US20180217060A1 - Portable laser biosensor - Google Patents
Portable laser biosensor Download PDFInfo
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- US20180217060A1 US20180217060A1 US15/712,120 US201715712120A US2018217060A1 US 20180217060 A1 US20180217060 A1 US 20180217060A1 US 201715712120 A US201715712120 A US 201715712120A US 2018217060 A1 US2018217060 A1 US 2018217060A1
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Definitions
- the invention described herein includes contributions by one or more employees of the Department of the Navy made in performance of official duties and may be manufactured, used, and licensed by or for the United States Government without payment of any royalties thereon.
- This invention (Navy Case 200,408) is assigned to the United States Government and is available for licensing for commercial purposes. Licensing and technical inquiries may be directed to the Technology Transfer Office, Naval Surface Warfare Center Corona Division, email: CRNA_CTO@navy.mil.
- the present disclosure relates generally to methods and apparatuses for detecting and identifying substances within a sample fluid. More particularly, the present invention relates to a portable, illustratively pocket wearable, laser based biosensor including modular components, and combining molecular absorption spectrophotometry and molecular fluorescence spectrophotometry.
- the present invention relates to a hand-held laser based biosensor that illustratively is portable (e.g., pocket wearable by a user), is modular (e.g., interchangeable modules), has improved selectivity (e.g., combined molecular absorption spectrophotometry and molecular fluorescence spectrophotometry), and has improved sensitivity (e.g., long absorption path length and long emission (fluorescence) region).
- a biosensor may find use in a variety of applications including, for example, in the military, food and drug industries, and with first responders (e.g., police and firefighters).
- a hand-held biosensor includes a radiation emitting module including light emitting module housing, and a light source received within the radiation emitting module housing and configured to generate excitation energy, illustratively a laser beam.
- the hand-held biosensor further includes a sample cell module including a sample cell module housing defining a chamber configured to receive a solution, a sample inlet in fluid communication with the chamber, and a waste outlet in fluid communication with the chamber.
- a first releasable coupling is positioned between the radiation emitting module and the sample cell module.
- a display module is in electrical communication with the processor, the display module including a display module housing, an absorption display supported by the display module housing and configured to provide an indication of the absorption spectral data from the absorption detector, and a fluorescence display supported by the display module housing and configured to provide an indication of a fluorescence spectral data from the fluorescence detector.
- a power source is in communication with the processor.
- a second releasable coupling is positioned between the display module and the sample cell module.
- a hand-held biosensor includes an outer casing extending between a proximal end and a distal end, and a radiation emitting module supported proximate the proximal end of the outer casing.
- a display module is supported proximate the distal end of the outer casing, and the sample cell module is supported intermediate the radiation emitting module and the display module.
- the sample cell module includes a sample cell module housing defining a chamber and including a light entry port, a light exit port axially spaced by the chamber from the light entry port, a longitudinal axis defined by the light entry port and the light exit port, and a reflective surface configured to reflect light from the radiation emitting module transverse to the longitudinal axis.
- the hand-held biosensor further includes an absorption detector, a fluorescence detector, and a processor in electrical communication with the absorption detector and the fluorescence detector, the processor being configured to receive absorption spectral data from the absorption detector and fluorescence spectral data from the fluorescence detector.
- the sample cell module includes an axial length between the light entry port and the light exit port, the axial length being at least about 5 centimeters.
- a method of constructing a hand-held biosensor includes the steps of providing a sample cell module including a sample cell module housing having a side wall defining a chamber and extending longitudinally between a proximal end and a distal end, a sample inlet in communication with the chamber, and a waste outlet in communication with the chamber.
- the method further includes the steps of providing a solution within the chamber of the sample cell module, providing a radiation emitting module including a radiation emitting module housing extending longitudinally between the proximal end and the distal end, a light source received within the radiation emitting module housing and configured to generate an excitation laser beam, and releasably coupling the distal end of the radiation emitting module housing to the proximal end of the sample cell module housing.
- the method further includes the steps of providing an absorption detector at the distal end of the sample cell, the absorption detector configured to detect the intensity of the laser beam (energy) passing through the solution in the sample cell chamber, the absorption detector including an absorption detector spectral filter, and providing a fluorescence detector configured to detect emissions produced by laser excited molecules as the laser beam passes through the solution of the sample cell chamber, the fluorescence detector including a fluorescence detector spectral filter.
- the method also includes the steps of providing a processor in electrical communication with the absorption detector and the fluorescence detector, the processor configured to receive absorption spectral data from the absorption detector and fluorescence spectral data from the fluorescence detector.
- the method also includes the steps of directing the electromagnetic radiation through the sample solution in the chamber of the sample cell, absorbing the electromagnetic radiation by the sample solution, sensing the intensity of the electromagnetic radiation absorbed by the sample solution by an absorption detector, and generating an absorption signal of interest from the absorption detector.
- the method further includes the steps of producing fluorescence emissions from the sample solution, sensing the fluorescence emissions by a fluorescence detector, and generating a fluorescence signal of interest from the fluorescence detector.
- the method also includes steps of displaying an indication of the absorption signal of the absorption display, and displaying an indication of the fluorescence signal on the fluorescence display.
