Rapid chemical testing assembly and methods thereof
11285480 · 2022-03-29
Assignee
Inventors
Cpc classification
B01L3/022
PERFORMING OPERATIONS; TRANSPORTING
B01L2300/0627
PERFORMING OPERATIONS; TRANSPORTING
B01L2400/0475
PERFORMING OPERATIONS; TRANSPORTING
B01L2300/0861
PERFORMING OPERATIONS; TRANSPORTING
B01L5/02
PERFORMING OPERATIONS; TRANSPORTING
B01L2200/16
PERFORMING OPERATIONS; TRANSPORTING
B01L2400/06
PERFORMING OPERATIONS; TRANSPORTING
International classification
Abstract
A testing assembly for the rapid detection of a desired chemical from a sample, the testing assembly having a sample collection device for obtaining the sample and depositing the sample into a chemical capture cartridge that operably engages with a sensing device, the chemical capture cartridge utilizing the microdiffusion of reagents to isolate the desired chemical from the sample and react the desired chemical to form a detectible complex that can be detected and measured. The testing assembly can be portable and can rapidly diagnose a toxic industrial chemical exposure in just a few minutes, preferably about a minute or less for cyanide exposure using a blood sample from a subject onsite. The testing assembly can be used to determine the presence and/or concentration of a toxic industrial chemical in a variety of samples, including biological, environmental, and industrial samples.
Claims
1. A testing assembly for the detection of a desired chemical analyte in a sample, the testing assembly comprising: a sample collection device; a chemical capture cartridge comprising: a chamber plate having a sample chamber and a capture chamber; a reagent plate having at least a first reagent bubble and a second reagent bubble, the first reagent bubble comprising a first liquid reagent and the second reagent bubble comprising a second liquid reagent; and at least one reagent channel plate located between the chamber plate and the reagent plate; wherein the at least one reagent channel plate comprises at least a first reagent channel that is configured to provide fluid communication between the sample chamber of the chamber plate and at least the first reagent bubble; wherein the at least one reagent channel plate comprises at least a second reagent channel that is configured to provide fluid communication between the capture chamber of the chamber plate and at least the second reagent bubble; and wherein the sample chamber configured to provide a headspace gas that is capable of being in fluid communication with the capture chamber; and a sensing device; wherein the sample collection device is configured to obtain the sample, insert the sample into the sample chamber of the chemical capture cartridge, and provide a cap for at least the sample chamber of the chemical capture cartridge; wherein the sample chamber of the chemical capture cartridge is configured to react the sample with at least the first liquid reagent to provide a headspace gas having the desired chemical analyte, the headspace gas having the desired chemical analyte capable of being transferred to the capture chamber, and the capture chamber of the chemical capture cartridge is configured to react the desired chemical analyte with at least the second liquid reagent to provide a desired detectable complex; and wherein the sensing device comprises an excitation source and a detector, wherein the excitation source is configured to cause the desired detectable complex to emit a detectible signal, the detector is configured to detect the detectible signal, and the sensing device is capable of providing a signal indicating the presence or absence of the desired chemical analyte.
2. The testing assembly of claim 1, wherein the sample collection device comprises: a plunger having at least one elongated leg extending from a top portion and operably connected with a first body, a second body and a third body, wherein the second body is located between the first and third bodies, the first body having a central aperture containing a valve, the second body having a central aperture that is capable of receiving a capillary holder projection of the third body; a capillary tube located within the capillary holder projection of the third body, the capillary tube having a proximate end extending out a bottom portion of the third body and a distal end extending through the capillary holder projection; and a wash solution contained within a wash solution bubble, the wash solution bubble located between the plunger and the first body.
3. The testing assembly of claim 2, wherein the plunger is configured to be operated between an undepressed position and a depressed position, wherein the capillary tube in the undepressed position is configured to not operably engage with the valve, and wherein the capillary tube in the depressed position is configured to operably puncture the valve and wash solution bubble.
4. The testing assembly of claim 3, wherein the capillary holder projection is configured to operably slide within a central aperture of the second body when the plunger is converted from the undepressed position to the depressed position.
5. The testing assembly of claim 3, wherein the second body comprises an air channel configured to provide an external fluid connection between the capillary tube and an exterior atmosphere when the plunger is in the undepressed position.
6. The testing assembly of claim 4, wherein the external fluid connection allows capillary action of the sample collection device to draw the sample within the capillary tube in the undepressed position.
7. The testing assembly of claim 6, wherein the external fluid connection is configured to be sealed by the capillary holder projection in the depressed position.
8. The testing assembly of claim 7, wherein a volume of the sample is between about 5 microliters and about 300 microliters.
9. The testing assembly of claim 4, wherein the wash solution bubble is configured to rinse the sample in the capillary tube into the sample chamber when the plunger is converted from the undepressed position to the depressed position.
10. The testing assembly of claim 1, wherein a volume of the sample is between about 5 microliters and about 300 microliters.
11. The testing assembly of claim 1, wherein the chemical capture cartridge further comprises at least one air channel plate located between the at least one reagent channel plate and the chamber plate.
12. The testing assembly of claim 11, wherein the at least one air channel plate comprises an external gas flow channel, wherein the external gas flow channel provides a fluid connection between the sample chamber and an external gas source.
13. The testing assembly of claim 12, wherein the external gas flow channel comprises at least one air channel outlet proximately located the lower portion of the sample chamber that contains fluid during normal operation.
14. The testing assembly of claim 13, wherein the at least one air channel plate further comprises a headspace gas channel, wherein the headspace gas channel providing a fluid connection between the headspace of the sample chamber and the capture chamber.
15. The testing assembly of claim 14, wherein the headspace gas channel comprises at least one headspace gas outlet proximately located the lower portion of the capture chamber that contains fluid during normal operation.
16. The testing assembly of claim 1, wherein the sample comprises a liquid sample selected from the group consisting of blood, saliva, water and oil.
17. The testing assembly of claim 16, wherein the desired chemical analyte in the sample is a toxic industrial chemical selected from the group consisting of cyanide, hydrogen sulfide, ammonia, hydrofluoric acid, carbon disulfide, azide, sulfur dioxide, chlorine, phosgene, 1,3-butadiene, arsine, phosphine, formaldehyde and methyl isocyanate.
18. The testing assembly of claim 1, wherein the desired detectable complex is a fluorometric probe that is capable of providing a fluorescence wavelength.
