WO2020154477A1 - Apparatus and methods for cleaning and/or exchanging medical devices - Google Patents
Apparatus and methods for cleaning and/or exchanging medical devices Download PDFInfo
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- WO2020154477A1 WO2020154477A1 PCT/US2020/014749 US2020014749W WO2020154477A1 WO 2020154477 A1 WO2020154477 A1 WO 2020154477A1 US 2020014749 W US2020014749 W US 2020014749W WO 2020154477 A1 WO2020154477 A1 WO 2020154477A1
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Classifications
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- G—PHYSICS
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- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
- G01N35/1095—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices for supplying the samples to flow-through analysers
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- A—HUMAN NECESSITIES
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- A61B10/02—Instruments for taking cell samples or for biopsy
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- A61B10/0045—Devices for taking samples of body liquids
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- A61B10/0233—Pointed or sharp biopsy instruments
- A61B10/0283—Pointed or sharp biopsy instruments with vacuum aspiration, e.g. caused by retractable plunger or by connected syringe
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- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
- A61B10/02—Instruments for taking cell samples or for biopsy
- A61B10/04—Endoscopic instruments
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
- H01J49/00—Particle spectrometers or separator tubes
- H01J49/02—Details
- H01J49/04—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components
- H01J49/0409—Sample holders or containers
- H01J49/0413—Sample holders or containers for automated handling
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
- A61B10/02—Instruments for taking cell samples or for biopsy
- A61B10/04—Endoscopic instruments
- A61B2010/045—Needles
Definitions
- the present invention relates generally to the field of medicine, molecular biology and biochemistry. More particularly, it concerns apparatus and methods for cleaning and/or exchanging surgical devices, including for example, those used for assessment of tissue samples using mass spectrometry.
- tissue evaluation is important in the diagnosis and management of cancer patients.
- Intra-operative pathologic assessment of excised tissues is routinely performed for diagnosis and surgical margin evaluation in a variety of cancer surgeries.
- the resected tissue specimens are sent to a nearby room, often called the“frozen room”, for tissue preparation, staining, and evaluation.
- the tissue specimen is frozen, sectioned, stained, and interrogated using light microscopy by an expert pathologist who carefully evaluates if the surgical margins contain cancer cells (positive margin) or not (negative margin).
- an apparatus comprises a cassette with a plurality of sample acquisition probes coupled to a mass spectrometer. It is understood the scope of the present disclosure includes other embodiments with a cassette comprising other types of medical devices coupled to other types of instruments. For example, embodiments of the present disclosure can be coupled to medical instruments performing spectroscopy utilizing infrared, ultraviolet, and fluorescence analysis. .
- Exemplary embodiments of the present disclosure include an apparatus and method for intra-surgical device exchange or washing to eliminate cross contamination between analyses. While the embodiments described herein are directed to sample acquisition systems, it is understood that the scope of the invention includes other systems for performing medical procedures. Exemplary embodiments are broadly applicable to other surgical devices prone to contamination issues that are used in the operating room, especially those that use mass spectrometry for analysis.
- Exemplary embodiments of the present disclosure provide multiple ways to eliminate contamination between each sample acquisition and analysis. For example, certain embodiments can automatically exchange the medical instruments and associated conduit. Other embodiments can provide a quick washing circle to regenerate the previously used conduit. For the new conduit exchange method, there are loading cassette(s) to provide ready- to-use conduit systems. For the conduit washing method, a washing port can be coupled to the analyzing system so that it could do online washing while the other instruments and conduit are being used.
- exemplary embodiments include an apparatus and method for automatic intra-surgical device exchange or cleaning with the goal of eliminating cross contamination between each procedure, including for example, a mass-spectrometry analytic measurement.
- Cross contamination or carry-over within surgical devices can be detrimental in the operating room and slow the analysis workflow in current clinical procedures.
- Exemplary embodiments therefore provide two different ways to eliminate contamination between each procedure by either automatically changing to a completely new device and conduit and/or including a quick washing cycle to clean or refresh the previously used device and conduit. These two approaches are not independent and can be used separately or in combination. For example, an exchange step may be carried out while a previously used device and conduit may be undergoing a cleaning step.
- Certain embodiments include an apparatus comprising: a cassette comprising a plurality of sample acquisition probes; and a sample processing instrument configured to receive a sample, where: the cassette is coupled to the sample processing instrument; a first sample acquisition probe is in fluid communication with the sample processing instrument when the cassette is in a first orientation; a second sample acquisition probe is in fluid communication with the sample processing instrument when the cassette is in a second orientation; and the cassette can be moved from the first orientation to the second orientation while the cassette is coupled to the sample processing instrument.
- the sample processing instrument is a mass spectrometer.
- the cassette rotates from the first orientation to the second orientation.
- the cassette moves linearly from the first orientation to the second orientation.
- Certain embodiments further comprise a first plurality of conduits, where: each sample acquisition probe is in fluid communication with an individual conduit of the first plurality of conduits; and each individual conduit of the first plurality of conduits is configured to place a single sample acquisition probe in fluid communication with the sample processing instrument when the cassette is oriented to align the individual conduit with the sample processing instrument.
- each conduit between each sample acquisition probe and the sample processing instrument comprises a valve configured to restrict flow through the conduit.
- the gas supply provides air, nitrogen or carbon dioxide to the probe (e.g., from a gas canister or the ambient air).
- the gas supply is a pressurized gas supply.
- the gas supply is the ambient air and the apparatus comprises a valve or conduit that is open to the ambient air.
- the pressurized gas supply provides a gas to the probe at a pressure between 0.1 psig and 5.0 psig, or more particularly between 0.5 psig and 2.5 psig.
- the pressurized gas supply provides a gas to the probe at a pressure less than 100 psig.
- the solvent comprises water, sterile water, ethanol, and/or an aqueous mixture including from 1 to 25% ethanol.
- Some embodiments further comprise: a second plurality of conduits in fluid communication with the first chamber and the plurality of sample acquisition probes; and a third plurality of conduits in fluid communication with the gas supply (e.g a gas canister or the ambient air) and the plurality of sample acquisition probes.
- each sample acquisition probe in the plurality of sample acquisition probes comprises a reservoir, a first conduit, a second conduit and a third conduit, where: the first conduit is in fluid communication with the first chamber; the second conduit is in fluid communication with the gas supply; and the third conduit is in fluid communication with the sample processing instrument.
- each sample acquisition probe in the plurality of sample acquisition probes comprises a funnel-shaped chamber in fluid communication with the reservoir, the first conduit, the second conduit and the third conduit.
- the funnel-shaped chamber comprises a larger end and a smaller end; and the larger end of the funnel-shaped chamber is proximal to the reservoir.
- Particular embodiments further comprise: a second chamber comprising a cleaning fluid; and a conduit in fluid communication with the second chamber and the plurality of sample acquisition probes.
- the sample acquisition probe is, or is comprised in, the cannula of a surgical instrument.
- the surgical instrument is a laparoscope, a trocar needle, a biopsy guide, or a multiple-lumen catheter.
- the surgical instrument manually operated.
- the surgical instrument is robotic.
- the surgical instrument comprises a tracking probe that can be detected by imaging.
- the imaging comprises visual, fluorescent, US, CT, MRI or OCT imaging.
- each sample acquisition probe of the plurality of sample acquisition probes comprises a distal probe end and the distal probe end comprises a shutter that can be closed to prevent fluid communication outside of the sample acquisition probe.
- the shutter is a balloon that can be inflated to prevent fluid communication outside of the probe.
- the balloon can be inflated with a gas or a liquid.
- the shutter is door that can be closed to prevent fluid communication outside of the probe.
- the shutter is configured such that is can be opened and closed multiple times.
- the shutter is controlled manually.
- the shutter is controlled robotically.
- the sample processing instrument is in electronic communication with a computer that can provide sample analysis.
- the computer provides a visual or auditory read-out of the sample analysis.
- each sample acquisition probe of the plurality of sample acquisition probes comprises a tracking device or dye to track a location of the probe.
- Certain embodiments include an apparatus comprising: a cassette comprising a plurality of medical devices; and a processing instrument coupled to the cassette, where: the medical devices are configured to contact tissue; the processing instrument is configured to receive tissue from the cassette; a first medical device of the plurality of medical devices is in fluid communication with the processing instrument when the cassette is in a first orientation; a second medical device is in fluid communication with the processing instrument when the cassette is in a second orientation; and the cassette can be moved from the first orientation to the second orientation while the cassette is coupled to the processing instrument.
- the plurality of medical devices comprises a plurality of sample acquisition probes.
- the processing instrument is a mass spectrometer.
- the cassette rotates from the first orientation to the second orientation. In certain embodiments, the cassette moves linearly from the first orientation to the second orientation.
- Particular embodiments further comprise a first plurality of conduits, where: each medical device is in fluid communication with an individual conduit of the first plurality of conduits; and each individual conduit of the first plurality of conduits is configured to place a single medical device in fluid communication with the processing instrument when the cassette is oriented to align the individual conduit with the processing instrument.
- each conduit between each medical device and the processing instrument comprises a valve configured to restrict flow through the conduit.
- Some embodiments further comprise: a first chamber comprising a solvent; and a gas supply.
- Specific embodiments further comprise: a second plurality of conduits in fluid communication with the first chamber and the plurality of medical devices; and a third plurality of conduits in fluid communication with the gas supply and the plurality of medical devices.
- Certain embodiments further comprise: a second chamber comprising a cleaning fluid; and a conduit in fluid communication with the second chamber and the plurality of medical devices.
- Particular embodiments include a method for exchanging medical instruments during a medical procedure, where the method comprises: acquiring a first sample acquisition probe from a cassette comprising a plurality of sample acquisition probes, wherein the first sample acquisition probe is acquired from the cassette when the cassette is in a first orientation; obtaining a first tissue sample with the first sample acquisition probe; changing the orientation of the cassette comprising the plurality of sample acquisition probes from a first orientation to a second orientation; acquiring a second sample acquisition probe from the cassette comprising a plurality of sample acquisition probes, where the second sample acquisition probe is acquired from the cassette when the cassette is in a second orientation; and obtaining a second tissue sample with the second sample acquisition probe.