- FIG. 2 is a longitudinal cross-sectional view of the biosensor of FIG. 1 ;
- FIG. 3 is an exploded longitudinal cross-sectional view of the biosensor of FIG. 2 ;
- FIG. 4 is a cross-sectional view similar to FIG. 2 , showing the light source emitting an excitation energy, illustratively a laser beam passing through a sample chamber to an absorption detector and a reflective surface reflecting fluorescence to a fluorescence detector;
- an excitation energy illustratively a laser beam passing through a sample chamber to an absorption detector and a reflective surface reflecting fluorescence to a fluorescence detector;
- FIG. 5 is a block diagram illustrating interaction between various components of the biosensor of FIG. 1 ;
- FIGS. 6A-6C are perspective views illustrating various steps of operation of the biosensor of FIG. 1 .
- an illustrative hand-held biosensor 10 is shown for use in detecting substances (e.g., biological molecules, often referred to as biomolecules or bio-agents) within a sample fluid (e.g., gas or liquid).
- the biosensor 10 includes an outer casing 12 extending along a longitudinal axis 14 between a proximal (or lower) end 16 and a distal (or upper) end 18 .
- the biosensor 10 is configured to have an ergonomic size, shape and weight, thereby facilitating operation by a user.
- the outer casing 12 is configured to have dimensions substantially like that of a conventional laser pointer and, as such, is small enough to be used or operated while being held in the hand or hands of a user, and may be stored within a conventional pocket of the user. More particularly, the outer casing 12 is illustratively cylindrical and has an axial length (l) of less than about 20 centimeters (7.87 inches) and an outer diameter (d) of less than about 4 centimeters (1.57 inches). In a further illustrative embodiment, the outer casing 12 has an axial length (l) of less than about 16 centimeters (6.30 inches) and an outer diameter (d) of less than about 3 centimeters (1.18 inches).
- the outer casing 12 has an axial length (l) of approximately 14.2 centimeters (5.6 inches), and an outer diameter (d) of approximately 2 centimeters (0.79 inches).
- a representative weight of the hand-held biosensor 10 is approximately 4 ounces.
- An external clip 20 is illustratively coupled proximate the distal end 18 of the outer casing 12 for coupling to clothing of a user, for example to a shirt pocket (not shown).
- the biosensor 10 illustratively includes a plurality of releasably coupled component sections or modules, including a radiation emitting module 22 , a sample cell module 24 , an absorption detector module 26 , and a display module 28 , all aligned along the longitudinal axis 14 .
- the radiation emitting module 22 is positioned adjacent the proximal end 16 of the biosensor 10
- the display module 28 is positioned adjacent the distal end 18 of the biosensor 10 .
- the radiation emitting module 22 illustratively includes a radiation emitting module housing 30 having a cylindrical side wall 32 extending between a proximal end 31 and a distal end 33 .
- An end cap 34 is illustratively threadably coupled to the proximal end 31 of the side wall 32 .
- Both the side wall 32 and the end cap 34 are illustratively formed of a durable, light weight material, such as anodized aluminum or thermoplastic.
- the radiation emitting module 22 is configured to emit electromagnetic radiation (e.g., laser light) toward the sample cell module 24 .
- a radiation source such as a laser diode 36 and a laser diode driver 37 are positioned within the radiation emitting module housing 30 and is configured to emit electromagnetic radiation.
- the laser diode 36 is configured to emit an ultraviolet radiation laser beam 38 in an axial direction (i.e., along the longitudinal axis 14 as shown in FIG. 4 ) toward a sample cell chamber 40 defined by the sample cell module 24 .
- a lens 41 is illustratively positioned proximate to, and distal of, the laser diode 36 . More particularly, the lens 41 is positioned between the laser diode 36 and the sample cell chamber 40 .
- the illustrative laser diode driver 37 is operably coupled to and positioned proximal of the laser diode 36 .
- the lens 41 may be of conventional design (e.g., formed of a quartz material) and is used for collimating the laser beam 38 to within a desired diameter, illustratively less than about 3 millimeters.
- a spatial filter 42 is illustratively positioned distal of the lens 41 , between the lens 41 and the sample cell chamber 40 .
- the spatial filter 42 may be of conventional design for blocking scattered light and thereby removing spatial noise. More particularly, the illustrative spatial filter 42 includes a mask 44 including a center opening 46 (illustratively having a diameter no greater than 3 millimeters) to allow only the laser beam 38 to pass therethrough, and blocking scattered laser light.
- a first spectral filter 48 is illustratively positioned distal of the spatial filter 42 . More particularly, the spectral filter 48 is illustratively positioned between the spatial filter 42 and the sample cell chamber 40 .
- the spectral filter 48 may comprise a band-pass/interference filter that permits only radiation from the laser diode 36 to pass therethrough.
- the spectral filter 48 allows only radiation (i.e., laser beam 38 ) of the laser diode 36 to pass therethrough (e.g., having a wavelength of about 275 nm+/ ⁇ 15 nm in the illustrative universal embodiment of biosensor 10 ).
- a first or proximal power switch 52 is illustratively in electrical communication with the proximal battery 51 and is supported by the end cap 34 proximate the proximal end 16 of the outer casing 12 .
- the proximal power switch 52 may be a toggle push button configured to be depressed by a user.