19. A testing assembly for the detection of cyanide in a sample, the testing assembly comprising: a sample collection device capable of collecting a sample volume between about 5 microliters and about 300 microliters; a chemical capture cartridge comprising: a chamber plate having a sample chamber for receiving the sample and a capture chamber; a reagent bubble plate having a plurality of reagent bubbles, each reagent bubble containing between about 5 microliters and about 5 milliliters of a separate reagent including at least one acid reagent, at least one base reagent, at least one napththalene-2-3-dialdeyde (NDA) reagent, and at least one taurine reagent; at least one reagent channel plate located between the chamber plate and the reagent plate, wherein the at least one reagent channel plate comprises at least one reagent channel configured to provide fluid communication between the sample chamber of the chamber plate and the at least one acid reagent bubble, and wherein the at least one reagent channel plate comprises at least one reagent channel configured to provide fluid communication between the capture chamber of the chamber plate and each of the at least one base, NDA and taurine reagent bubbles; and at least one air channel plate located between the at least one reagent channel plate and the chamber plate, wherein the at least one air channel plate comprises an external gas flow channel configured to provide a fluid connection between an external gas source and the sample chamber, and wherein the at least one air channel plate comprises a headspace gas channel configured to provide a fluid connection between the headspace of the sample chamber and the capture chamber; and a sensing device; wherein the sample collection device is configured provide a cap for at least the sample chamber of the chemical capture cartridge and discharge the sample into the sample chamber; wherein the sample chamber of the chemical capture cartridge is configured to react the sample with at least the acid reagent to provide a headspace gas comprising hydrogen cyanide, a volume of the external gas source is configured to transfer the headspace gas from the sample chamber to a mixture of the base, NDA and taurine reagents in the capture chamber to form a detectible cyanide complex with NDA and taurine; wherein the sensing device comprises an excitation source and a detector for indicating the presence or absence of cyanide; and wherein the testing assembly is capable of providing an analysis in less than about 60 seconds with a detection limit of about 2 μM.
20. A device for the detection of cyanide in a sample, the device comprising: a chamber plate having a sample chamber for receiving a sample and a capture chamber; a reagent bubble plate having a plurality of reagent bubbles, each reagent bubble containing between about 5 microliters and about 5 milliliters of a separate reagent, the separate reagents including at least one acid reagent, at least one base reagent, at least one napththalene-2-3-dialdeyde (NDA) reagent, and at least one taurine reagent; at least one reagent channel plate located between the chamber plate and the reagent plate, wherein the at least one reagent channel plate comprises at least one reagent channel configured to provide fluid communication between the sample chamber of the chamber plate and the at least one acid reagent bubble, and wherein the at least one reagent channel plate comprises at least one reagent channel configured to provide fluid communication between the capture chamber of the chamber plate and each of the at least one base, NDA and taurine reagent bubbles; and at least one air channel plate located between the at least one reagent channel plate and the chamber plate, wherein the at least one air channel plate comprises an external gas flow channel configured to provide a fluid connection between an external gas source and the sample chamber, and wherein the at least one air channel plate comprises a headspace gas channel configured to provide a fluid connection between the headspace of the sample chamber and the capture chamber; wherein the sample chamber of the chemical capture cartridge is configured to react the sample with at least the acid reagent to provide a headspace gas comprising hydrogen cyanide, and the hydrogen cyanide in the headspace gas is capable of reacting with the mixture of the base, NDA and taurine reagents in the capture chamber to form a detectible cyanide complex.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1) Subject matter hereof may be more completely understood in consideration of the following detailed description of various embodiments in connection with the accompanying figures, in which:
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(48) While various embodiments are amenable to various modifications and alternative forms, specifics thereof have been shown by way of example in the drawings and will be described in detail. It should be understood, however, that the intention is not to limit the claimed inventions to the particular embodiments described. On the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the subject matter as defined by the claims.
DETAILED DESCRIPTION OF THE DRAWINGS
(49) Unless the context indicates otherwise the following terms shall have the following meaning and shall be applicable to the singular and the plural:
(50) The terms “a,” “an,” “the,” “at least one,” and “one or more” are used interchangeably. Thus, for example, a cartridge that contains “a” reagent means that the cartridge may include “one or more” reagents.
(51) The term “acid” means any chemical substance that has a pH of less than 7.
(52) The term “base” means any chemical substance that has a pH of more than 7.
(53) The term “sensing device” means an instrument which is used to detect biological, chemical or physical events of a sample. A reader can detect, but is not limited to detection of, intensity, absorbance, fluorescence, luminescence, time-resolved fluorescence, fluorescence polarization, and light scattering and nephelometry of a sample. Depending on the desired detection, a reader may include an appropriate filter and multiple well formats. The types of detection may be optionally and preferably controlled using software and a suitable database.
(54) The term “sample” refers to a specimen for scientific testing or analysis, including, but not limited to, a fluid specimen from a subject, such as a blood or saliva specimen from an animal, and a fluid or swab specimen collected from an innate object.
(55) The term “sample chamber” refers to an enclosed space or cavity into which a sample is placed.
(56) The term “UV-VIS based confirmatory analysis” when used with respect to a method for sample analysis refers to use of absorption spectroscopy or reflectance spectroscopy in the ultraviolet-visible spectral region. Sample analysis may be performed by measuring the absorption or reflectance of electronic transitions in a certain spectrum. With reference to sample analysis, UV/VIS can include determination of the kinetics or rate constant of a chemical reaction.
(57) The term “headspace transfer” means an aliquot of a volatile material in a vapor or gas phase located above a liquid or solid sample being conveyed to another location by a pressure drop, capillary action, carrier gas flow, purge and trap, and the like.
(58) The present invention is directed at a chemical diagnostic assembly that can isolate a desired chemical from a collected sample for the rapid detection of the desired chemical compound or component. In some aspects, the diagnostic assembly comprises a sample collection device 100, a chemical capture cartridge 200, and a sensing device 300. In some aspects, the sample collection device 100 can be used to obtain a sample to be inserted into the chemical capture cartridge 200 to isolate the desired chemical component from the remaining portion of the sample to the extent the desired chemical component is present, and if present, be detected using the sensing device 300. While the chemical diagnostic assembly of the present invention, including the sample collection device 100, chemical capture cartridge 200, and sensing device 300, in the following description is disclosed with respect to cyanide detection, the present invention is applicable to collecting, isolating and/or detecting various other chemical compounds and components, including, but not limited to the toxic industrial chemicals hydrogen sulfide, ammonia, hydrofluoric acid, carbon disulfide and/or azide, and the like.