- Some embodiments further comprise priming the sample acquisition probe with solvent prior to obtaining the first tissue sample.
- changing the orientation of the cassette comprising the plurality of sample acquisition probes from a first orientation to a second orientation comprises rotating the cassette.
- changing the orientation of the cassette comprising the plurality of sample acquisition probes from a first orientation to a second orientation comprises linearly translating the cassette.
- obtaining the first tissue sample with the first sample acquisition probe comprises: applying a first fixed volume of a solvent to a first tissue site through the cannula of a surgical instrument; and collecting the applied solvent to obtain a first liquid sample.
- obtaining the second tissue sample with the second sample acquisition probe comprises: applying a second volume of the solvent to a second tissue site through the cannula of the surgical instrument; and collecting the applied solvent to obtain a second liquid sample.
- the first volume of solvent and the second volume of solvent are not applied as a spray.
- the first volume of solvent is applied as a first droplet and wherein the second volume of solvent is applied as a second droplet.
- the surgical instrument is a laparoscope, a trocar needle, or a biopsy guide.
- the surgical instrument is manually operated.
- the surgical instrument is robotic. Certain embodiments further comprise applying a dye to the first tissue site and to the second tissue site.
- the imaging comprises visual, fluorescent, US, CT, MRI or OCT imaging.
- the first volume of solvent and the second volume of solvent are applied using a pressure of less than 100 psig.
- the fixed or discrete volume of a solvent is applied at using a pressure of less than 10 psig.
- the fixed or discrete volume of a solvent is applied at using a mechanical pump to move the solvent through a solvent conduit.
- collecting the applied solvent comprises applying a negative pressure to pull the sample into a collection conduit and/or applying a gas pressure to push the sample into a collection conduit.
- the solvent is applied through a solvent conduit that is separate from the collection conduit.
- the gas pressure is applied through a gas conduit that is separate from the solvent conduit and the collection conduit.
- applying a gas pressure to push the sample into the collection conduit comprises applying a pressure of less than 100 psig.
- the method produces no detectable physical damage to the tissue.
- the method does not involve application of ultrasonic or vibrational energy to the tissue.
- the solvent is sterile.
- the solvent is pharmaceutically acceptable formulation.
- the solvent is an aqueous solution.
- the solvent is sterile water.
- the solvent consists essentially of water.
- the solvent comprises from about 1 to 20% of an alcohol.
- the alcohol comprises ethanol.
- the first volume of solvent is between about 0.1 and 100 pL and wherein the second volume of solvent is between about 0.1 and 100 pL.
- the first volume of solvent is between about 1 and 50 pL and the second volume of solvent is between about 1 and 50 pL.
- collecting the applied solvent is between 0.1 and 30 seconds after the applying step. In specific embodiments, collecting the applied solvent is between 1 and 10 seconds after the applying step.
- the first tissue site is an internal tissue site that is being surgically assessed and wherein the second tissue site is an internal tissue site that is being surgically assessed.
- the first liquid sample and the second liquid sample are collected with a probe.
- the method is an intraoperative or post-operative method.
- the method further comprise subjecting the first tissue sample and the second tissue sample to mass spectrometry analysis.
- the mass spectrometry comprises ambient ionization MS.
- the first tissue sample and the second tissue sample to mass spectrometry analysis comprises determining a first profile corresponding to the first tissue site and a second profile corresponding to the second tissue site. Some embodiments, further comprise comparing the first profile and the second to a reference profile to identify tissue sites that include diseased tissue. Specific embodiments further comprise resecting tissue sites that are identified to include diseased tissue. In certain embodiments, resecting tissue sites comprises laser ablation. Specific embodiments, further comprise comparing the first profile and the second to a reference profile to determine the tissue type at the first tissue site and the second tissue type. Certain embodiments further comprise resecting tissues of an identified type. In particular embodiments, the identified tissue type is a cancerous tissue or a non- cancerous type of organ tissue. In specific embodiments, the method is performed using an apparatus in accordance with exemplary embodiments disclosed herein.
- Certain embodiments include an apparatus for producing samples for mass spectrometry analysis, where the apparatus comprises: a chamber comprising a solvent; a gas supply; a mass spectrometer; and a probe comprising a reservoir, a first conduit, a second conduit, a third conduit, and a vacuum port, where: the first conduit is in fluid communication with the chamber; the second conduit is in fluid communication with gas supply; and the third conduit is in fluid communication with the mass spectrometer.
- the vacuum port is configured as an indented ring that extends around a perimeter of the probe.
- the vacuum port is configured as an end of a channel that extends to a surface of the probe configured to contact tissue.
- the vacuum port is one of a plurality of vacuum ports.
- the plurality of vacuum ports are in fluid communication with a pneumatic channel multiplexer.
- the plurality of vacuum ports are in fluid communication with the pneumatic channel multiplexer via a plurality of pneumatic channels.
- the pneumatic channel multiplexer is a circumferential ring extending around the device.
- Certain embodiments further comprise a vacuum source in fluid communication with the vacuum port.
- the gas supply is a pressurized gas supply.
- Specific embodiments include an apparatus comprising: a plurality of sample acquisition probes coupled to a plurality of conduits, where the plurality of conduits comprises solvent supply conduits and sample acquisition conduits; one or more chambers containing solvent; a plurality of valves configured to control flow of the solvent through the solvent supply conduits; and a sample processing instrument configured to receive a sample, where: each of the plurality of sample acquisition probes and solvent supply conduits can be individually coupled to the one or more chambers containing solvent; and each of the plurality of sample acquisition probes and sample acquisition conduits can be individually coupled to the sample processing instrument.
- the sample processing instrument is a mass spectrometer with an inlet port; the apparatus comprises a pump in fluid communication with the one or more chambers containing solvent; each solvent supply conduit is configured to be coupled to the pump via a Luer lock mechanism; and/or each sample acquisition conduit is configured to be directly coupled to the inlet of the mass spectrometer via a Luer lock mechanism.
- each of the plurality of sample acquisition conduits can be individually coupled to the sample processing instrument via a quick release mechanism.
- the quick release mechanism is a Luer lock or a friction fit coupling.
- each of the plurality of solvent supply conduits can be individually coupled to the solvent supply by a quick release mechanism.
- the quick release mechanism is a Luer lock or a friction fit coupling.
- each of the plurality of sample acquisition probes and sample acquisition conduits can be individually coupled to the sample processing instrument via a quick release mechanism.
- each of the plurality of sample acquisition probes and sample acquisition conduits can be individually coupled to the sample processing instrument via a friction fit coupling.
- each of the plurality of sample acquisition probes and sample acquisition conduits can be individually coupled to the sample processing instrument via a Luer Lock fitting.
- Certain embodiments include a method of obtaining a plurality of samples, the method comprising: obtaining an apparatus as disclosed herein; coupling a first solvent supply conduit to a first sample acquisition probe and to the one or more chambers containing solvent; coupling a first sample acquisition conduit in fluid communication with the first sample acquisition probe to the sample processing instrument; obtaining a first sample with the first sample acquisition probe; de-coupling the first sample acquisition from the sample processing instrument; analyzing the first sample with the sample processing equipment; coupling a second solvent supply conduit in fluid communication with a second sample acquisition probe to the one or more chambers containing solvent; coupling a second sample acquisition conduit in fluid communication with the second sample acquisition probe to the sample processing instrument; obtaining a second sample with the second sample acquisition probe; and analyzing the second sample with the sample processing equipment.
- Particular embodiments further comprise priming the first sample acquisition probe with solvent prior to obtaining the first tissue sample.
- coupling the second sample acquisition conduit to the sample processing instrument is performed while the sample processing instrument is analyzing the first sample.
- Particular embodiments further comprise: de-coupling the second sample acquisition from the sample processing instrument; coupling a third solvent supply conduit in fluid communication with a third sample acquisition probe to the one or more chambers containing solvent; coupling a third sample acquisition conduit in fluid communication with the third sample acquisition probe to the sample processing instrument; obtaining a third sample with the third sample acquisition probe; and analyzing the third sample with the sample processing equipment.
- Some embodiments further comprise: de-coupling the second sample acquisition from the sample processing instrument; coupling the first solvent supply conduit in fluid communication with the first sample acquisition probe to the one or more chambers containing solvent; coupling the first sample acquisition conduit in fluid communication with the first sample acquisition probe to the sample processing instrument; obtaining a third sample with the first sample acquisition probe; and analyzing the third sample with the sample processing equipment.
- Specific embodiments further comprise: de-coupling the second sample acquisition from the sample processing instrument; coupling a third solvent supply conduit in fluid communication with the first sample acquisition probe to the one or more chambers containing solvent; coupling a third sample acquisition conduit in fluid communication with the first sample acquisition probe to the sample processing instrument; obtaining a third sample with the first sample acquisition probe; and analyzing the third sample with the sample processing equipment.
- Certain embodiments include a method for cleaning a medical instrument during a medical procedure, where the method comprises: obtaining a first tissue sample with a first sample acquisition probe when the first sample acquisition probe is in a first location; moving the first sample acquisition probe to a second location; cleaning the first sample acquisition probe when the first sample acquisition probe is in the second location; moving the first sample acquisition probe to the first location; and obtaining a second tissue sample with the first sample acquisition probe when the first sample acquisition probe is in the first location.
- the first sample acquisition probe is located in a cassette, and moving the first sample acquisition probe to the second location comprises rotating the cassette.
- washing the first sample acquisition probe comprises directing a cleaning fluid from a chamber to the first sample acquisition probe via a conduit.
- obtaining the first tissue sample with the first sample acquisition probe comprises: applying a first fixed volume of a solvent to a first tissue site through the cannula of a surgical instrument; and collecting the applied solvent to obtain the first tissue sample.
- obtaining the second tissue sample with the first sample acquisition probe comprises: applying a second fixed volume of the solvent to a second tissue site through the cannula of the surgical instrument; and collecting the applied solvent to obtain the first tissue sample.
- an apparatus and method for obtaining a mass spectrometry profile comprising using a probe to apply a fixed or discrete volume of a solvent to an assay site (e.g ., a tissue site); using the probe to collect the applied solvent to obtain a liquid sample; and subjecting the liquid sample to mass spectrometry analysis.