- the sample cell module 24 is illustratively positioned distal of the radiation emitting module 22 and includes a sample cell module housing 54 defining the sample cell chamber 40 .
- a sample inlet 58 is positioned at a proximal end 60 of the housing 54 and is in selective fluid communication with the sample cell chamber 40 .
- a waste outlet 62 is positioned at a distal end 64 of the housing 54 and is in selective fluid communication with the sample cell chamber 40 .
- both the sample inlet 58 and the waste outlet 62 may include a resilient septum 66 and 68 , respectively.
- the septum 66 of the sample inlet 58 is configured to receive the tip 70 of a conventional syringe 72 including a plunger 74 slidably received within a barrel 76 .
- the septum 68 of the waste outlet 62 may receive the tip 78 of tubing 80 which is coupled to a collection device, such as a vial 82 ( FIG. 6A ).
- a light entry port 96 is illustratively formed within the proximal end wall 90
- a light exit port 98 is illustratively formed within the distal end wall 92
- the light entry port 96 and the light exit port 98 are aligned along the longitudinal axis 14 , and each has an illustrative diameter of about 5 millimeters centimeters (0.20 inches).
- the sample cell module housing 54 is illustratively sealed from external light, except for the light entry port 96 and the light exit port 98 .
- the sample cell module housing 54 illustratively defines a quartz sample cell chamber 40 .
- An inner surface 100 of the sample cell module housing 54 may be textured for self-cleaning.
- the inside surface 100 of the sample cell module housing 54 is nano-textured using, for example, ultra-short pulsed laser (USPL) beams or other known techniques to render the inner surface super-hydrophobic (i.e., water repelling) and/or super-lipophobic (i.e., repelling organic solvents/fats).
- USPL ultra-short pulsed laser
- the quartz sample cell chamber 40 as opposed to plastic vials or cells, reduces the chances of reaction and degradation, and promotes resulting prolonged usage and duration when used with various bio-agents.
- the walls of the quartz sample cell chamber 40 allows the laser light (illustratively 275 nm wavelength) and the fluorescence radiation (illustratively 345 nm wavelength) to pass through.
- a fluorescence detector 102 is illustratively supported adjacent a first side 104 of the sample cell module housing 54 . More particularly, the fluorescence detector 102 may comprise a strip detector coupled to the side wall 84 of the sample cell module housing 54 .
- the fluorescence detector 102 is configured to detect electromagnetic radiation having a wavelength of interest, illustratively between 200 nm and 1000 nm. In one illustrative embodiment, the fluorescence detector 102 is configured to detect electromagnetic radiation having a wavelength of about 345 nm. In one illustrative embodiment, the fluorescence detector 102 is a high quantum-efficiency avalanche photodiode-array, such as 1.5 mm UV-VIS (200-1000 nm), Si APD, Stock No. 59-184, available from Edmund Optics Inc. of Barrington, N.J.
- a fluorescence filter 106 is illustratively supported internally of the fluorescence detector 102 . More particularly, the fluorescence filter 106 is illustratively positioned between the sample cell chamber 40 and the fluorescence detector 102 .
- the fluorescence filter 106 comprises a spectral filter, such as a narrow band-pass filter configured to allow only fluorescence light of a wavelength of interest to pass therethrough.
- the fluorescence filter 106 allows only radiation having a wavelength between about 295 nm and 420 nm, and more particularly about 345 nm, to pass therethrough.
- a curved reflective surface 108 is illustratively supported adjacent a second side 110 of the sample cell module housing 54 , opposite the fluorescence detector 102 adjacent the first side 104 of the sample cell module housing 54 .
- the curved reflective surface 108 is defined by a polished surface or a mirror, illustratively a concave or spherical mirror 112 configured to curve-fit with the sample cell module housing 54 .
- the mirror 112 is configured to collect and focus light or fluorescence emission 113 ( FIG. 4 ) toward the fluorescence detector 102 .
- the reflective surface 108 is illustratively configured to collect and focus light 113 with a wavelength of about 345 nm.
- the laser beam 38 is an electromagnetic radiation of approximately 275 nm wavelength, which is used to uniquely excite amino-acids tryptophan (Trp) and tyrosine (Tyr) in the sample solution in sample cell chamber 40 .
- Fluorescence emission 113 (the 345 nm wavelength of light emitted from excited amino-acids tryptophan and tyrosine in this example) is collected with mirror 112 and reflected to the direction of the fluorescence detector 102 .
- a blank solution within the sample cell chamber 40 generates no fluorescence detection, provides background from the fluorescence detector 102 , and gives a background-subtracted zero fluorescence reading at a fluorescence display 150 .
- Any fluorescence signals above zero represents detection at the fluorescence detector 102 of the 345 nm wavelength of light, characteristically representing the presence of amino-acids tryptophan and/or tyrosine in the sample solution within the sample cell chamber 40 and symbolizing detection of biomolecules.
- a first releasable coupling 114 is positioned between the radiation emitting module 22 and the sample cell module 24 .
- internal threads 116 on the distal end 33 of the radiation emitting module 22 engage external threads 118 on the proximal end 60 of the sample cell module 24 .
- Other releasable couplings may be substituted for cooperating threads, including, for example bayonet couplings, resilient fingers, lock washers, etc.