(59) Referring now to
(60) Referring to
(61) Top portion 112 generally has a top surface 113 that may have a generally smooth surface. In some aspects, the plunger 110 has two or more elongated legs 114 extending from the top portion 112 in a direction opposite the top surface 113. In some aspects, as shown in
(62) Each elongated leg 114 is shown as having one or more protruding tabs 116 proximate the peripheral edge of the elongated leg 114 between the top portion 112 and a distal end 124. In some aspects, each elongated leg 114 has opposing protruding tabs 116 proximate the peripheral edge of the elongated leg 114. In some aspects, each elongated leg 114 has two or more pairs of opposing protruding tabs 116 proximate the peripheral edge of the elongated leg 114 located between the top portion 112 and the distal end 124. In some aspects, each elongated leg 114 has three pairs of opposing protruding tabs 116 proximate the peripheral edge of the elongated leg 114 located between the top portion 112 and the distal end 124. In use, the protruding tabs 116 help to align plunger 110 as it is inserted through apertures or slots of other components comprising the sample collection device 100 and keep plunger 110 locked in an unpressed position prior to plunger 110 being pressed to depose a sample and also locked in a pressed position after plunger 110 has been pressed to depose a sample.
(63) For example, as shown in
(64)
(65) The pair of protruding tabs 116′″ located closest to the top surface in
(66) As shown in
(67) Slots 118 may be apertures extending through elongated leg 114 and/or partial depressions that do not extend through elongated leg 114. Slots 118 may be configured to have an elongated shape extending from the length of protruding tab 116. In use, slots 118 are configured to allow the material of elongated leg 114 to flex when force or pressure is exerted on protruding tab 116 during normal use. In some aspects if the material of elongated legs 114 is rigid, a pair of slots 118 on opposing sides of elongated legs 114 proximate protruding tabs 116 will allow inward flex of the material as protruding tabs 116 are depressed inward towards slots 118, which allows the elongated legs 114 to freely move through slots of other components, such as slots 156, 186, during depression of plunger 110. In some aspects, slots 118 may also allow depression of a pair of protruding tabs 116 for removal of plunger 110 after use of sample collection device 100.
(68) In some aspects, the plunger 110 has two or more stop legs 120 extending from the top portion 112 in a direction opposite the top surface 113. In some aspects, as shown in
(69) As shown in
(70) According to another embodiment shown in
(71) When depression stop 170 is removed from collection device 100 and plunger 110 is moved to the depressed position, such as shown in
(72) During normal operation the pair of stop legs 120 in
(73) When protruding tabs 116 and stop legs 120 are operably engaged with the bottom surface 154 of main bottom body 150 in the depressed state, such as illustrated in
(74) Referring now to
(75) In some aspects, as shown in
(76) In some aspects main top body 130 may also have one or more projections 142 located on the bottom surface of main top body 130. In some aspects, as shown in
(77) As shown in
(78) Main top body 130 also may comprise an aperture 138, which is shown in
(79) As seen in
(80) In some alternative aspects, which are not shown, plunger 110 may have one stop leg 120 having ledge 122 and an opposing elongated stop leg 120 without ledge 122, and main top body 130 may have one indent 136 on one side and a slot replacing indent 136 on the opposite side, such that the depression stop 170 is side specific. In some aspects, the one indent 136 operably guides stop leg 120 and slot may operably guide the opposing elongated leg as plunger 110 is inserted through apertures or slots of other components of sample collection device 100. In some aspects, such as shown in
(81) Referring now to
(82) Top surface 152 and bottom surface 154 are generally a smooth surface and can comprise the same surface area and dimensions as the bottom surface of main top body 130 and top portion 112 of plunger 110. In some aspects, such as shown in
(83) In certain preferred aspects, top surface 152 also has the same contour as bottom surface of main top body 130, such that the main top body 130 and main bottom body 150 may operably couple during normal use. In some aspects, a thin layer of adhesive may be applied between at least a portion of top surface 152 of main bottom body 150 and at least a portion of the bottom surface of main top body 130 to securely attach main top body 130 to main bottom body 150. The adhesive may also form a seal between main top body 130 to main bottom body 150. In some aspects, as shown in
(84) Main bottom body 150 may comprise an aperture 160, as shown in
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(86) In some aspects main bottom body 150 may also have one or more depressions 166, such as the two depressions, shown in
(87) Main bottom body 150 may also comprise air channel 158, which as shown in
(88) Referring now to
(89) Referring to
(90) Referring now to
(91) In
(92) In some aspects, elongated legs 173 are a length such that they are capable of extending at least partially through other components of sample collection device 100 as seen in
(93) According to certain aspects, elongated peak 178 or handle portion 179 function as a griping mechanism for insertion and removal of depression stop 170 during normal use. In some aspects as shown in
(94) Referring now to
(95) Top portion 181 generally has a top surface 182 that may have a smooth surface. In some aspects, top surface 182 has the same configuration and contour as the bottom surface 154 of the main bottom body 150. In some aspects, capillary cap 180 has a capillary holder 191 projecting from top portion 181 in a direction extending away from and perpendicular with top surface 182. In some aspects, capillary holder 191 has a capillary aperture 184 having a generally configured in a circular shape to receive at least a top portion of capillary tube 192, which is depicted in
(96) In some aspects, capillary holder 191 has a ridge 190, which has a corresponding shape and contour as ridge 162 of aperture 160 of the main bottom body 150. In some aspects ridge 190 is rectangular in shape, which can be received by the rectangular-shaped ridge 162 of aperture 160. In some aspects, at least a portion of capillary holder 191 is capable of being inserted into aperture 160 of main bottom body 150. During normal use, ridge 190 is capable of operably coupling with ridge 162 of aperture 160 to function as a locking mechanism when the capillary cap 180 and main bottom body 150 are pressed together and operably engaged. For instance, ridge 190 selectively engages with ridge 162 of aperture 160 of main bottom body 150, which functions to lock capillary holder in place and prevents capillary holder 191 from moving or rotating within aperture 160.
(97) As shown in
(98) Bottom projections 187 are shown as having one or more fins 188. According to certain aspects, the one or more fins 188 are proximate the periphery of each bottom projection 187 and extend from each bottom projection 187 in a direction parallel to top surface 182. In some aspects, fins 188 are spaced in successive rows such that there is a space between each fin 188. Fins 188 are such a length that bottom projection 187 can be inserted into the respective chamber (286, 288) of chemical capture cartridge 200, such that fins 188 during normal use function to align and secure capillary cap 180 as it is inserted into chemical capture cartridge 200. In some aspects when capillary cap 180 is inserted in chemical capture chamber 200, fins 188 form a seal between capillary cap 180 and the respective chamber 286, 288 of chemical capture cartridge 200 and prevent flow of air or other components into or out of the chemical capture cartridge 200.