- a method for assessing tissue samples comprising obtaining a plurality of liquid samples from a plurality of tissue sites in a subject and subjecting the plurality of liquid samples to mass spectrometry.
- Still a further embodiment provides an apparatus for obtaining or producing samples (e.g., from tissues) for mass spectrometry analysis, the apparatus comprising: a chamber comprising a solvent; a gas supply; a mass spectrometer; a probe comprising a reservoir, a first conduit, a second conduit and a third conduit, wherein: the reservoir is in fluid communication with the first conduit, the second conduit and the third conduit; the first (solvent) conduit is in fluid communication with the chamber; the second (gas) conduit is in fluid communication with gas supply (e.g., a gas canisters or the ambient air); and the third (collection) conduit is in fluid communication with the mass spectrometer.
- the gas supply can be a pressurized gas supply.
- the gas supply can comprise the atmosphere surrounding the apparatus.
- the probe is, or is comprised in, the cannula of a surgical instrument.
- the surgical instrument may be a laparoscope, trocar needle, biopsy guide, or multiple-lumen catheter.
- the surgical instrument manually operated.
- the surgical instrument is robotic.
- the probe comprises a distal probe end and the distal probe end comprises a shutter that can be closed to prevent fluid communication outside of the probe.
- the shutter is a balloon that can be inflated to prevent fluid communication outside of the probe.
- the balloon can be inflated with a gas or a liquid.
- the shutter is a door that can be closed to prevent fluid communication outside of the probe. In other aspects, the shutter is configured such that is can be opened and closed multiple times. The shutter may be controlled manually or robotically.
- the first, second or third conduit is more than 1 meter in length. In additional aspects, the first conduit is in fluid communication with the third conduit; and the second conduit is in fluid communication with the third conduit. In further specific aspects, the first conduit is disposed within the third conduit. In other aspects, the second conduit is disposed within the third conduit.
- the first conduit and the second conduit are disposed within the third conduit.
- the first conduit comprises a first distal end; the second conduit comprises a second distal end; the third conduit comprises a third distal end; and the first distal end and the second distal end are located within the third conduit.
- the third distal end is located within the probe.
- the first distal end is located a first distance from the distal probe end; the second distal end is located a second distance from the distal probe end; the third distal end is located a third distance from the distal probe end; the first distance is greater than the third distance; and the second distance is greater than the third distance.
- the first distal end and the second distal end terminate proximal to a sample collection region of the third conduit.
- the sample collection region is located between the first and second distal ends and the third distal end.
- the sample collection region is in fluid communication with the mass spectrometer via the third conduit.
- the apparatus further comprises a control system configured to control; a solvent flow from the chamber through the first conduit to the first distal end; a gas flow from the gas supply through the second conduit to the second distal end; and a sample flow through the third conduit to the mass spectrometer.
- the apparatus may additionally comprise a fourth conduit, wherein the first conduit, the second conduit and the third conduit are each in fluid communication with the fourth conduit.
- the apparatus may further comprise a first valve configured to control flow between the first conduit and the fourth conduit; and a second valve configured to control flow between the second conduit and the fourth conduit.
- the apparatus may further comprise a third first valve configured to control flow between the third conduit and the fourth conduit.
- the gas supply provides air, nitrogen or carbon dioxide to the probe.
- the gas supply is a pressurized gas supply that provides a gas to the probe at a pressure between 0.1 psig and 5.0 psig.
- the pressurized gas supply provides a gas to the probe at a pressure between 0.5 psig and 2.5 psig. In specific aspects, the pressurized gas supply provides a gas to the probe at a pressure less than 100 psig.
- the gas for use in an apparatus of the embodiments may be provided by a pressurized gas supply.
- the gas can be pumped into an apparatus.
- the gas can be pulled through an apparatus by use of a vacuum.
- the vacuum is provided by the mass spectrometer inlet. In further aspects, an additional vacuum system is employed.
- the solvent comprises water. In more specific aspects, the solvent comprises sterile water. In several aspects, the solvent comprises ethanol. In certain specific aspects, the solvent comprises an aqueous mixture including from 1 to 25% ethanol.
- the probe comprises a tracking device or dye to track a location of the probe.
- the apparatus may further comprise a control system configured to control: a solvent flow from the chamber through the first conduit; a gas flow from the gas supply through the second conduit; and a sample flow through the third conduit to the mass spectrometer.
- the control system is configured to: control the solvent flow at a flow rate between 200 and 5000 microliters per minute for a period of time between 1 and 3 seconds; control the gas flow at a flow rate between 0.1 and 15 psig for a period of time between 5 and 50 seconds; and/or control the sample flow for a period of time between 5 and 50 seconds.
- the control system comprises programing that initiates solvent flow.
- the mass spectrometer is in electronic communication with a computer that can provide sample analysis.
- the computer provides a visual or auditory read-out of the sample analysis.
- the apparatus may additionally comprise a waste container in fluid communication with the third conduit.
- the apparatus may further comprise a valve configured to diverge a fluid from the third conduit to the waste container.
- the apparatus may further comprise a pump configured to remove contents of the waste container.
- the apparatus may comprise a pump in fluid communication with the third conduit.
- the pump is configured to increase the velocity of the contents within the third conduit.
- the apparatus may further comprise a heating element coupled to the third conduit. In a specific aspect, the heating element is a heating wire.
- the apparatus may comprise an ionization device in fluid communication with the third conduit.
- the ionization device is an electrospray ionization (ESI) device.
- the ionization device is an atmospheric pressure chemical ionization (APCI) device.
- the ionization device is to form a spray proximal to an inlet for mass spectrometer.
- the third conduit is not directly coupled to the mass spectrometer.
- the apparatus may further comprise a venturi device in fluid communication with the third conduit. In certain aspects, the apparatus does not include device for application of ultrasonic or vibrational energy.
- a method for assessing tissue samples from a subject comprising (a) applying a fixed or discrete volume of a solvent to a tissue site in the subject through the cannula of a surgical instrument; (b) collecting the applied solvent to obtain a liquid sample; and (c) subjecting the sample to mass spectrometry analysis.
- the fixed or discrete volume of a solvent is not applied as a spray.
- the fixed or discrete volume of a solvent is applied as a droplet.
- the surgical instrument is a laparoscope, trocar needle, or biopsy guide. The surgical instrument may be manually operated or robotic.
- the cannulas comprised in a probe having a distal probe end and the distal probe end comprises a shutter that can be closed to prevent fluid from passing out of the cannula of the probe.
- the shutter is a balloon that can be inflated to prevent fluid communication outside of the probe.
- the balloon can be inflated with a gas.
- the shutter is a door than can be closed to prevent fluid communication outside of the probe.
- the shutter can be an iris diaphragm, a mechanical closure, gate, or tapenade.
- the shutter can be manually controlled or may be automated.
- the shutter may be on a timer that activates the shutter after solvent has been in contact with the tissue site for a predetermined time period (e.g at least about 1, 2, or 3 seconds).
- a predetermined time period e.g at least about 1, 2, or 3 seconds.
- the fixed or discrete volume of a solvent is applied at using a pressure of less than 100 psig.
- the fixed or discrete volume of a solvent is applied at using a pressure of less than 10 psig.
- the fixed or discrete volume of a solvent is applied using a mechanical pump to move the solvent through a solvent conduit.
- collecting the applied solvent comprises applying a negative pressure to pull the sample into a collection conduit and/or applying a gas pressure to push the sample into a collection conduit.
- collecting the applied solvent comprises applying a negative pressure to pull the sample into a collection conduit and applying a positive pressure to push the sample into a collection conduit.
- the solvent is applied through a solvent conduit that is separate from the collection conduit.
- the gas pressure is applied through a gas conduit that is separate from the solvent conduit and the collection conduit.
- applying a gas pressure to push the sample into a collection conduit comprises applying a pressure of less than 100 psig.
- the method produces no detectable physical damage to the tissue. In some aspects, the method does not involve application of ultrasonic or vibrational energy to the tissue.
- the solvent may be sterile. In specific aspects, the solvent may be a pharmaceutically acceptable formulation, and further an aqueous solution, and still further sterile water. In further specific aspects, the solvent consists essentially of water. In other aspects, the solvent comprises from about 1 to 20% of an alcohol. In some aspects, the alcohol comprises ethanol. In still additional aspects, the discrete volume of solvent is between about 0.1 and 100 pL. In certain aspects, the discrete volume of solvent is between about 1 and 50 pL. In further aspects, collecting the applied solvent is between 0.1 and 30 seconds after the applying step. In another aspect, collecting the applied solvent is between 1 and 10 seconds after the applying step. In some aspects, the tissue site in an internal tissue site that is being surgically assessed.
- the method additionally comprises collecting a plurality liquid samples from a plurality of tissue sites.
- the liquid samples are collected with a probe.
- the probe is washed between collection of the different samples.
- the probe is disposable and is changed between collection of the different samples.
- the probe comprises a collection tip and further comprising ejecting the collection tip from the probe after the liquid samples are collected.
- the plurality of tissue sites comprises 2, 3, 4, 5, 6, 7, 8, 9 or 10 tissues sites.
- the plurality of tissue sites surrounds a section of tissue that has been surgically resected.
- the resected tissue is a tumor.
- the method is further defined as an intraoperative or post-operative method.
- the mass spectrometry comprises ambient ionization MS.
- subjecting the sample to mass spectrometry analysis comprises determining a profile corresponding to the tissue site.
- the method comprises comparing the profile to a reference profile to identify tissue sites that include diseased tissue.
- Still a further aspect comprises resecting tissue sites that are identified to include diseased tissue.
- the method is performed using an apparatus in accordance with the embodiments and aspects described above.
- the mass spectrometer is in communication with a computer that provides a sample analysis.
- the results of each sample analysis are provided by a visual or auditory output from the computer.
- the results of each sample analysis by the computer can be indicated by a differently colored light that is illuminated or by a different frequency of sound produced.
- the mass spectrometer is a mobile the mass spectrometer.
- the mass spectrometer can comprise an uninterruptable power supply (e.g., a battery power supply).
- the mass spectrometer comprises an inlet that may be closed to keep instrument vacuum.
- the mass spectrometer is separated from the probe by a mesh filter (e.g., to block contamination).