- the absorption detector module 26 illustratively includes an absorption detector module housing 120 .
- the absorption detector module housing 120 illustratively includes a cylindrical side wall 122 extending between a proximal end 124 and a distal end 126 .
- the side wall 122 is illustratively formed of a durable, light weight material, such as anodized aluminum or thermoplastic.
- An absorption detector 128 is received within the absorption detector module housing 120 , and is configured to detect emission intensity/energy produced by electromagnetic radiation passing through a solution in the sample cell chamber 40 . In response, the detector 128 produces absorption spectral data.
- the absorption detector 128 is an absorption spot detector.
- the absorption detector 128 in a universal embodiment of the biosensor 10 may comprise a deep ultraviolet (DUV) photodiode. Since the absorption detector 128 directly senses the laser beam, sensitivity is not an issue. In a selective embodiment of the biosensor 10 that employs a longer wavelength, a wide variety of known diodes are readily available.
- DUV deep ultraviolet
- the absorption detector 128 is configured to detect electromagnetic radiation having a wavelength of between about 200 nm and 980 nm, and more particularly a wavelength of about 275 nm. More particularly, the absorption detector 128 may comprise a silicon photodiode, such as 5.7 mm 2 DUV Photodiode with Ceramic Housing, Stock No. 84-982, available from Edmund Optics Inc. of Barrington, N.J.
- the illustrative absorption detector 128 senses the intensity of the laser beam 38 .
- the original intensity of the laser beam 38 (for example, 275 nm wavelength) passes through a blank solution in the sample cell chamber 40 , is detected from the absorption detector 128 , is registered and showed as zero absorption signal at an absorption display 152 .
- An absorption signal higher than zero represents a partial absorption of the laser beam 38 .
- the approximately 275 nm wavelength in this example indicates the presence of the amino acids tryptophan (Trp) and/or tyrosine (Tyr) in the sample solution in the sample cell chamber 40 , and therefore, the presence of biomolecules.
- a molecule absorbs its unique excitation radiation and emits a red shifted characteristic radiation. The intensity of this emission is monitored by the fluorescence detector 102 .
- a biomolecule absorbs laser light 38 of wavelength 275 nm and emit fluorescence light 113 of wavelength 345 nm.
- the emission from a sample cell having a volume less than 1 cm 3 (0.06 in 3 ) generated with diffused-lamp-excitation is collected right-angle to the source-radiation and focused onto a spot-detector.
- the biosensor 10 of the present disclosure employs an intense, directional, laser-beam for optically-thin excitation of a relatively long (approximately 5 cm (1.96 inches)) sample path; and generates a long emission image that is collected at a right angle to the laser source by the concave reflective mirror (surface) 112 and focused onto the fluorescence strip detector 102 .
- the detector and the emission image has an approximately overlapped dimension, resulting in high sensitivity.
- the fluorescence measurement may illustratively be set between 295 nm and 420 nm, primarily for Trp. In one such illustrative embodiment, this is set at 345 nm through the fluorescence band-pass filter 106 .
- a second releasable coupling 140 is positioned between the sample cell module 24 and the absorption detector module 26 .
- internal threads 142 on the distal end 64 of the sample cell module 24 engage external threads 144 on the proximal end 124 of the absorption detector module 26 .
- Other releasable couplings may be substituted for cooperating threads, including, for example bayonet couplings, resilient fingers, lock washers, etc.
- the memory 147 may include a random-access memory configured to store information such as the date, locations, and the number of positive hits for particular biomolecules based upon the electromagnetic radiation wavelengths sensed by the detectors 102 and 128 .
- An electrical coupler for example a communication port or transmitter (not shown), may be operably coupled to the controller 145 for providing electrical communication with the processor 146 to supply data to external devices, for example.
- the display module 28 is illustratively positioned distal of the absorption detector module 26 and includes a display module housing 148 .
- Fluorescence display 150 is supported within the display module housing 148 and is configured to provide an indication of the fluorescence spectral data from the processor 146 as received from the fluorescence detector 102 .
- Absorption display 152 is supported within the display module housing 148 and is configured to provide an indication of the absorption spectral data from the processor 146 as received from the absorption detector 128 .
- the fluorescence display 150 illustratively comprises a digital readout (e.g., a liquid crystal display (LCD)) configured to display fluorescence spectral data from the processor 146 as received from the fluorescence detector 102 .
- the absorption display 152 illustratively comprises a digital readout (e.g., a liquid crystal display (LCD)) configured to display absorption data from the processor 146 as received from the absorption detector 128 .
- a second or distal power switch 170 is illustratively in electrical communication with the distal battery 169 and is supported by the end cap 160 proximate the distal end 18 of the outer casing 12 .
- the distal power switch 170 may be a toggle push button that is configured to be depressed by a user.
- the biosensor 10 is returned to the upright position with the longitudinal axis 14 extending in a vertical direction with the proximal end 16 positioned below the distal end 18 .
- a blank solution e.g., water solution
- the tip 70 of the syringe 72 is received within the septum 66 of the sample inlet 58 .
- the plunger 74 is depressed thereby injecting the blank into the sample cell chamber 40 .
- the processor 146 will electronically generate zero absorbance at the absorption display 152 and zero signal at the fluorescence display 150 .