(99) In some aspects, as shown in
(100) During normal use, elongated legs 173 of depression stop 170 are inserted between capillary cap 180 and main bottom body 150, as shown in
(101) Sample collection device 100 may be used with a capillary tube 192, which is shown in
(102) The sample collection device 100 may contain a solution reagent component 194 shown in
(103) As shown in
(104) Referring now to
(105) As depicted in
(106) In some aspects, bubble protector slide 210, as shown in
(107) Referring now to
(108) In some aspects, each reagent bubble 222, 226, 230, and 234 houses a reagent within the reagent bubble. In some aspects, the reagents within each reagent bubble 222, 226, 230, and 234 may be the same or different among the various reagent bubbles. One of ordinary skill will appreciate that the type of reagent in each reagent bubble will depend upon the specific chemical being tested. In some aspects, each reagent bubble 222, 226, 230, and 234 can house between about 5 μL and about 5 mL, in some aspects between about 10 μL and about 1 mL, in some other aspects between about 15 μL and about 750 and in some other aspects between about 20 μL and about 500 μL.
(109) In some preferred aspects relating cyanide detection, reagent bubble plate 212 of
(110) In some aspects, bubble protector plate 220, as shown in
(111) Bubble protector plate 220 is shown in
(112) As shown in
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(114) As shown in
(115) Plate coupling may also be configured to have one or more recess configured to couple with clips 223 of bubble protector plate 220, which allows the bubble protector plate 220 to be snapped onto plate coupling as a locking mechanism. For instance, recesses are configured to allow plate coupling and bubble protector plate 220 to be operably engaged and prohibits the plate coupling and bubble protector plate 220 from being disconnected from each other during normal operation.
(116) Referring now to the fluid connectivity of plate coupling.
(117) Referring now specifically to the reagent fluid connection between bubble plate 212 and chamber plate 280, as shown in
(118) Reagent channel plate 240 may also contain one or more reagent channels corresponding to reagent bubble plate 212 and the desired flow to chamber plate 280. For instance, as shown in
(119) Referring now to
(120) In certain aspects, reagent bubble 222 is in fluid connection with fluid outlet 222″ via fluid inlet 222′ and reagent channel 224 of reagent channel plate 240, aperture 222′″ of spacer plate 260 and then outlet 222″ of air channel plate 268. In certain aspects, reagent inlet 222′ corresponds with Taurine bubble 222, such that reagent outlet 222″ is in fluid connection with Taurine bubble 222.
(121) In certain aspects, reagent bubble 226 is in fluid connection with fluid outlet 226″ via fluid inlet 226′ of reagent channel plate 240, aperture 226′″ of spacer plate 260, and then outlet 260″ of air channel plate 268. In certain aspects, reagent inlet 226′ corresponds with acid bubble 226, such that reagent outlet 226″ is in fluid connection with acid bubble 226.
(122) In certain aspects, reagent bubble 230 is in fluid connection with fluid outlet 230″ via fluid inlet 230′ and reagent channel 232 of reagent channel plate 230, aperture 230′″ of spacer plate 260 and then outlet 230″ of air channel plate 268. In certain aspects, reagent inlet 230′ corresponds with base bubble 230, such that reagent outlet 230″ is in fluid connection with base bubble 230.
(123) In certain aspects, reagent bubble 234 is in fluid connection with fluid outlet 234″ via fluid inlet 234′ of reagent channel plate 240, aperture 234′″ of spacer plate 260, and then outlet 234″ of air channel plate 268. In certain aspects, reagent inlet 234′ corresponds with NDA bubble 234, such that reagent outlet 234″ is in fluid connection with NDA bubble 234.
(124) As shown from
(125) Referring now to the fluid connectivity of gas flow provided by air channel plate 268 into chamber plate 280, as shown in
(126) Air channel plate 268 may also have one or more air channels between the sample chamber 288 and the capture chamber 286. In some aspects, air channel plate 268 comprises at least one air channel 238 providing a fluid connection between the headspace of sample chamber 288 and capture chamber 286 via sample chamber outlet 238′, air channel 238 in air channel plate 268 and capture chamber inlet 238″. In some aspects, sample chamber outlet 238′ provides fluid connection to air channel 238 via an aperture through air channel plate 268 with air channel 238 being a channel on the side of air channel plate 268 that operably engages with channel spacer plate 260. In some aspects, capture chamber inlet 238″ provides fluid connection to air channel 238 via an aperture through air channel plate 268 with air channel 238 being a channel on the side of air channel plate 268 that operably engages with channel spacer plate 260. In some aspects, fluid chamber 238 provides fluid connection between the head space in sample chamber 288 and the capture chamber 286, such that the capture chamber inlet 238″ is located proximate the lower portion of capture chamber 286 proximate the reagents or solution within the capture chamber 286 to agitate or bubble the headspace gas through the reagents. In such aspects, the headspace gas bubbled through the reagents in the capture chamber 286 facilitates capture of the desired chemical component with the one or more reagents. Gas outlet 290, as shown in
(127) As shown in
(128) In some aspects, capture chamber 286 comprises at least one side having a clear portion to enable excitation of the desired detectible complex and detection of a signal. In some aspects, capture chamber 286 comprises at least two sides each having a clear portion to enable excitation of the desired detectible complex and detection of a signal. In some aspects, capture chamber 286 comprises a first side having a clear portion and an adjacent side having a clear portion. In some aspects, the capture chamber 286 contains at least three sides having a clear portion. In some aspects, the capture chamber 286 contains at least four sides having a clear portion. In some aspects, the clear portion comprises glass, optical glass, pyrex glass, UV quartz, IR quartz, or sapphire. In some aspects, the capture chamber 286 is comprised of a material that provides the ability to provide an excitation source and detect a signal by the sensing device 300. In some aspects, the excitation light source is applied in a perpendicular configuration to the detector in sensing device 300.
(129) During normal use, sample collection device 100 is used to obtain a sample and then the sample collection device 100 is operably coupled to chemical capture cartridge 200 by inserting capillary cap 180 into the top of sample chamber 288, as shown in
(130) According to certain aspects, sensing device 300 can be used to determine the presence of a particular analyte or chemical component or compound. In some aspects, the analyte may be cyanide. In some aspects, the diagnostic testing of the presence of absence of a particular component or analyte begins with preparing a sample. In some aspects, a sample may be a liquid sample such as blood, saliva, water, or oils. According to an alternative embodiment, a sample may be a solid such as dirt or debris from a chemical exposure site. In some aspects, preparing a sample comprises collecting and adding a sample to capillary tube 192. In some aspects, preparing sample may comprise using a swab to gather saliva from a subject. In some aspects, preparing a sample may comprise drawing blood from subject to be drawn into capillary tube 192. For instance, blood may be taken from a patient by a finger stick to cause the subject to bleed. A liquid sample may be drawn into capillary tube 192 of sample collection device 100. In some aspects, while the sample is being obtained in capillary tube 192, plunger 110 is in the unpressed position.