- the reservoir is configured to form a droplet of the solvent.
- the pressurized gas supply provides a gas to the probe at a pressure between 0.1 psig and 5.0 psig.
- the pressurized gas supply provides a gas to the probe at a pressure between 0.5 psig and 2.5 psig.
- the pressurized gas supply provides air to the probe.
- the pressurized gas supply provides an inert gas such as nitrogen or carbon dioxide to the probe.
- a gas supply for use according to the embodiments is at atmospheric pressure.
- the conduit for delivery of gas may be supplied by the atmosphere around the apparatus.
- the apparatus further comprises a pump configured to transfer the solvent from the chamber to the first conduit.
- the apparatus may comprise a first valve configured to control a flow from the third conduit to the mass spectrometer.
- the third conduit is under a vacuum when the first valve is in the open position.
- the apparatus may comprise a second valve configured to control a flow of gas (e.g., pressurized gas) through the second conduit.
- the solvent may comprise water and/or ethanol.
- the probe is formed from polydimethylsiloxane (PDMS) and/or polytetrafluoroethylene (PTFE). In some aspects, the probe is disposable.
- the probe may include a collection tip that is ejectable (e.g. capable of being ejected from the probe).
- the probe comprises a tracking device configured to track a location of the probe.
- the reservoir has a volume between 1 microliter and 500 microliters, between about 1 microliter and 100 microliters or between about 2 microbters and 50 microbters. In additional aspects, the reservoir has a volume between 5.0 microbters and 20 microbters.
- the apparatus may additionally comprise a control system configured to control: a solvent flow (e.g., flow of a fixed or discrete volume of solvent) from the chamber through the first conduit to the reservoir; a gas flow from the gas supply through the second conduit to the reservoir; and a sample flow from the reservoir through the third conduit to the mass spectrometer.
- a solvent flow e.g., flow of a fixed or discrete volume of solvent
- control system is configured to: control the solvent flow at a flow rate between 100 and 5000 microliters per minute (e.g., between 200 and 400 microliters per minute) for a period of time between 1 and 3 seconds; control the gas flow at a flow rate between 1 and 10 psig for a period of time between 10 and 15 seconds; and control the sample flow for a period of time between 10 and 15 seconds.
- control system comprises a trigger or button to initiate solvent flow.
- control system comprises a pedal (i.e., that can be operated by foot action) to initiate solvent flow.
- a pedal i.e., that can be operated by foot action
- control system is configured to control: a solvent flow (e.g., flow rate for a fixed period of time) from the chamber through the first conduit to the reservoir.
- a solvent flow e.g., flow rate for a fixed period of time
- an apparatus of the embodiments does not include a device for producing ultrasonic or vibrational energy (e.g., in sufficient amounts to disrupt tissues).
- a further embodiment provided a method for assessing tissue samples from a subject comprising applying a solvent to a tissue site on the subject, collecting the applied solvent to obtain a liquid sample, and subjecting the sample to mass spectrometry analysis.
- the solvent may be sterile.
- the solvent is pharmaceutically acceptable formulation.
- the solvent is an aqueous solution.
- the solvent may be sterile water or consist essentially of water.
- the solvent may comprise from about 1% to 5%, 10%, 15%, 20%, 25% or 30% of an alcohol.
- the solvent comprises 0.1% to 20% of an alcohol, 1% to 10% of an alcohol or 1% to 5% 1% to 10% of an alcohol (e.g ., ethanol).
- the alcohol may be ethanol.
- applying the solvent to the tissue comprises applying a discrete volume of solvent to the tissue site.
- the solvent is applied in a single droplet.
- the solvent is applied in a discrete number of droplets from 1 to 10.
- the solvent is applied to the sample from the reservoir via a channel independent of the gas.
- the solvent is applied to the sample under low pressure.
- the solvent is applied by a mechanical pump such that solvent is applied to the tissue site (e.g., moved into a reservoir where it is in contact with the tissue site) with minimal force thereby exerting minimal pressure (and producing minimal damage) at a tissue site.
- the low pressure may be less than 100 psig, less than 90 psig, less than 80 psig, less than 70 psig, less than 60 psig, less than 50 psig, or less than 25 psig. In some embodiments, the low pressure is from about 0.1 psig to about 100 psig, from about 0.5 psig to about 50 psig, from about 0.5 psig to about 25 psig, or from about 0.1 psig to about 10 psig. In particular aspects, the discrete volume of solvent is between about 0.1 and 100 pL, or between about 1 and 50 pL. In further aspects, collecting the applied solvent is between 0.1 and 30 seconds after the applying step.
- collecting the applied solvent is between 1 and 10 seconds after the applying step (e.g., at least 1, 2, 4, 5, 6, 7, 8 or 9 seconds).
- a method of the embodiments does not involve application of ultrasonic or vibrational energy to a sample or tissue.
- a method of the embodiments comprises applying a fixed or discrete volume of a solvent (e.g., using mechanical pump) to a tissue site through a solvent conduit.
- the fixed or discrete volume of a solvent is moved through a solvent conduit into a reservoir where it is in direct contact with a tissue site (e.g., for 0.5-5.0 seconds).
- collecting the applied solvent comprises applying a negative pressure to pull the sample into a collection conduit and/or applying a gas pressure to push the sample into a collection conduit.
- the solvent is applied through a solvent conduit that is separate from the collection conduit.
- a gas pressure is applied to push the sample into the collection conduit the gas pressure is applied through a gas conduit that is separate from the solvent conduit and the collection conduit.
- the applied gas pressure of less than 100 psig.
- the gas pressure is preferably less than 10 psig, such as 0.1 to 5 psig.
- a method of the embodiments is defined as producing no detectable physical damage to the tissue being assessed.
- the method may additionally comprise collecting a plurality liquid samples from a plurality of tissue sites.
- the device e.g the probe
- a device used to collect the samples includes a disposable collection tip (probe) that can be changed between each sample collection.
- the collection tip may be ejectable (e.g. capable of being ejected from the device).
- the plurality of tissue sites comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or more tissues sites in vivo.
- the plurality of tissue sites surround a section of tissue that has been surgically resected (e.g., ex vivo).
- the resected tissue is a tumor.
- the method may be defined as an intraoperative method.
- a further embodiment provides a method of identifying a sampled tissue site and a method to communicate location of the site to the device (probe) operator.
- Identification of a sampled tissue site allows the operator to access the molecular information recorded at sampled tissue site at a time after sampling molecules collected from the tissue.
- At least three types of identification approaches are recognized.
- an exogenous material is attached to the sampled tissue site that identifies the sampled molecular information.
- the device (probe) is equipped with a tracking sensor/emitter that allows recording the location of the probe (device) and communication to an imaging device when the molecular information is sampled.
- the tissue region is modified so that the site may be easily identified after harvesting tissue molecules.
- materials that may be attached to the sampled tissue site include, for example, a suture, a surgical clip, a biocompatible polymer that adheres to the tissue, or an RFID chip that is attached to a magnetic bead that allows easy reading and removal.
- the probe may contain an RF emitter that is part of a RF surgical tracking system, an ultrasound emitter or reflector that is part of an intra-operative US imaging system.
- the tracking system records location of the probe in the associated imaging system (e.g., RF, US, CT, MRI) that may be in communication with the device.
- the operator may then identify any of the sampled tissue sites at a later time by referring to the recorded image(s) that can indicate the location of sampled sites to the operator.
- the tissue is modified.
- a laser source in communication with the probe may be used to ablate or coagulate a pattern into the tissue that identifies the sampled site. Any of these three approaches may be combined. For example, approach 1, 2 and 3 could be combined wherein an exogenous material is attached to the tissue site after harvesting tissue molecules and a laser patterns the exogenous tissue while an RF sensor records location of the harvest location and communicates to the imaging device.
- the mass spectrometry comprises ambient ionization MS.
- a probe in contact with a tissue site can be in fluid communication with the MS via a conduit.
- conduit between the probe and tissue site is less than about 10m, 8m, 6m or 4m from MS.
- the conduit is between about 0.5, 1.0, 1.5, 2.0, 2.5, 3.0 and 4.0m in length.
- subjecting the sample to mass spectrometry analysis may comprise determining a profile corresponding to the tissue site.
- the method may additionally comprise comparing the profile to a reference profile to identify tissue sites that include diseased tissue.
- the method also comprises resecting tissue sites that are identified to include diseased tissue.
- the method is performed using an apparatus in accordance with any of the embodiments and aspects described above.
- the invention provides an ex vivo method for assessing tissue samples comprising obtaining a plurality of liquid samples from a plurality of tissue sites in a subject, subjecting the plurality of liquid samples to mass spectrometry to obtain a plurality of profiles corresponding to the tissue sites, and comparing the plurality of profiles to reference profiles to identify tissue sites that include diseased tissue.
- the liquid samples are comprised in a solvent.
- the diseased tissues comprise cancer cells.
- the diseased tissue sites for assessment by methods and devices of the embodiments comprise (or are suspected of comprising) cancer cells.
- Cancer cells that may be assessed according to the embodiments include but are not limited to cells or tumor tissues from a thyroid, parathyroid, lymph node, bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, pancreas, prostate, skin, stomach, testis, tongue, or uterus (or tissues surrounding such tumors).
- the cancer may be a neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinom
- the cancer is a thyroid cancer, brain cancer (e.g., a glioma), a prostate cancer, a breast cancer (e.g., a triple negative breast cancer), a pancreatic cancer (e.g. , a pancreatic ductal adenocarcinoma), acute myeloid leukemia (AML), melanoma, renal cell cancer or a cancer that has metastasized to a lymph node.
- brain cancer e.g., a glioma
- a prostate cancer e.g., a triple negative breast cancer
- a pancreatic cancer e.g. , a pancreatic ductal adenocarcinoma
- AML acute myeloid leukemia
- melanoma renal cell cancer or a cancer that has metastasized to a lymph node.
- sample or“liquid samples” can refer to extracts from tissues or other biological specimens (e.g., extracts comprising proteins and metabolites) obtained by contacting tissue or biological specimen with a solvent according to the embodiments.
- a sample can be an extract from a non-biological specimen, such as the surface on an object (e.g., a forensic sample).