- a sample solution is next received within the barrel 76 of the syringe 72 .
- the tip 70 of the syringe 72 is received within the septum 66 of the sample inlet 58 .
- the plunger 74 is depressed thereby injecting the sample solution into the sample cell chamber 40 .
- a filtered sample solution is received within the barrel 76 by pulling the plunger 74 with a filter 178 attached between the syringe 72 and the tip 70 received in the sample solution.
- the filter 178 is then detached.
- the tip 70 of the syringe 72 is received within the septum 66 of the sample inlet 58 .
- the plunger 74 is depressed thereby injecting the filtered sample solution into the sample cell chamber 40 .
- the method continues by the user depressing the power buttons 52 , 170 to “on” positions, thereby activating the radiation emitting module 22 , the display module 28 , the fluorescence detector 102 and the absorption detector 128 .
- the laser diode 36 emits electromagnetic radiation, illustratively light (e.g., laser beam 38 ), through the entry port 96 and the sample chamber 40 .
- the light passes through the sample solution in the sample cell chamber 40 , where the absorption portion of the light (i.e., intensity of the laser beam 38 absorbed by the sample solution) is directed to the exit port 98 and to the absorption detector 128 , and the fluorescence portion of the light (i.e., intensity of excited or fluorescence emissions from the sample solution as a result of the laser beam 38 ) is reflected by the reflective surface 108 at a right angle to the electromagnetic radiation laser beam 38 (i.e., the longitudinal axis 14 ) to the fluorescence detector 102 .
- the absorption portion of the light i.e., intensity of the laser beam 38 absorbed by the sample solution
- the fluorescence portion of the light i.e., intensity of excited or fluorescence emissions from the sample solution as a result of the laser beam 38
- Absorption values from the absorption detector are transmitted to the processor 146 and then displayed on the absorption display 152 .
- Fluorescence values from the fluorescence detector are transmitted to the processor 146 and then displayed on the fluorescence display 150 .
- a baseline value can be set with the blank solution, where the display readings can be adjusted to zero values for background subtraction via the processor 146 . Positive reading valves above zero indicate presence of biomolecules. The process may then continue by returning to the step of injecting the cleansing solution via the syringe 72 .
- the biosensor 10 is relatively small. More particularly, the biosensor 10 is of a small size and is light weight, similar to those of a pen/laser pointer. The biosensor 10 also includes the capability to provide both absorption and fluorescence measurements simultaneously in of a field acquired sample solution. The biosensor 10 may find utility in a variety of applications, including in the military, food and health industries, and with first responders.
- the biosensor 10 of the present disclosure facilitates portability by having a small size, being light weight, being durable, having low power requirements and being pocket wearable.
- the biosensor 10 includes modular components thereby allowing choices of integration into a variety of different purpose specific biosensors.
- the biosensor 10 of the present disclosure also provides for improved sensitivity. More particularly, the biosensor 10 provides for high sensitivity from the sample cell including a long absorption path length and a long emission (fluorescence) region. Additionally, the biosensor 10 operates with a laser beam, sample cell, and detectors enclosed in a light sealed assembly to prevent the detectors receiving interference from external light sources. Further, the sample cell of the biosensor may be recalibrated (i.e., zeroed) by using a blank solution or empty sample cell chamber, resulting in a higher signal-to-noise ratio, thereby increasing the sensitivity of the biosensor 10 .
- the biosensor 10 demonstrates reliability by providing simple to read displays, providing repeatable performance with no operator interpretation required in reading results. Additionally, the occurrence of false or incorrect results is easily identifiable.
- the absorption measurement may receive interference by beam-blockage from opaque particles and the fluorescence (emission) measurement may receive interference by beam-scattering from reflective particles. Receiving an absorption reading but not a fluorescence reading, or vice versa, may be an indication of a possible false/incorrect result. Therefore, having both an absorption reading and a fluorescence reading works as a double-assurance, thereby increasing the confidence on each result of the biosensor.
- Native absorption and fluorescence provides a major advantage for biomolecule detection because all biomolecules contain amino acids (e.g., phenylalanine, tryptophan, and tyrosine) and, therefore, by laser or appropriate light exposure directly on the sample solution followed by simultaneous positive absorption detection and positive fluorescence detection indicate the presence of biomolecules (e.g., phenylalanine, tryptophan, and tyrosine). That is, tryptophan and tyrosine characteristically absorb the laser or light wavelength of 275 nm and, when excited, emit their fluorescence radiation at 345 nm.
- amino acids e.g., phenylalanine, tryptophan, and tyrosine
- simultaneous positive absorption detection and positive fluorescence detection indicate the presence of biomolecules (e.g., phenylalanine, tryptophan, and tyrosine). That is, tryptophan and tyrosine characteristically absorb the laser or light wavelength of 275 nm
- operation of the biosensor 10 of the present disclosure provides for improved assay time. Simply activate the power buttons and read the displays which provide instance results in the field.
- the components of the biosensor are relatively inexpensive, thereby providing for a cost low enough for wide distribution.
- the modular design of the biosensor 10 provides component choices. Assembling particular modules making the biosensor 10 functions as a universal biosensor for all biomolecules (based on native molecular absorption spectrophotometry and native fluorescence spectrophotometry) or as a selective biosensor (based on specific-tagging of selective biomolecules followed by characteristic absorption and fluorescence from the tagged biomolecules).