(131) In some aspects the volume of a sample collected may range from a sub microliter to about 300 microliters, preferably about 10 to about 100 microliters, preferably about 25 to about 75 microliters, more preferably about 50 microliters. In some aspects, the volume of sample collected may be adjusted according to the dimensions of capillary 192. In some aspects, the overall volume deposition can be adjusted by tuning the capillary volume and the volume of wash necessary for sample delivery, or addition of sample directly in the sample chamber 288.
(132) In certain aspects relating to cyanide detection, the volume of sample collected in capillary tube 192 is between about 5 μL and 300 μL, in some aspects between about 10 μL and 150 μL, in some other preferable aspects between about 20 μL and 60 μL, and in some other most preferable aspects about 25 μL. In some aspects, the cyanide sample is a blood sample in an amount between about 5 μL and 300 μL, in some aspects between about 10 μL and 150 μL, in some other preferable aspects between about 20 μL and 60 μL, and in some other most preferable aspects about 25 μL.
(133) In some alternative aspects, instead of using sample collection device 100, a desired sample may be added directly into sample chamber 288 of chemical capture cartridge 200. In such aspects, sample collection device 100 may still be operably coupled, such as to provide solution from reagent bubble 194 during the process of depressing plunger 110, and as a cap for sample and capture chambers 288, 286. In some alternative aspects, sample collection device 100 may not be used and sample chamber 288 and capture chamber 286 may be sealed with means for sealing, such as appropriate sealing caps.
(134) In some preferred aspects, the sample is a liquid sample such as blood, saliva, water, or oil that is collected using sample collection device 100 and inserted into sample chamber 288 by operably coupling sample collection device 100 with chemical capture cartridge 200. For example, a sample may be contained within capillary tube 192 and sample collection device is operably coupled to chemical capture cartridge 200 by operably engaging capillary cap 180 with the receiving portion of sample chamber 288, such that sample chamber 288 is capped with capillary cap 180. According to an alternative embodiment, a sample may be a solid such as dirt or debris from a chemical exposure site. In this alternative embodiment, after the sample is added to sample chamber 288, the chemical capture cartridge 200 may still be capped using sample collection device 100. In such instances, sample collection device 100 may be used to deliver a desired reagent from into sample chamber 288 by depressing plunger 110.
(135) The chemical capture cartridge 200 having coupled collection device 100 (or another appropriate cap in the instance of a solid sample added without using the sample collection device 100) may then be inserted into the cartridge receiving portion of sensing device 300. Once chemical capture cartridge 200 is properly inserted into sensing device 300, plunger 110 may be moved from the undepressed position to the depressed position. In some aspects, depression stop 170 must be removed to depress plunger 110 and insert the sample contained within capillary tube 192 into sample chamber 288.
(136) In some aspects, by depressing plunger 110, capillary holder 191 having capillary aperture 184 holding at least a portion of capillary tube 192 is forced up into aperture 160 to a location such that capillary holder 191 seals air channel 158 and operably engages valve 197. The depression of plunger 110 also ruptures reagent bubble 194 forcing the reagent through valve 197 and into capillary tube 192, which flushes the sample out of the capillary tube 192 and sample chamber 288. As previously discussed, plunger 110 in the depressed position forms a sealed sample collection device 100 that also serves as a sealed cap to the sample chamber 288. The depressing of plunger 110 can be by manual actuation or automated. In some aspects, closing a lid of the sensing device containing the chemical capture cartridge 200 having coupled collection device 100 may provide the actuating force to depress plunger 110.
(137) In some aspects after the sample is added to the sample chamber 288, reagents may be added to the respective sample chamber 288 and capture chamber 286. In some aspects, the addition of the reagents to the sample chamber 288 and capture chamber 286 may be done simultaneous or about simultaneous with plunger 110 being depressed to deposit sample into the sample chamber 288. In some aspects, the addition of the reagents to the sample chamber 288 and capture chamber 286 is automated by the sensing device 300 upon the sensing device 300 being actuated. In some aspects, the sensing device 300 is actuated by pressing a start button. In some aspects, bubble protector slide 210 is slidably removed from bubble protector plate 220 and pressure is exerted on bubble plate 212 such that reagent bubbles 222, 226, 230 and 234 are depressed to force the respective reagents into the respective chamber. In some aspects, the bubble protector slide 210 is slidably removed from bubble protector plate 220 prior to chemical capture cartridge 200 being inserted into sensing device 300. In some aspects, the bubble protector slide 210 is slidably removed from bubble protector plate 220 after chemical capture cartridge 200 is inserted into sensing device 300.
(138) In some aspects, reagent bubble 226 results in a first reagent being provided into sample chamber 288 to react with the sample. In some aspects, depressing reagent bubbles 222, 230 and 234 results in at least three reagents being provided into capture chamber 286. One of ordinary skill in the art will appreciate that it is contemplated that one or more reagents may be provided to the sample chamber 288 to react with the sample, and one or more reagents may be provided to the capture chamber 286. In some aspects, the reaction of the at least one or more reagents in the sample chamber 288 with the sample can cause gas evolution 410 in the headspace of the sample chamber 288. The injection of air or another inert gas 412 into sample chamber 288 allows the headspace gas to be transferred from the sample chamber 288 to the capture chamber 286. In some aspects, air is injected into sample chamber 288 via air inlet 284. In some aspects, up to about 100 mL of air or other inert gas is delivered through air introduction inlet 284. In some aspects, air or another inert gas is delivered through air introduction inlet 284 and flows continuously into sample chamber 288 with the head space gas continuously flowing into capture chamber 286 with excess gas venting out of capture chamber 286 during the sensing cycle. In some aspects, air injection forces the gas in the headspace of sample chamber 288 to flow into capture chamber 286 proximate the one or more reagents in the capture chamber 288. In some aspects, the headspace gas in sample chamber 288 flows into capture chamber 286 and is bubbled through a mixture of two or more reagents, which captures the desired analyte to form a complex that may be detected.