- essentially free in terms of a specified component, is used herein to mean that none of the specified components has been purposefully formulated into a composition and/or is present only as a contaminant or in trace amounts. The total amount of the specified component resulting from any unintended contamination of a composition is therefore well below 0.01%. Most preferred is a composition in which no amount of the specified component can be detected with standard analytical methods.
- “a” or“an” may mean one or more.
- the words“a” or“an” when used in conjunction with the word “comprising”, the words“a” or“an” may mean one or more than one.
- “another” or“a further” may mean at least a second or more.
- the terms“conduit” and“tube” are used interchangeably and refer to a structure that can be used to direct flow of a gas or liquid.
- FIG. 1 Representative schematic of a front view of an apparatus for exchanging medical devices.
- FIG. 2 Representative schematic of a side view of an apparatus for exchanging medical devices
- FIG. 3 Representative schematic of a front view of an apparatus for exchanging medical devices in a first position.
- FIG. 4 Representative schematic of a front view of an apparatus for exchanging medical devices in a second position.
- FIG. 5A Representative schematic of a top view of an apparatus for exchanging medical devices.
- FIG. 5B Representative schematic of a top view of one embodiment of an apparatus for exchanging medical devices.
- FIG. 5C Representative schematic of a top view of a second embodiment of an apparatus for exchanging medical devices.
- FIG. 5D Photographic representation of a top view of one embodiment of an apparatus for exchanging medical devices during use.
- FIG. 5E Photographic representation of a top view of the embodiment of FIG.
- FIG. 6 Representative schematic of a mass spectroscopy probe for minimally invasive surgery.
- FIG. 7 Multilumen tubing for use with the mass spectroscopy probe for minimally invasive surgery.
- FIG. 8 A cannula and trocar needle for housing and inserting the mass spectrometry probe for minimally invasive surgery.
- FIG. 9 Representative schematic of a mass spectrometry probe for minimally invasive surgery. This embodiment includes a shutter for occluding the probe.
- FIG. 10 Mass spectra of mouse brains tissue section from the minimally invasive mass spectrometry probe using Q Exactive Orbitrap Mass Spectrometer. PTFE tubing of 1.5 meters was used with an inner diameter of 2 mm and outer diameter of 4 mm.
- FIG. 11 Mass spectra of mouse brains tissue section from the minimally invasive mass spectrometry probe using Q Exactive Orbitrap Mass Spectrometer. PTFE tubing of 3.5 meters was used with an inner diameter of 2 mm and outer diameter of 4 mm.
- FIG. 12 Mass spectra of mouse brains tissue section from the minimally invasive mass spectrometry probe using Q Exactive Orbitrap Mass Spectrometer. PTFE tubing of 4.5 meters was used with an inner diameter of 2 mm and outer diameter of 4 mm.
- FIG. 13 Mass spectra of mouse brain tissue section from the minimally invasive mass spectrometry probe using Q Exactive Orbitrap Mass Spectrometer.
- FIG. 14 Representative schematic of a mass spectrometry probe for minimally invasive surgery. Depicted on the lower left is the multichannel probe tip.
- FIG. 15 Simulated laparoscopic surgery shown from a laparoscopic optical camera on a simulated uterus. Shown on the right are forceps holding the minimally invasive mass spectrometry probe.
- FIG. 16 Mass spectra generated from a 16 pm mouse brain section using 4.5 meter long tubing compared to the water background.
- FIG. 17 Mass spectra generated with the minimally invasive mass spectrometry probe using Q Exactive Orbitrap Mass Spectrometer and conduits of 1.5-4.0 mm diameter.
- FIG. 18 Depiction of the mechanics of a balloon shutter for use with the minimally invasive mass spectrometry probe.
- FIG.19 Mass spectra of human lung tissue section from the minimally invasive mass spectrometry probe using Q Exactive Orbitrap Mass Spectrometer.
- FIG. 20 Diagram of washing chamber for minimally invasive mass spectrometry probe.
- FIG. 21 Representative schematic with of a device without a pneumatic applicator that can provide a vacuum pressure to a surface in contact with the device.
- FIG. 22 Representative schematic with of a device with a pneumatic applicator that can provide a vacuum pressure to a surface in contact with the device ⁇
- FIG. 23 End view of a device with the vacuum ports that includes an additional indented ring that extends around the perimeter of the device and provides vacuum pressure to the surface in contact with the device.
- the instant application provides apparatus and methods for exchanging and/or cleaning medical devices using surgical procedures.
- a cartridge contains medical devices that can be exchanged by changing the orientation of the cartridge.
- FIG. 1 a front schematic view is shown of an apparatus 100 comprising a cassette 110 further comprising a plurality of sample acquisition probes 120.
- cassette 110 is configured to rotate in a clockwise direction.
- FIG. 2 illustrates a side schematic view of an alternate configuration of apparatus 100 that moves linearly rather than rotates. It is understood that the present disclosure includes both embodiments and the principles of operation of each embodiment are equivalent. Accordingly, aspects of rotating components can be equally applied to linearly translating components, and vice versa.
- Cassette 110 is coupled to a sample processing instrument 130 via a coupling mechanism 140.
- Apparatus 100 is configured such that one of the sample acquisition probes 120 is in fluid communication with a sample processing instrument 130 while the remaining sample acquisition probes 120 remain ready for use.
- apparatus 100 allows medical personnel to quickly and efficiently switch between the sample acquisition probes 120. The ability can to switch to a different probe for each sample acquisition can reduce cross contamination between different samples acquired and delivered to analysis instrument 130.
- sample processing instrument 130 may be a mass spectrometer, while in other embodiments sample processing instrument 130 may be any instrument suitable for processing a sample, including for example analyzing or storing the sample.
- Coupling mechanism 140 couples a sample acquisition conduit 180 to sample processing instrument 130 to allow a sample acquired by a sample acquisition probe 120 to be processed.
- Coupling mechanism 140 is configured to couple an individual conduit 180 via any suitable manner that allows for de-coupling and coupling of sample acquisition conduits 180 when the orientation of cassette 110 is changed.
- coupling mechanism 140 may include a flexible seal 145 that engages a sample acquisition conduit 180 (in fluid communication with a first probe 120) so that the sample acquisition conduit 180 is in fluid communication with sample processing instrument 130 when cassette 110 is in a particular orientation. As the orientation of the cassette 110 is changed, flexible seal 145 can disengage such that the conduit 180 is no longer in fluid communication with sample processing instrument 130.
- a different sample acquisition conduit 180 (in fluid communication with a second probe 120) is engages flexible seal 145 such that the sample acquisition conduit 180 is in fluid communication with sample processing instrument 130.
- flexible seal 145 may be elastomer or other suitable polymer.
- FIGS. 3 and 4 another embodiment of an apparatus 100 includes the capability to wash a sample acquisition probe 120 after use.
- This embodiment includes a chamber 150 in fluid communication with a sample acquisition probe 120 via a conduit 155.
- Chamber 150 comprises a cleaning fluid that can be directed to a sample acquisition probe 120 via conduit 155 in order to clean the probe after it has been used.
- Cassette 110 can then be rotated to provide a clean sample acquisition probe 120 for each sample procedure.
- sample acquisition probe 120 in location 1 at the top of FIG. 3 is originally designated as the working port in fluid communication with a sample processing instrument (e.g . mass spectrometer).
- sample acquisition probe 120 in location 1 can be used to acquire a sample and deliver it to the sample processing instrument.
- cassette 110 can then be rotated clockwise as shown in FIG. 4.
- sample acquisition probe 120 in location 6 is now at the working port location and can be used to acquire and deliver a different sample to the sample processing instrument.
- Sample acquisition probe 120 in location 1 is now in fluid communication with chamber 150 and can be cleaned. Cleaning fluid from chamber 150 can be directed through sample acquisition probe 120 to remove any material that remains from the previous sample acquisition procedure. This provides a clean sample acquisition probe 120 for subsequent procedures using the sample acquisition probe 120 in location 1 as cassette 110 is rotated.
- cassette 110 can then be rotated to as needed to acquire multiple samples.
- the probe will be cleansed of potential contamination that could affect subsequent sample acquisitions with the probe.
- apparatus 100 includes a rotating or translating cassette of sample acquisition probes. Instead, there are two sample acquisition probes 120. One sample acquisition probe 120 is used sample acquisition and analysis while the other probe is replaced with a clean probe.
- apparatus 100 includes one or more chambers 160 comprising a solvent, including for example, water or another fluid (delivered via a solvent supply conduit 165) suitable for use in sample acquisition.
- apparatus 100 comprises a gas supply 170 and conduit 175. During use, solvent from chamber 160 and gas from gas supply 170 can be directed through a sample acquisition probe 120 to assist in acquiring a sample from a sample site.
- coupling mechanism 141 is a quick release coupling mechanism.
- a quick release coupling mechanism is defined as a mechanism that allows for coupling and de-coupling of components without the use of external tools.
- sample acquisition conduit 180 and processing instrument 130 can be coupled and de-coupled via coupling mechanism 141 in an efficient manner (e.g. less than five seconds) without the need to use external tools to perform the coupling and de-coupling process.
- coupling mechanism 141 may comprise a friction fit to couple and seal conduit sample acquisition 180 to processing instrument 130.
- coupling mechanism 141 may comprise a Luer Lock to couple and seal conduit 180 to processing instrument 130.
- a third sample acquisition probe 120 (e.g . a new probe or a probe that has been previously cleaned) with sample acquisition conduit 180 can be readied for use.
- sample acquisition conduit 180 for the second probe is removed from processing instrument 130, and a sample acquisition conduit 180 coupled to a third sample acquisition probe 120 can be coupled to processing instrument 130.
- a third sample can then be obtained while a fourth probe 120 and sample acquisition conduit 180 is readied for use.
- the process can then be repeated to allow a different sample acquisition probe 120 to be used for each sample. This procedure allows the sample acquisition process to proceed efficiently because a clean, uncontaminated sample acquisition probe 120 and sample acquisition conduit 180 is ready for use after each sample is acquired.
- Apparatus 100 further comprises solenoid valves (not labeled in FIG.
- the solenoid valves can be controlled to allow solvent (e.g. water) to flow through the conduit when apparatus 100 is being used to acquire and analyze a sample.