- the laser diode 36 emits an electromagnetic radiation (e.g., laser beam 38 ) of approximately 275 nm wavelength that is directed to pass through a sample in the sample cell chamber 40 .
- the absorption detector 128 senses the intensity of the laser beam 38 (275 nm wavelength) absorbed, and the fluorescence detector 102 detects the collected light intensity, specifically of approximately 345 nm wavelength, emitted from the sample solution.
- a positive detection (signal above background from a blank solution) from the detectors 102 and 128 indicates the sample solution contains biomolecules.
Abstract
Description
- The present application claims priority to U.S. Provisional Patent Application Ser. No. 62/451,216, filed Jan. 27, 2017 (Attorney Docket NC 200,319), the disclosure of which is expressly incorporated herein by reference.
- The invention described herein includes contributions by one or more employees of the Department of the Navy made in performance of official duties and may be manufactured, used, and licensed by or for the United States Government without payment of any royalties thereon. This invention (Navy Case 200,408) is assigned to the United States Government and is available for licensing for commercial purposes. Licensing and technical inquiries may be directed to the Technology Transfer Office, Naval Surface Warfare Center Corona Division, email: CRNA_CTO@navy.mil.
- The present disclosure relates generally to methods and apparatuses for detecting and identifying substances within a sample fluid. More particularly, the present invention relates to a portable, illustratively pocket wearable, laser based biosensor including modular components, and combining molecular absorption spectrophotometry and molecular fluorescence spectrophotometry.
- Molecular absorption spectrophotometry (MAS) and molecular fluorescence spectrophotometry (MFS) are well established analytical techniques. More particularly, a variety of dedicated molecular absorption spectrophotometers and dedicated molecular fluorescence spectrophotometers are available from a variety of chemical instrument manufacturers. Some of these devices are portable. While simultaneous operation of MAS and MFS has been performed in research laboratories for solving specialized, fundamental problems; there are no known portable combination absorption-fluorescence spectrophotometers available in the market for the field testing of substances within a fluid sample.
- There remains a need for the efficient field testing of substances within a fluid sample, combining both molecular absorption spectrophotometry (MAS) and molecular fluorescence spectrophotometry (MFS), in a single spectrophotometer, for performing both absorption and fluorescence measurements and providing rapid results to the user.
- The present invention relates to a hand-held laser based biosensor that illustratively is portable (e.g., pocket wearable by a user), is modular (e.g., interchangeable modules), has improved selectivity (e.g., combined molecular absorption spectrophotometry and molecular fluorescence spectrophotometry), and has improved sensitivity (e.g., long absorption path length and long emission (fluorescence) region). Such a biosensor may find use in a variety of applications including, for example, in the military, food and drug industries, and with first responders (e.g., police and firefighters).
- According to an illustrative embodiment of the present disclosure, a hand-held biosensor includes a radiation emitting module including light emitting module housing, and a light source received within the radiation emitting module housing and configured to generate excitation energy, illustratively a laser beam. The hand-held biosensor further includes a sample cell module including a sample cell module housing defining a chamber configured to receive a solution, a sample inlet in fluid communication with the chamber, and a waste outlet in fluid communication with the chamber. A first releasable coupling is positioned between the radiation emitting module and the sample cell module. An absorption detector is configured to detect emission intensity produced by the electromagnetic radiation passing through the solution in the sample cell chamber and produce absorption spectral data in response thereto, and produce absorption spectral data in response thereto, the absorption detector including an absorption detector spectral filter. A fluorescence detector is configured to detect molecular emissions produced by the laser excited molecules as the laser beam passes through the solution in the sample cell chamber and produces fluorescence spectral data in response thereto, the fluorescence detector including a fluorescence detector spectral filter. A processor is in electrical communication with the absorption detector and the fluorescence detector, the processor being configured to receive the absorption spectral data from the absorption detector and the fluorescence spectral data from the fluorescence detector. A display module is in electrical communication with the processor, the display module including a display module housing, an absorption display supported by the display module housing and configured to provide an indication of the absorption spectral data from the absorption detector, and a fluorescence display supported by the display module housing and configured to provide an indication of a fluorescence spectral data from the fluorescence detector. A power source is in communication with the processor. A second releasable coupling is positioned between the display module and the sample cell module.
- According to another illustrative embodiment of the present disclosure, a hand-held biosensor includes an outer casing extending between a proximal end and a distal end, and a radiation emitting module supported proximate the proximal end of the outer casing. A display module is supported proximate the distal end of the outer casing, and the sample cell module is supported intermediate the radiation emitting module and the display module. The sample cell module includes a sample cell module housing defining a chamber and including a light entry port, a light exit port axially spaced by the chamber from the light entry port, a longitudinal axis defined by the light entry port and the light exit port, and a reflective surface configured to reflect light from the radiation emitting module transverse to the longitudinal axis. The hand-held biosensor further includes an absorption detector, a fluorescence detector, and a processor in electrical communication with the absorption detector and the fluorescence detector, the processor being configured to receive absorption spectral data from the absorption detector and fluorescence spectral data from the fluorescence detector. The sample cell module includes an axial length between the light entry port and the light exit port, the axial length being at least about 5 centimeters.