(139) In some aspects with respect to cyanide detection, reagent bubble 226 results in an acid reagent being provided into sample chamber 288 to react with the sample. In some aspects, depressing reagent bubbles 222, 230 and 234 results in taurine, a base reagent and NDA, respectively, being provided into capture chamber 286. In the case of cyanide detection, the reaction of the acid reagent with the cyanide within the sample can cause HCN gas evolution 410 in the headspace of the sample chamber 288. The injection of air or another inert gas 412 into sample chamber 288 allows the headspace gas to be transferred from the sample chamber 288 to the capture chamber 286. In some aspects, air is injected into sample chamber 288 via air inlet 284. In some aspects, up to about 20 mL of air or other inert gas is delivered through air introduction inlet 284. In some aspects, air or another inert gas is delivered through air introduction inlet 284 and flows continuously into sample chamber 288 with the head space gas continuously flowing into capture chamber 286 with excess gas venting out of capture chamber 286 during the sensing cycle. In some aspects, air injection forces HCN gas in the headspace of sample chamber 288 to flow into capture chamber 286 proximate the reagents in the capture chamber 288. In some aspects, the HCN headspace gas in sample chamber 288 flows into capture chamber 286 and is bubbled through a mixture of base reagent, taurine, and NDA, which captures the cyanide to form a NDA-Taurine-CN complex.
(140) In some aspects, sensing device 300 contains an exciting LED to cause the desired complex in the capture chamber 286 to emit a detectible signal. In some aspects, the detectible signal is fluorescence. In some aspects related to cyanide detection, an LED at a wavelength range of about 410 nm is used to excite the NDA-Taurine-CN complex, and the resulting fluorescence is then measured by a sensor in the sensing device 300. The reaction of cyanide in the form of HCN gas in the capture chamber 286 containing NDA and Taurine in the presence of a base reagent to form florescent β-isoindole is shown in Scheme 1 below.
(141) ##STR00001##
(142) The sensing device 300 can provide a signal of the presence or absence of the desired analyte. In some aspects, the sensing device 300 contains software with a calibration table to provide a readout of the amount of the desired analyte in the sample.
(143) In some aspects, the time between starting the detection process once the capture cartridge 200 device is inserted into the sensing device 300 and the detection process is started and the signal or readout from the sensing device 300 is preferably less than 2 minutes, in some aspects less than 90 seconds, and more preferably about 60 seconds or less.
(144) While the foregoing description has been in the context of cyanide detection, it is contemplated that sample collection device 100, chemical capture cartridge 200 device and/or sensing device 300 may be configured to be used with other analytes, such as other TICs. In some aspects, sensing device 300 may be configured to have more than one LED to excite various complexes, such that sample collection device 100, chemical capture cartridge 200 device and sensing device 300 can be universally used for detecting various analytes.
(145) For example, sample collection device 100, chemical capture cartridge 200 device and sensing device 300 may be used for H.sub.2S detection in a sample. In some aspects, the LED in sensing device 300 would be modified or selected and different reagents may be used in chemical capture cartridge 200. An example reagent specific for H.sub.2S may be 4-Azido-7-nitro-2,1,3-benzoxadiazole (NBD-Azide).
(146) Examples of TICs and corresponding potential fluorometric probes that may be used with the sample collection device 100, chemical capture cartridge 200 device and sensing device 300, including cyanide, are listed in Table 2.
(147) TABLE-US-00002 TABLE 2 Proposed chemistry for TIC analyte diagnostic detection. Sample Capture Toxic Chamber Gaseous Chamber Captured Chemical Reaction.sup.a Species Reaction Species Fluorometric Probe.sup.b Cyanide Acidification HCN Basification CN.sup.− NDA-Taurine Cyanide (via KMnO.sub.4/Acid HCN Basification CN.sup.− NDA-Taurine SCN.sup.− analysis) Hydrogen Acidification H.sub.2S Basification HS.sup.− Azide Reagent Sulfide (H.sub.2S) Ammonium Basification H.sub.3N Acidification NH.sub.4.sup.+ O-Phthaldehyde Carbon NA CS.sub.2 Amine CS.sub.2 Amino fluorescent Disulfide Reaction agent (CS.sub.2) Hydrogen Acidification HF Basification F.sup.− Indole-azadiene Fluoride (HF) Azide (N.sub.3.sup.−) Acidification HN.sub.3 Basification N.sub.3.sup.− Naphthalimide/alkyne Sulfur Acidification SO.sub.2 Basification H.sub.2SO.sub.3.sup.− Cyanine-based dye; Dioxide (SO.sub.2) α,β-unsaturated Chlorine (Cl.sub.2) KMnO.sub.4/Acid HOCl Basification .sup.−OCl Fluorescein derivative Phosgene NA COCl.sub.2 Amine COCl.sub.2 Amino fluorescent (COCl.sub.2) Reaction agent 1,3-butadiene NA Butadiene Thiol Butadiene Di-thiol fluorescent dioxide Reaction dioxide agent Arsine (AsH.sub.3) NA AsH.sub.3 Thiol AsH.sub.3 Thiol fluorescent Reaction agent Phosphine NA PH3 Thiol PH.sub.3 Thiol fluorescent (PH.sub.3) Reaction agent Formaldehyde NA CH.sub.2O NA CH.sub.2O Naphthalene (CH.sub.2O) derivative Methyl NA MIC Thiol MIC Thiol or Thioic Acid Isocyanate Reaction fluorescent agent (MIC) .sup.aReferences indicate the reaction in the sample chamber will produce the specified gaseous species. .sup.bReferences indicate the fluorometric probe or type of probe which will produce a fluorescent product in the sensor.
(148) In some aspects, a TIC can be detected using the foregoing disclosed sample collection device 100, chemical capture cartridge 200 device and/or sensing device 300. Analysis of a desired analyte comprises sample preparation for deposition into the chemical capture cartridge 200. The sample collection device 100 can be used to obtain a sample in the microliter range, in some aspects a blood sample, which is then deposited into chemical capture cartridge 200 where microdiffusion and reaction with a selective fluorometric reagent occurs. Chemical capture cartridge 200 is placed in sensing device 300 that uses a fluorometric reader. During diagnostic testing, sensing device 300 delivers the carrier gas via a predetermined sequence and fluorometric analysis is conducted (i.e., sensing device 300 contains a select LED and photodiode pair to excite the sample and measure the fluorescent emission, respectively). For instance, in some aspects for the analysis of cyanide, a blood sample is placed in the sample chamber 288 and acidified to convert all CN to HCN(g). The gaseous HCN is then transferred into the capture chamber 286 via a carrier gas that is inserted proximate the reagents in capture chamber 286, such that the carrier gas is bubbled through the reagent solution in capture chamber 286. HCN(g) is captured in basic solution by conversion to non-volatile CN.sup.−. The fluorescence signal is then measured after reaction of CN with a fluorescent probe.