- solvent e.g. water
- the solenoid valves can be positioned to restrict the solvent flow and allow air to flow to processing instrument 130.
- a control system can be utilized to control operation of the solenoid valves and fluid flow through the conduits.
- FIG. 5B a schematic view is shown of apparatus 100 in which syringe pumps 161 with Luer Lock fittings 162 are used to couple to the conduits and provide solvent flow.
- FIG. 5C shows and embodiment similar to that of FIG. 5B, but syringe pumps 161 utilize a needle fitting 163 to couple to the conduits and provide solvent flow.
- FIGS. 5D and 5E provide photographs of an apparatus 100 similar to FIG. C during use.
- the embodiment shown in FIGS. 5D and 5E incorporate a needle fitting providing fluid flow from the syringe activated by the syringe pump.
- the solenoid valves control fluid flow during sample acquisition as previously described.
- the instant application provides methods and devices for minimally invasive molecular assessment of samples, such as tissue samples.
- the methods can be used to assess multiple tissue sites during an operation (or biopsy) of the tissue. This feature allows for accurate identification of diseased tissues (e.g tissue sites retaining cancer cells) in“real-time” allowing surgeons to more accurately address only the diseased tissue relative to surrounding normal tissues.
- the methods disclosed here can involve delivery of a fixed or discrete volume of solvent to a tissue site, followed by collection of a liquid sample from the site and analysis of the liquid sample by mass spectrometry.
- solvent is applied as discrete droplets and at low pressure.
- These methods allow for accurate collection of samples from a distinct tissue site while avoiding damage to the tissue being assessed.
- the resulting mass spectrometry profile from collected samples allows for differentiation of diseased versus normal tissue sites.
- the method can be repeated at multiple sites of interest to very accurately map molecular changes (e.g., in a tissue).
- the profiles of samples could be differentiated even without the use of an ionization source.
- methods of the embodiments could be used in conjunction with an ionization source, the use of such a source is not required.
- These methodologies can allow assessment of plurality of tissue sites over a short range of time, thereby allowing for very accurate assessment of the boundaries of diseased versus normal tissues.
- the methods detailed herein can be used to collect and analyze samples from a wide range of sources.
- the methods can be used to assess surgical, forensic, agriculture, pharmaceutical, and/or oil/petroleum samples.
- the materials (PDMS and PTFE) and solvent (e.g ., water only solvents) used in the devices of the embodiments are biologically compatible, such that they can be used in surgery in for real-time analysis.
- the devices can be very compact, it can be hand-held and used in used in minimally invasive surgical procedures, or non-surgical procedures.
- the present invention provides devices of extended length and increased compactness for delivery of fixed or discrete volumes of solvents to tissues for use in minimally invasive surgeries.
- these methods can be encapsulated in a variety of form factors such as a conduit, ranging from 0.5 mm to 10.0 mm inner diameter (e.g., with an inner diameter of between about 1.0 and 5.0; 1.0 and 10.0; 2.0 and 8.0; or 5.0 and 10.0 mm).
- the site of delivery of a fixed or discrete volume of solvent, followed by collection of a liquid sample may be inside the body, such as a surgical site.
- two smaller conduits may be inserted into a third, larger, conduit to create a multi-lumen catheter.
- the multi-lumen catheter can have 2, 3, 4, 5, 6 or more luminal spaces with each having an internal diameter of, e.g., 0.05 to 5.0 mm; 0.1 to 5.0 mm; 0.25 to 3.0mm; or 0.5 mm to 10.0 mm.
- the multi-lumen catheter may be attached to a mass spectrometry device for analysis of sample tissues inside the body during surgery, while avoiding unnecessary damage to surrounding tissues.
- the device may be used through cannulas or catheters in minimally invasive surgical or endoscopy procedures, or may be used in non-surgical procedures through needle guides or biopsy guides.
- the present invention can be integrated into a robotic surgical system allowing several regions of the human body cavity to be quickly sampled and analyzed.
- the device be used to analyze tissues using a database of molecular signatures and machine learning algorithms, allowing diagnosis in real time for each sampled region.
- the present invention may be used in a wide variety of oncological and other surgical interventions, such as endometriosis, for which real time characterization and diagnosis of tissues are needed.
- the present disclosure provides an attachment to the probe, for fine manipulation of the probe during minimally or non-invasive procedures.
- the attachment to the probe may be a fin.
- the present invention may further comprise a device for grasping the probe, external to the probe, in order to manipulate the probe during laparoscopic procedures.
- the grasping device may be used to hold, rotate, or move the probe, or may grasp the fin attached to the probe, in order to move or rotate the probe.
- the present invention maintains a reservoir using a multi-lumen catheter with recessed ports for depositing water and nitrogen gas during laparoscopic surgical procedures.
- a multi-lumen catheter may be formed, for example, using a multi-lumen extrusion as is well known in the art. These catheters may be utilized in any cannula. The most commonly used cannulas are of 5 mm and 10 mm diameters, and are typically used for laparoscopic surgeries.
- the present disclosure provides tools, devices and methods for manipulation of the probe during endoscopy.
- multi -lumen tubing may be used with an external vacuum source in order to attach the probe to the tissue surface while analyzing.
- the present invention provides a shutter system that occludes the orifice of the minimally invasive surgical device.
- this shutter system may be a catheter balloon that is integrated within the device or added separately to the device.
- the shutter, or balloon may close the probe tip, preventing unwanted biological material from entering the device, including the lumens and tubing, upon insertion of the catheter into the patient.
- the shutter or balloon may disallow endogenous biological fluids from entering the mass spectrometer after analysis has been initiated, thus preventing contamination of the results. Finally, closing of the shutter or balloon may prevent excess nitrogen gas and water from entering the body.
- the present invention may be used with robotic manipulation.
- the technologies of the present invention may integrate in modem surgical theaters through an accessory port, or via a robotic arm. These devices may be integrated into robotic systems such as the Intuitive Surgical da Vinci robotic surgical system.
- a device of the present invention may have its own dedicated arm in a robotic system, or be handled by robotic graspers by incorporating a“fin” onto the probe. Smaller and larger diameters can also be used to be coupled to any existing catheters, cannulas and also needle/biopsy guides.
- a tracking probe can be integrated with this device in order to display and record where the tissue sample has been analyzed to better assist the surgeon in localizing the sampling points both intraoperatively or otherwise.
- an ultrasound emitter on the device may be utilized to display the probe when sampling.
- the probe may be integrated with a tracking device based on radio frequency technology, such as the Biosense Webster Carto system. In that case, the probe may display the device/sampling location on any of a variety of imaging modalities, such as intraoperative UltraSound (US)/Computed Tomogrpahy (CT)/Magnetic Resonance Imaging (MRI)/ Optical Coherence Tomography (OCT).
- US intraoperative UltraSound
- CT Computed Tomogrpahy
- MRI Magnetic Resonance Imaging
- OCT Optical Coherence Tomography
- fluorescent imaging and molecular dyes may be used to track the analyzed areas and charted to provide 2-dimensional or 3-dimensional spatial imaging. More simply, the probe tip may be coated with a surgical dye which is then stamped on the tissue to track the region analyzed. Yet another tracking approach is to integrate an RF emitter into the probe so that the spatial location may be tracked.
- the probe of the present invention may be used to assist surgeons and medical professionals during minimally invasive surgical interventions by providing comprehensive and definitive diagnostic molecular information in vivo and in real time, without necessarily causing damage or alteration to the patient’s native living tissues.
- the handheld MasSpec Pen has demonstrated a capacity to do this during non- laparoscopic/endoscopic surgical procedures (U.S. Patent Application No. 15/692,167 incorporated herein by reference, in its entirety).
- the present invention is suitable for ex vivo analysis of tissues (fresh, frozen, sections, biopsies) or other clinical specimens that might be examined by a pathologist, and may be used for chemical analysis of any given sample for which direct analysis is desired in confined and spatially limited domains (animals, plants, explosives, drugs, etc).
- tissue types may be analyzed as well, including but not limited to, breast, kidney, lymph node, thyroid, ovary, pancreatic and brain tissues.
- the probe of the present invention may be used in conjunction with surgical instruments for the treatment of a disease.
- surgical instruments may be used to excise or ablate cells or tissues, including, but not limited to, laser ablation tools, tools for cauterization or electrocauterization, or tools for the manual dissection of tissue such as a scalpel.
- a device of the embodiments further comprises a shutter system that can occlude the orifice, and creates a separation between the reservoir and the tissue.
- the shutter system can activate after the droplet rests for 3 seconds and before the droplet is transported to the mass spectrometer.
- the shutter can be an iris diaphragm, a mechanical closure, gate, or tapenade.
- An additional design for the shutter is a balloon mechanism, which seals the exterior of the device from the tissue. The balloon can be positions on the distal end of the conduit, e.g., perpendicular to the pen or probe.
- the balloon When activated, the balloon expands and fills up the reservoir towards the direction of the tissue. This accomplishes at least 3 things: first it gently lifts the pen tip off of the tissue using the inflated balloon, insuring that there is no damage to the tissue. This is to ensure that the probe remains nondestructive and biocompatible in case the analyzed tissue is determined to be‘normal’. Secondly, it seals the solvent droplet that is inside the reservoir and prevents leakage or absorbance of lipids after the sampling window. Thirdly, it creates a seal at the end of the conduit, which will allow for more effective transfer of the droplet to the mass spectrometer.
- a reservoir includes using a multi-lumen catheter, e.g., with recessed ports for depositing water and nitrogen gas.
- the reservoir also retains the water during the extraction period.
- a multi-lumen catheter can be formed for example using a multi-lumen extrusion as is well known in the art. It has been demonstrated that these catheters can be utilized in any cannula, most commonly 5mm and 10mm diameters, for laparoscopic surgeries. This technology is compatible with robotic manipulation such as the Intuitive Surgical da Vinci robotic surgical system.
- the Laparoscopic/Endoscopic probes will easily integrate in current surgical theaters through an accessory port or via a robotic arm. Smaller and larger diameters can also be used to be coupled to any existing catheters, cannulas and also needle/biopsy guides.
- a probe system of the embodiments can incorporate additional valves.