- According to another illustrative embodiment of the present disclosure, a method of constructing a hand-held biosensor includes the steps of providing a sample cell module including a sample cell module housing having a side wall defining a chamber and extending longitudinally between a proximal end and a distal end, a sample inlet in communication with the chamber, and a waste outlet in communication with the chamber. The method further includes the steps of providing a solution within the chamber of the sample cell module, providing a radiation emitting module including a radiation emitting module housing extending longitudinally between the proximal end and the distal end, a light source received within the radiation emitting module housing and configured to generate an excitation laser beam, and releasably coupling the distal end of the radiation emitting module housing to the proximal end of the sample cell module housing. The method further includes the steps of providing an absorption detector at the distal end of the sample cell, the absorption detector configured to detect the intensity of the laser beam (energy) passing through the solution in the sample cell chamber, the absorption detector including an absorption detector spectral filter, and providing a fluorescence detector configured to detect emissions produced by laser excited molecules as the laser beam passes through the solution of the sample cell chamber, the fluorescence detector including a fluorescence detector spectral filter. The method also includes the steps of providing a processor in electrical communication with the absorption detector and the fluorescence detector, the processor configured to receive absorption spectral data from the absorption detector and fluorescence spectral data from the fluorescence detector. The method further includes the steps of providing a display module in electrical communication with the processor, the display module including the display module housing extending between a proximal end and a distal end, an absorption display supported by a display module housing and configured to provide an indication of the absorption spectral data, and a fluorescence display supported by the display module housing and configured to provide an indication of the fluorescence spectral data. The method further includes the steps of releasably coupling the distal end of the sample cell module housing to the proximal end of the display module housing, and providing a power source in electrical communication with the processor.
- According to further illustrative embodiment of the present disclosure, a method of detecting a substance within a fluid sample using a hand-held biosensor includes the steps of providing a sample cell module including a sample cell module housing having a side wall defining a chamber and extending along a longitudinal axis between a proximal end and a distal end, a sample inlet in fluid communication with the chamber, and a waste outlet in fluid communication with the chamber, and fluidly coupling a waste collection vial to the waste outlet. The method further includes the steps of injecting a sample solution through the sample inlet into the chamber of the sample cell module, and generating an electromagnetic radiation with a laser light source. The method also includes the steps of directing the electromagnetic radiation through the sample solution in the chamber of the sample cell, absorbing the electromagnetic radiation by the sample solution, sensing the intensity of the electromagnetic radiation absorbed by the sample solution by an absorption detector, and generating an absorption signal of interest from the absorption detector. The method further includes the steps of producing fluorescence emissions from the sample solution, sensing the fluorescence emissions by a fluorescence detector, and generating a fluorescence signal of interest from the fluorescence detector. The method also includes steps of displaying an indication of the absorption signal of the absorption display, and displaying an indication of the fluorescence signal on the fluorescence display.
- Additional features and advantages of the present invention will become apparent to those skilled in the art upon consideration of the following detailed description of the illustrative embodiments exemplifying the best modes of carrying out the invention as presently perceived.
- A detailed description of the drawings particularly refers to the accompanying figures, in which:
-
FIG. 1 is a perspective view of an illustrative portable, illustratively pocket wearable, biosensor of the present disclosure; -
FIG. 2 is a longitudinal cross-sectional view of the biosensor ofFIG. 1 ; -
FIG. 3 is an exploded longitudinal cross-sectional view of the biosensor ofFIG. 2 ; -
FIG. 4 is a cross-sectional view similar toFIG. 2 , showing the light source emitting an excitation energy, illustratively a laser beam passing through a sample chamber to an absorption detector and a reflective surface reflecting fluorescence to a fluorescence detector; -
FIG. 5 is a block diagram illustrating interaction between various components of the biosensor ofFIG. 1 ; and -
FIGS. 6A-6C are perspective views illustrating various steps of operation of the biosensor ofFIG. 1 . - Various embodiments of the invention described herein are not intended to be exhaustive or to limit the invention to precise forms disclosed. Rather, the embodiments selected for description have been chosen to enable one skilled in the art to practice the invention.