(149) In some aspects, the analytical diagnostic process to detect the presence or absence of an analyte comprises obtaining a sample of whole blood, which can be obtained by a fingerstick of a subject and collecting the whole blood sample in capillary tube 192 of sample collection device 100. In some aspects, the whole blood sample is about 15 μL to about 50 μL, preferably about 20 μL to about 40 μL, and more preferably about 25 μL. Sample collection device 100 is operably coupled to chemical capture cartridge 200 device, which are then inserted into sensing device 300. Plunger 110 is depressed using water in reagent bubble 194 to wash the whole blood sample into sample chamber 288 and sensing device 300 is actuated. In some aspects, wash solution in reagent bubble 194 also functions to dilute the whole blood sample. In some aspects, sensing device 300 is actuated by pressing a button to initiate analysis. Upon actuation of sensing device 300, the remaining analysis steps can be automated by sensing device 300. In some aspects, the analysis steps conducted by sensing device 300 include depressing reagent bubbles 222, 226, 230 and 234 to release the respective reagents into sample chamber 288 and capture chamber 286.
(150) In some aspects relating to cyanide detection, an acid reagent is released into sample chamber 288, and a base reagent, NDA and taurine are released into capture chamber 286. In some aspects, the acid reagent liberates cyanide from the biological sample in sample chamber 288, the base reagent captures the liberated cyanide in capture chamber 286, and NDA and Taurine produce a cyanide selective fluorometric mixture in capture chamber 286. During the analysis process, approximately at least 50 mL and up to about 200 mL, preferably at least 75 mL and up to about 150 mL, and more preferably at least 100 mL and up to about 120 mL ambient air is transferred through the air introduction inlet 284, which flows into sample chamber 288 and then conducts headspace transfer into capture chamber 286 via air channel 239, air channel inlet 239′, air channel 239a and air channel outlets 239″. In some aspects, excess pressure formed from headspace transfer is released from capture chamber 286 through air outlet 290. In some aspects, the headspace gas of sample chamber 288 is bubbled through reagent mixture in capture chamber 286.
(151) In some aspects, ambient air is continuously introduced into sample chamber 288 for at least 15 seconds and up to less than 60 seconds, preferably at least 35 seconds and up to about 55 seconds, more preferably at least 40 seconds and up to about 50 seconds.
(152) In some other aspects, ambient air is continuously introduced into sample chamber 288 for at least 15 seconds and up to less than about 5 minutes, preferably at least 20 seconds and up to about 4 minutes, more preferably at least 40 seconds and up to about 2 minutes or less.
(153) In some aspects, ambient air is introduced into sample chamber 288 in a sequence comprising a continuous phase followed by a pulsing phase prior to a resting phase where no ambient air is introduced before fluorescence analysis. In some aspects, the continuous phase is for at least 15 seconds and up to less than 50 seconds, preferably at least 20 seconds and up to about 45 seconds, preferably at least 25 seconds and up to about 35 seconds, more preferably about 30 seconds. In some aspects, the pulsing phase is at least 5 seconds and up to about 30 seconds, preferably at least 10 seconds and up to about 20 seconds, more preferably about 12 seconds, wherein each pulse is about 0.5 seconds followed by about 2 seconds of rest. In some aspects, the resting phase with no ambient air introduction prior to fluorescence analysis is at least 5 seconds up to about 30 seconds, preferably at least 10 seconds up to about 20 seconds, more preferably about 15 seconds. In some aspects, the sequence comprises the continuous phase for about 30 seconds followed by the pulsing phase for about 12 seconds followed by the resting phase for about 15 seconds.
(154) In some aspects, upon headspace transfer into capture chamber 286 allows the analyte to react and form a detectible compound. In some aspects relating to cyanide detection, the biological sample in sample chamber 288 is acidified to convert CN to HCN(g) in the headspace. The gaseous HCN headspace is then transferred into the capture chamber 286 and bubbled through the reagent solution in capture chamber 286, such that HCN(g) is captured in basic solution by conversion to non-volatile CN.sup.−, which then reacts with cyanide to produce a fluorescent CN-NDA-taurine product to form a detectible complex. In some aspects, a fluorescence signal can be measured after reaction of CN with a fluorescent probe to form a detectible complex and excitation of the detectible complex at an appropriate wavelength and detection at an appropriate wavelength. In some aspects, the CN-NDA-taurine complex is irradiated with 410 nm light via an LED and the fluorescence is measured via a photodiode at 510 nm. In some aspects, the measured fluorescence signal can generate a signal on the sensing device 300. In some aspects, the measured fluorescence signal can be converted to concentration and displayed to the analyst and determined if it is above (“Exposure Detected”) or below (“No Exposure”) the threshold value. In some aspects, the sensing device 300 has a limit of detection of about 5 μM. In some aspects, the sensing device 300 has a linear range of about 10 μM to about 200 μM. In some aspects, the threshold is set at about 5 μM above the maximum cyanide concentration seen in the blood of cigarette smokers. In some aspects, the threshold value is about 15 μM. In some aspects, the period of time for analysis upon initiating analysis on the sensing device is less than 90 seconds, in some aspects at least 30 seconds up to about 90 seconds, preferably at least 30 seconds and up to about 60 seconds, in some aspects about 60 seconds.
(155) In some aspects, sensing device 300 may contain an irradiating means for exciting the detectible complex that contains a wavelength range or an array of wavelengths such that sensing device 300 may be used for detecting various analytes. For example, sensing device 300 may contain two or more LEDs each having a different wavelength that may be chosen by the analyst prior to actuating sensing device 300. In some other aspects, sensing device 300 may have a light source that provides a broad wavelength spectrum such that a wavelength range or specific wavelength may be chosen by the analyst prior to actuating sensing device 300.
(156) In some aspects, sensing device 300 may contain an array of photodiodes for measuring fluorescence at various wavelengths. In some aspects, the analyst may choose the desired wavelength range or wavelength prior to actuating sensing device 300. In some aspects, sensing device 300 may automate the desired photodiode based upon the irradiating wavelength range or wavelength chosen prior to actuation.
(157) Sensing device 300 is preferably a size such that it is portable to be used out at a desired location in the field. In some aspects, the size of sensing device 300 can be up to about 30 cm in length, up to about 30 cm in width, and up to about 30 cm in height, such that it is about 9000 cm.sup.3. In some other aspects, the size of sensing device 300 is up to about 28 cm in length, up to about 20 cm in width, and up to about 12 cm in height, such that it is up to about 6700 cm.sup.3. In some preferred aspects, the size of sensing device 300 is up to about 20 cm in length, up to about 14 cm in width, and up to about 10 cm in height, such that it is up to about 2800 cm.sup.3. More preferably, the size of sensing device 300 is up to about 19.6 cm in length, up to about 13.2 cm in width, and up to about 9.5 cm in height, such that it is up to about 2500 cm.sup.3.