- micro-solenoid valves can be located at each conduit, e.g., at the distal end of the sampling probe. These will be individually controlled by an arduino, microcontroller, or signal. In some cases the value operation is automated. In other cases it can be manually controlled.
- valves are positioned in the inner wall of the solvent conduit sealing the conduits. Thus, by using such values, only two or even one conduit can be used in the sampling operation. For example, a delivering solvent conduit and a return conduit to transfer the droplet to the mass spectrometer. Additional micro-solenoids could be implanted to have more control. For example, three or four micro-solenoids can be into the probes of the embodiments.
- Laparoscopic/Endoscopic probes of the embodiments is a‘fin’ that can be grasped by forceps, robotic tools, or laparoscopic graspers. This will allow the probe to be used in a variety of modalities without sacrificing resolution or sensitivity.
- the fin itself is a gradual sloped protrusion from the exterior of the conduit running parallel to said conduit. It is textured to provide extra traction for the grasping mechanism.
- a tracking probe can be integrated with this device in order to display and record where the tissue sample has been analyzed to better assist the surgeon in localizing the sampling points both intraoperatively or otherwise.
- an ultrasound emitter on the device may be utilized to display the probe when sampling.
- the probe can be integrated with a tracking device based on radio frequency technology, such as the e.g., Biosense Webster Carto system. With this approach, the probe displays the device/sampling location on any various imaging modalities like intraoperative UltraSound (US)/Computed Tomography (CT)/Magnetic Resonance Imaging (MRI)/ Optical Coherence Tomography (OCT).
- US intraoperative UltraSound
- CT Computed Tomography
- MRI Magnetic Resonance Imaging
- OCT Optical Coherence Tomography
- tissue sites that are assessed by a probe of the embodiments can be marked.
- a dye that is up-taken by cancerous cells and normal cells which will mark where the probe has been placed.
- a chemical dye can be delivered using an additional conduit in the catheter or by using a multilumen catheter.
- An alternative delivery of a tracking dye is to dissolve it in the solvent that we use to analyze the tissue.
- one advantage of using a dye within the solvent is that it will directly correlate with where the tissue sample was taken, instead of the peripheral region.
- the chemical dye would be present in the mass spectra and would have to be distinguished from biomolecules in a sample.
- the dye may be visible (e.g., in white operating room light).
- the dye may be a fluorescent dye.
- the pen tip can be coated with a surgical dye, which is then stamped on the tissue to track the region analyzed.
- a tracking approach can be used to virtually map the tissues sites analyzed.
- a RF emitter can be integrated into a probe so that the spatial location may be tracked.
- dyes or probe tracking
- tissues analyzed can be charted to provide 2 dimensional and 3 dimensional spatial imaging.
- a probe system can include a filter.
- a filter can prevent biological tissue from going into the conduits.
- a filter mesh system can be incorporated within the device to prevent smaller bodies of tissue, protein aggregates, or coagulated cell clusters from entering. This mesh could be placed at the opening and have contact with the tissue, or be positioned higher up within the probe, such that no tissue contact occurs.
- a filter mesh comprises average aperture sizes of less than about 1.0, 0.5, 0.25 or 0.1 mm. Since solid matter can damage a mass spectrometer, such a filter system can increase instrument lifespan without negatively effecting signal detected.
- an endoscopic/laparoscopic probe of the embodiments is integrated with a microcontroller, user interface, and/or associated hardware that will operate with appropriate software.
- a light such as a LED will be incorporated to provide visual feed back to the user, for example, to indicate that the probe is ready for sampling, in the process of doing so, or needs to be replaced/repaired.
- Acoustic feedback can also be used, for instance, to let the user know what step of the process the device is in ( e.g since physical cues may be unavailable laparoscopically).
- a user interface system can also be integrated with the device, such as in a foot pedal and buttons on the housing of the probe.
- the present disclosure provides methods of determining the presence of diseased tissue (e.g., tumor tissue) or detecting a molecular signature of a biological specimen by identifying specific patterns of a mass spectrometry profile.
- Biological specimens for analysis can be from animals, plants or any material (living or non-living) that has been in contact with biological molecules or organisms.
- a biological specimen can be samples in vivo (e.g. during surgery) or ex vivo.
- a profile obtained by the methods of the embodiments can correspond to, for example, proteins, metabolites, or lipids from analyzed biological specimens or tissue sites. These patterns may be determined by measuring the presence of specific ions using mass spectrometry.
- Some non-limiting examples of ionizations methods that can be coupled to this device include chemical ionization, laser ionization, atmospheric-pressure chemical ionization, electron ionization, fast atom bombardment, electrospray ionization, thermal ionization.
- Additional ionization methods include inductively coupled plasma sources, photoionization, glow discharge, field desorption, thermospray, desorption/ionization on silicon, direct analysis in real time, secondary ion mass spectroscopy, spark ionization, and thermal ionization.
- the present methods may be applied or coupled to an ambient ionization source or method for obtaining the mass spectral data such as extraction ambient ionization source.
- Extraction ambient ionization sources are methods with, in this case, liquid extraction processes dynamically followed by ionization.
- extraction ambient ionization sources include air flow-assisted desorption electrospray ionization (AFADESI), direct analysis in real time (DART), desorption electrospray ionization (DESI), desorption ionization by charge exchange (DICE), electrode- assisted desorption electrospray ionization (EADESI), electrospray laser desorption ionization (ELDI), electrostatic spray ionization (ESTASI), Jet desorption electrospray ionization (JeDI), laser assisted desorption electrospray ionization (LADESI), laser desorption electrospray ionization (LDESI), matrix-assisted laser desorption electrospray ionization (MALDESI), nanospray desorption electrospray ionization (nano-DESI), or transmission mode desorption electrospray ionization (TM-DESI).
- AFADESI air flow-assisted desorption electrospray ionization
- DART direct analysis in real
- ionization efficiency can be optimized by modifying the collection or solvent conditions such as the solvent components, the pH, the gas flow rates, the applied voltage, and other aspects which affect ionization of the sample solution.
- the present methods contemplate the use of a solvent or solution which is compatible with human issue.
- solvent which may be used as the ionization solvent include water, ethanol, methanol, acetonitrile, dimethylformamide, an acid, or a mixture thereof.
- the method contemplates a mixture of acetonitrile and dimethylformamide.
- the amounts of acetonitrile and dimethylformamide may be varied to enhance the extraction of the analytes from the sample as well as increase the ionization and volatility of the sample.
- the composition contains from about 5: 1 (v/v) dimethylformamide: acetonitrile to about 1:5 (v/v) dimethylformamide: acetonitrile such as 1: 1 (v/v) dimethylformamide: acetonitrile.
- the solvent for use according to the embodiments is a pharmaceutically acceptable solvent, such as sterile water or a buffered aqueous solution.
- Example 1 Minimally invasive probe for mass spectrometry design
- the system developed consists of three main parts: 1) a syringe pump that is programmed to deliver a discrete solvent volume using a controlled flow rate; 2) tubing systems integrated to two-way pinch valves for controlled solvent and gas transport; 3) a probe tip which is used for direct sampling of biological tissues.
- the tubing systems and probe tip are also integrated into a minimally invasive surgical device such as a cannula or catheter for use in laparoscopic or endoscopic surgeries.
- Several iterations of the system were explored and optimized with the ultimate goal of minimizing tissue damage, maximizing tissue-analyte extraction, and maximizing solvent transmission to the mass spectrometer.
- FIG. 6 shows a schematic figure of one example of a minimally invasive apparatus for analyzing biological tissue.
- the syringe pump feeds solvent and gas into the minimally invasive probe via micro- PTFE tubing.
- the probe maintains contact with the sample, retains solvent during interaction with the tissue.
- the tip was manufactured using 3D-printing and is made of biologically compatible polydimethylsiloxane (PDMS).
- PDMS biologically compatible polydimethylsiloxane
- the probe has three main ports: one for the incoming tubing system, a central port for gas delivery, and a third for the outgoing tubing system. All ports come injunction at a small reservoir where the droplet is retained and exposed to the tissue sample for a controlled amount of time, allowing for efficient extraction of molecules. The size of the reservoir determines the spatial resolution of the device. A solvent volume of 10 pL is exposed to the tissue sample.
- FIG. 7 shows the three conduit tubes.
- the three conduit tubes used are made of polytetrafluoroethylene (PTFE), which is also biologically compatible.
- PTFE polytetrafluoroethylene
- the tube from the syringe pump is used to deliver solvent from syringe pump to the probe tip, while the other micro-PTFE tube is used to deliver an inert gas (N2 or CO2) to the probe tip.
- the gas serves three main purposes: 1) tissue drying prior to analysis; 2) prevent solvent gap due to the mass spectrometer’s vacuum when the reservoir is closed by contacting the tissue specimen; 2) assist solvent transport from tissue to the mass spectrometer through the wider PTFE tubing.
- FIG. 14 shows a schematic of the minimally invasive probe which includes a diagram of the tip of the probe in the lower left portion of the figure, including the three conduit tubes and the reservoir at the base (labelled 4).
- the middle conduit tube may comprise a funnel- shaped (e.g. tapered) chamber near the reservoir such that the larger end of the funnel-shaped chamber is proximal to the reservoir and the smaller end of the tapered chamber is distal from the reservoir.
- FIG. 8 shows two of the possible devices to house the minimally invasive probe.
- the cannula shown has the gas and solvent tubing entering the top, as well as the tubing to the mass spectrometer.
- the probe is shown emerging from the bottom of the cannula.
- the probe may also be introduced into the body cavity using a trocar needle.
- FIG. 15 depicts a simulated laparoscopic uterine surgery, and shows that the minimally invasive probe may be controlled by forceps.
- a shutter system that occludes the orifice of the minimally invasive probe may be employed as shown in FIG. 9.
- One option for the shutter is to use a catheter balloon which may close the probe tip, a diagram of which is shown in FIG. 18, preventing unwanted biological material from entering the device, including the lumens and tubing, upon insertion of the catheter into the patient.
- the shutter may disallow endogenous biological fluids from entering the mass spectrometer after analysis has been initiated, thus preventing contamination of the results. Closing of the shutter can also prevent excess nitrogen gas and water from entering the body.
