from one or more areas of the target;

second means arranged and adapted to mix said aerosol, mist or vapour with a substrate or solvent at the joint;

third means for delivering the mixture of the aerosol, smoke or vapor and the matrix or solvent to an ion analyzer or mass spectrometer; and

delivery means arranged and adapted to deliver said aerosol, smoke or vapour to said junction;

wherein the first device and the transfer device are removable and/or replaceable from the third device and the ion analyzer or mass spectrometer.

35. A method comprising:

providing a surgical tool with identification means, wherein the surgical tool is arranged and adapted to generate aerosol, smoke or vapor from one or more regions of the target; and

In response to the identification means, operating parameters of the surgical tool are set or controlled.

36. An apparatus comprising:

A surgical tool with identification means, wherein the surgical tool is arranged and adapted to generate aerosol, smoke or vapor from one or more regions of a target.