EXAMPLES
(158) The present invention can further be understood by the following examples, which are intended for exemplary purposes without unduly limiting or importing limitations into the claimed subject matter.
(159) Calibration of Sensing Device
(160) The concentration accuracy of a sensing device for cyanide detection was verified by using both a laboratory-based GC-MS method and direct UV-Vis analysis using rabbit whole blood spiked with cyanide at concentrations ranging from 2 μM to 100 μM. Calibration curves for the range of samples were generated by using both a conventional GC-MS and UV-Vis analysis method, both with R.sup.2>0.9, as shown in
(161) Analysis Protocol and Instrument Sequence (≤60 Seconds Analysis Time)
(162) A blood sample (25 μL of blanks, samples, and standards) was placed in the sample chamber of the chemical capture cartridge. De-ionized water (“DI”) (80 μL) was placed in the sample chamber. The chemical capture cartridge was then inserted into the sensing device and the “start” button was pressed. Pushing of the start button induced simultaneous injection of 200 μL each of all reagents (listed in Table 4). After reagent injection, headspace transfer of cyanide was performed by turning on the pump to deliver air (200 mL/min through the cartridge) for 34.12 seconds. Following headspace transfer, pulsed bubbling (0.5 seconds on and 2 seconds rest) was performed for 12.5 seconds. A 13.38 second delay was carried out to allow the NDA-taurine-cyanide reaction to occur. Fluorescence of the capture chamber solution was then measured and recorded. The measured results were compared to UV-VIS measurements for validation, which correlated with an R.sup.2>0.9.
(163) TABLE-US-00003 TABLE 4 Reagents for Analysis Protocol Ingredient or Step Chamber Parts Sample Collection Device Blood Sample 25 μL De-ionized water Sample 80 μL Reagents 2M H.sub.2SO.sub.4 in 1:1 H.sub.2O:EtOH Sample 200 μL 0.1M NaOH Capture 200 μL 0.002M NDA Capture 200 μL 0.1M Taurine Capture 200 μL
In-Vivo Cyanide Diagnostic Analysis
(164) The chemical capture cartridge and sensing device used in the Calibration of Sensing Device above were also used to diagnose CN exposure in-vivo using the blood CN concentrations of rabbits following cyanide exposure. New Zealand white rabbits (3.5-5.5 kg) were anesthetized, intubated, ventilated and then exposed intravenously to a lethal dose of CN (6.8 mM NaCN in 0.9% NaCl at 1 mL/min) in a laboratory setting. Blood was drawn from the rabbits just prior to exposure (pre-exposure) and after approximately 15, 25, 30, 35 min after CN infusion, and approximately 5 min prior to apnea (blood also drawn at apnea when appropriate). Each sample was flash frozen in liquid nitrogen and stored at −80° C. until analysis. As shown in
(165) TABLE-US-00004 TABLE 3 Cyanide Sensing Parameters. Sensor Parameter Desired Value Sensing Device Diagnostic Accuracy* ≥99% 100% (N = 51 samples; 14 non-exposed, 37 exposed) Analysis Time* ≤60 s 60 s Detection Limit at Biol. ≤10 μM 2 μM Relevant Conc.* Size* Handheld ✓ Precision ≤20% RSD ≤8% RSD Accuracy 100 ± 20% 100 ± 12% Sample Volume ≤50 μL 15 μL Cyanide Recovery >75% 75% (aq); 55% (blood) Linear Range At least 10-200 μM 15-75** μM Interferents None None Known Reagent Stability Months ≥70 days Sample Prep and Automated Single button push Fluorometric Analysis Rapid Calibration ≤5-point 2-point calibration calibration
H.sub.2S Diagnostic Analysis
(166) The sensing device used in the Calibration of Sensing Device above was modified to add the optical components necessary for H.sub.2S and a fluorometric reagent 4-Azido-7-nitro-2,1,3-benzoxadiazole (NBD-Azide) specific for H.sub.2S was used. The fluorometric reagent was tested, and was found to selectively react with H.sub.2S. Detection of aqueous H.sub.2S was conducted by adding solid NBD-Azide to the sample cartridge and a solution of NaOH at pH 8.5 with 100% ethanol (3:7) with 0.01% SLS was optimum for capturing and analyzing gaseous H.sub.2S. H.sub.2S was also measured from spiked blood sample at 500 μM, which validated that the sensing device could be used for an analyte besides cyanide.
(167) Various embodiments of systems, devices, and methods have been described herein. These embodiments are given only by way of example and are not intended to limit the scope of the claimed inventions. It should be appreciated, moreover, that the various features of the embodiments that have been described may be combined in various ways to produce numerous additional embodiments. Moreover, while various materials, dimensions, shapes, configurations and locations, etc. have been described for use with disclosed embodiments, others besides those disclosed may be utilized without exceeding the scope of the claimed inventions.
(168) Persons of ordinary skill in the relevant arts will recognize that the subject matter hereof may comprise fewer features than illustrated in any individual embodiment described above. The embodiments described herein are not meant to be an exhaustive presentation of the ways in which the various features of the subject matter hereof may be combined. Accordingly, the embodiments are not mutually exclusive combinations of features; rather, the various embodiments can comprise a combination of different individual features selected from different individual embodiments, as understood by persons of ordinary skill in the art. Moreover, elements described with respect to one embodiment can be implemented in other embodiments even when not described in such embodiments unless otherwise noted.
(169) Although a dependent claim may refer in the claims to a specific combination with one or more other claims, other embodiments can also include a combination of the dependent claim with the subject matter of each other dependent claim or a combination of one or more features with other dependent or independent claims. Such combinations are proposed herein unless it is stated that a specific combination is not intended.
(170) Any incorporation by reference of documents above is limited such that no subject matter is incorporated that is contrary to the explicit disclosure herein. Any incorporation by reference of documents above is further limited such that no claims included in the documents are incorporated by reference herein. Any incorporation by reference of documents above is yet further limited such that any definitions provided in the documents are not incorporated by reference herein unless expressly included herein.
(171) For purposes of interpreting the claims, it is expressly intended that the provisions of 35 U.S.C. § 112(f) are not to be invoked unless the specific terms “means for” or “step for” are recited in a claim.