- the use of a shutter in the lengthened probes necessary for minimally invasive surgery may help mitigate the unpredictable and often tumultuous nature of internal organ movement and organ systems during surgery which could affect signal acquisition.
- the minimally invasive mass spectrometry probe may also include a vacuum tube separate from the sample vacuum above. The purpose of this second vacuum tube is to gently secure, or latch, the tip of the probe onto the tissue during analysis.
- the time events involved in the device operation are automated and precisely controlled by software that communicates with an Engineering system and two two-way pinch valves. All pinch valves are closed until the process is initiated when, under 300 pL/min, a pulse is sent to the pump to infuse the solvent for two seconds and stop, generating a 10 pL droplet filling in the minimally invasive probe reservoir.
- the gas and mass spectrometer tubes are closed at pinch valves, allowing the solvent in the reservoir to interact with the tissue for three seconds to extract the molecules.
- the pinch valves controlling the gas and mass spectrometer tubes are opened simultaneously, allowing the droplet to transfer to the mass spectrometer for ionization and molecular analysis.
- a pulse is sent to the pump to infuse the solvent for another 12 seconds and stop, to completely drive all the extracted molecules into the mass spectrometer.
- the gas and mass spectrometer tubes are left open for another 20 seconds to allow all the solvent in the mass spectrometer tube to go into the mass spectrometer.
- the total analyzing time is 37 seconds.
- the probe may be washed between analyses in a variety of methods.
- the tip of the probe is wiped with sterile water.
- An additional design that can facilitate the washing step is a retractable design that will wash the exterior of the probe without having to remove the device from the patient (FIG. 20).
- the design consists of a chamber with valves located at the openings to maintain a water and gas seal.
- a longer tube that contains the probe tip, water, and gas conduits will transect only the top valve when the tip is located in the washing chamber, but will pass through both valves when the tip is deployed into the patient environment. After the probe tip, tubing, or both have become contaminated during the surgery process, the probe will withdraw into the washing chamber.
- Water tubes can be located inside the washing chamber and point upwards providing a strong jet of cleaning solvent. Two positions of vacuum tubing will be located above the first and second valve to remove dirtied solvent. The vacuum tube placed above the first valve is an emergency tube in case any water breaks the first valve barrier. The entire system will fit smoothly inside of a trocar, and the deployable probe will be located inside of this system. The vacuums located inside the probe will also operate during this cleaning process, which will flush the tubing until clean.
- the system described herein operates by directly connecting the transfer tube to the mass spectrometer inlet for transporting the analyte-containing solvents to the mass spectrometer for molecular analysis.
- This set up greatly simplifies operational details and precludes the use of ionization sources.
- the solvent is then transported to the mass spectrometer and directly infused without the need of an additional ionization source. Since the system is fully automated so that each 10 pL solvent droplet is delivered separately to the inlet, the mass spectrometer operates without any impact on its performance. Rich molecular information is obtained in this manner, similar to what is observed from other solvent-extraction ambient ionization techniques such as desorption electrospray ionization.
- the ionization mechanism may be similar to inlet ionization.
- the ionization occurs in the inlet pressure drop region between atmosphere and vacuum. Because of the nature of minimally invasive surgical techniques, the diameter of tubing, and length of tubing is of critical importance. A variety of tube lengths were tested for the delivery of solvent to the mass spectrometer, as seen in FIGS. 10-13).
- FIGS. 10-13 show the total ion chromatograms obtained from mouse brain sections during the total analysis period while using tubing lengths of 1.5 meters up to 4.5 meters. Rich molecular profiles were observed in all cases. At a tube length of 4.5 meters the molecular profile is easily established over the background signal of the water (FIG. 16).
- FIG. 17 shows total ion chromatograms obtained using conduit sizes from 1.5 mm to 4.0 mm. Again, rich molecular profiles were observed with each conduit size.
- human lung tissue was analyzed (FIG. 19), and generated a robust molecular profile.
- the molecular profiles generated by the minimally invasive mass spectrometry probe can also be used for tissue typing.
- a series of tissue samples were evaluated with the minimally invasive mass spectrometry probe and were able to be identified with an overall accuracy of 98.55% (Table 1).
- Thyroid 42 0 1 0 0 0 0 0 0
- the system was able to identify lymph, breast, and lung tissues with 100% accuracy, thyroid and parathyroid with between 97% and 99% accuracy, ovarian with 95.35% accuracy, and pancreas tissue with 83.33% accuracy.
- These tissue typing results were generated from selected features of the mass spectrometry profiles shown in Table 2. Table 2. Selected features for tissue typing.
- the minimally invasive mass spectrometry probe can be used to differentiate between normal and cancerous tissues.
- the system predicted normal tissues with greater than 89% accuracy, and cancer tissues with greater than 91% accuracy as seen in Table 3.
- Table 4 Selected features used for the prediction of cancer tissues.
- Mass Spectrometer Q Exactive Hybrid Quadrupole-Orbitrap mass spectrometer (Thermo Scientific, San Jose, CA) was used. Full-scan was carried out at the range of m/z 500-1800, and the other mass spectrometric parameters were listed as follows: resolving power 140,000, micro scan 2, maximum injection time 300 ms, capillary temperature 350 °C and S-lens RF level 100.
- Biological Tissues Wild-type mouse brains were purchased from Bioreclamation IVT. 62 frozen human tissue specimens including breast, thyroid, lymph node, ovarian, and kidney were obtained from Cooperative Human Tissue Network and Baylor College Tissue Bank. Samples were stored in a -80°C freezer. Tissue slides were sectioned at 16 pm using a CryoStarTM NX50 cryostat. Frozen tissue specimen were thawed under room temperature before use.
- the system has a high potential to be used in laparoscopic and endoscopic surgeries for real-time analysis. More than that, due to the small dimension of the device, it can be integrated to a robotic surgical system, such as the Da Vinci surgical system, through an accessory port or one of its robotic arms. Several regions of the human body cavity can be quickly sampled during surgery with or without wash/flush steps in between each analysis, and analyzed by using a database of molecular signatures and machine learning algorithms. Therefore, the diagnosing results may be provided in real time for each sampled region.
- This system can be broadly used in a wide variety of oncological and other surgical interventions (such as endometriosis) for which real time characterization and diagnosis of tissues are needed.
- FIGS. 21-23 an embodiment is shown with a pneumatic applicator that can provide a vacuum pressure to a surface in contact with the device.
- FIG. 21 shows a side view and section views of a device without the pneumatic applicator for comparison.
- FIG. 22 illustrates section and end view of a device with pneumatic anchor or vacuum ports configured to provide suction to the surface in contact with the device.
- the vacuum ports are in fluid communication with pneumatic channels and a pneumatic channel multiplexer (shown in the section view) that provide a vacuum pressure to the ports via a vacuum source.
- the pneumatic channel multiplexer is a circumferential ring extending around the device and in fluid communication with the pneumatic channels.
- the ports are formed by the ends of the channels that extend from the circumferential ring multiplexer to the surface at the end of the device configured to contact tissue.
- the vacuum ports may comprise additional features, as shown and discussed below.
- the device e.g . a MasSpec Pen
- pneumatic application contains anchor ports that (when in contact with a tissue surface) apply a vacuum pressure to anchor the tissue to the pen tip.
- a small positive gauge pressure may be applied with a clean gas (e.g, nitrogen). Transitions between vacuum and positive pressure gas flow can be initiated either by a human operator or autonomously utilizing a contact sensor.
- One purpose of the small positive gauge pressure is to maintain open pneumatic anchor channels when the Pen is not in contact with the tissue surface. The flow of clean gas will keep the pneumatic anchor channels free of fluids or debris that may enter while the pen is in contact with a tissue surface.
- the pneumatic applicator can be operated without the small positive gauge pressure and utilize the vacuum port only.
- FIG. 23 illustrates an end view of a device where the vacuum ports include an additional indented ring that extends around the perimeter of the device and provides vacuum pressure to the surface in contact with the device.
- the indented ring is in fluid communication with the end of the channels that extend from the circumferential ring multiplexer so that a greater area is created for the vacuum ports. This can allow a greater vacuum force to be generated when the device is applied to the tissue.
- Embodiments with vacuum pressure application may be operated in a number of different ways.
- human operation with a foot pedal can be used to initiate vacuum.
- the foot pedal can be configured to operate in a two state mode where a partial depression activates the vacuum while a full depression initiates a MasSpec Pen measurement.
- autonomous operation with a contact sensor can be used to either initiate vacuum and/or to provide small positive pressure flow.
- the use of a threshold sensor detects the contact pressure between the device and the tissue surface. When the contact pressure sensor transitions from below to above the threshold level, the vacuum is activated. When the contact pressure drops from above to below the threshold pressure, the small positive pressure is applied.
- Contact pressure sensors known in the art may include snap switches, springs, PVDF films, etc.
- the pneumatic ports may be operated by a vacuum pressure only. In such examples, a trap can be employed to capture tissue fluids and debris to maintain a vacuum pressure.
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Abstract
Description
Claims
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BR112021014553-2A BR112021014553A2 (en) | 2019-01-25 | 2020-01-23 | EQUIPMENT AND METHODS FOR CLEANING AND/OR CHANGING MEDICAL DEVICES |
EP20744884.6A EP3914891A4 (en) | 2019-01-25 | 2020-01-23 | Apparatus and methods for cleaning and/or exchanging medical devices |
US17/383,981 US20220196697A1 (en) | 2019-01-25 | 2021-07-23 | Apparatus and methods for cleaning and/or exchanging medical devices |
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US201962796834P | 2019-01-25 | 2019-01-25 | |
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EP (1) | EP3914891A4 (en) |
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IT202000028598A1 (en) * | 2020-11-27 | 2022-05-27 | Sense4Med S R L | DEVICE AND METHOD OF DETECTING AND CONTROLLING THE GAS FLOW IN A SAMPLING/INJECTION MEDICAL INSTRUMENT |
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CN115363628B (en) * | 2022-09-02 | 2024-06-11 | 郑州人民医院(郑州人民医院医疗管理中心) | Ultrasonic three-dimensional imaging omnidirectional scanning equipment |
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US20220196697A1 (en) | 2022-06-23 |
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WO2020154477A4 (en) | 2020-10-01 |
EP3914891A4 (en) | 2022-09-28 |
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