- Referring initially to
FIGS. 1-4 , an illustrative hand-heldbiosensor 10 is shown for use in detecting substances (e.g., biological molecules, often referred to as biomolecules or bio-agents) within a sample fluid (e.g., gas or liquid). Illustratively, thebiosensor 10 includes anouter casing 12 extending along alongitudinal axis 14 between a proximal (or lower)end 16 and a distal (or upper)end 18. Thebiosensor 10 is configured to have an ergonomic size, shape and weight, thereby facilitating operation by a user. With reference toFIG. 2 , theouter casing 12 is configured to have dimensions substantially like that of a conventional laser pointer and, as such, is small enough to be used or operated while being held in the hand or hands of a user, and may be stored within a conventional pocket of the user. More particularly, theouter casing 12 is illustratively cylindrical and has an axial length (l) of less than about 20 centimeters (7.87 inches) and an outer diameter (d) of less than about 4 centimeters (1.57 inches). In a further illustrative embodiment, theouter casing 12 has an axial length (l) of less than about 16 centimeters (6.30 inches) and an outer diameter (d) of less than about 3 centimeters (1.18 inches). In one illustrative embodiment, theouter casing 12 has an axial length (l) of approximately 14.2 centimeters (5.6 inches), and an outer diameter (d) of approximately 2 centimeters (0.79 inches). A representative weight of the hand-heldbiosensor 10 is approximately 4 ounces. Anexternal clip 20 is illustratively coupled proximate thedistal end 18 of theouter casing 12 for coupling to clothing of a user, for example to a shirt pocket (not shown). - The
biosensor 10 illustratively includes a plurality of releasably coupled component sections or modules, including aradiation emitting module 22, asample cell module 24, anabsorption detector module 26, and adisplay module 28, all aligned along thelongitudinal axis 14. Illustratively, theradiation emitting module 22 is positioned adjacent theproximal end 16 of thebiosensor 10, and thedisplay module 28 is positioned adjacent thedistal end 18 of thebiosensor 10. - With reference to
FIGS. 3 and 4 , theradiation emitting module 22 illustratively includes a radiation emittingmodule housing 30 having acylindrical side wall 32 extending between aproximal end 31 and adistal end 33. Anend cap 34 is illustratively threadably coupled to theproximal end 31 of theside wall 32. Both theside wall 32 and theend cap 34 are illustratively formed of a durable, light weight material, such as anodized aluminum or thermoplastic. - The
radiation emitting module 22 is configured to emit electromagnetic radiation (e.g., laser light) toward thesample cell module 24. Illustratively, a radiation source, such as alaser diode 36 and alaser diode driver 37 are positioned within the radiation emittingmodule housing 30 and is configured to emit electromagnetic radiation. More particularly, thelaser diode 36 is configured to emit an ultravioletradiation laser beam 38 in an axial direction (i.e., along thelongitudinal axis 14 as shown inFIG. 4 ) toward asample cell chamber 40 defined by thesample cell module 24. As further detailed herein, in an illustrative universal embodiment ofbiosensor 10, the wavelength of thelaser beam 38 emitted by thelaser diode 36 is illustratively between 260 nm and 290 nm, and more particularly about 275 nm, for native absorption and native fluorescence. In an illustrative selective embodiment ofbiosensor 10, the wavelength of thelaser beam 38 emitted by thelaser diode 36 will be centered approximately at the excitation wavelength for absorption and fluorescence of the labeled biomolecule. Thelaser diode 36 is illustratively soldered to thelaser diode driver 37. Illustratively, a suitablelaser diode driver 37 is the CW Laser Diode Driver LSC-025 (0.82 inches×0.29 inches×0.20 inches), available from Laser Components USA, Inc. of Bedford, N.H. - A
lens 41 is illustratively positioned proximate to, and distal of, thelaser diode 36. More particularly, thelens 41 is positioned between thelaser diode 36 and thesample cell chamber 40. The illustrativelaser diode driver 37 is operably coupled to and positioned proximal of thelaser diode 36. Thelens 41 may be of conventional design (e.g., formed of a quartz material) and is used for collimating thelaser beam 38 to within a desired diameter, illustratively less than about 3 millimeters. - A
spatial filter 42 is illustratively positioned distal of thelens 41, between thelens 41 and thesample cell chamber 40. Thespatial filter 42 may be of conventional design for blocking scattered light and thereby removing spatial noise. More particularly, the illustrativespatial filter 42 includes amask 44 including a center opening 46 (illustratively having a diameter no greater than 3 millimeters) to allow only thelaser beam 38 to pass therethrough, and blocking scattered laser light. - A first
spectral filter 48 is illustratively positioned distal of thespatial filter 42. More particularly, thespectral filter 48 is illustratively positioned between thespatial filter 42 and thesample cell chamber 40. Thespectral filter 48 may comprise a band-pass/interference filter that permits only radiation from thelaser diode 36 to pass therethrough. For example, thespectral filter 48 allows only radiation (i.e., laser beam 38) of thelaser diode 36 to pass therethrough (e.g., having a wavelength of about 275 nm+/−15 nm in the illustrative universal embodiment of biosensor 10). - The
radiation emitting module 22 further includes a first orproximal power source 50 illustratively in electrical communication with theradiation emitting module 22. Thefirst power source 50 may comprise aproximal battery 51 releasably supported within theend cap 34. Theproximal battery 51 is illustratively a rechargeable button cell battery. In one illustrative embodiment, a military grade 3.0 Volt Saft BA5367U Lithium Sulfur Dioxide (1 inch×1 inch×0.075 inch) battery produced by Saft SA in France may be used. Another illustrative battery is the BA5367U battery together with a DC/DC High Voltage DBC-Series (0.83 inch×0.83 inch×0.32 inch) Module, available from Laser Components USA, for raising the voltage output. - A first or
proximal power switch 52 is illustratively in electrical communication with theproximal battery 51 and is supported by theend cap 34 proximate theproximal end 16 of theouter casing 12. Theproximal power switch 52 may be a toggle push button configured to be depressed by a user. - The
sample cell module 24 is illustratively positioned distal of theradiation emitting module 22 and includes a samplecell module housing 54 defining thesample cell chamber 40. Asample inlet 58 is positioned at aproximal end 60 of thehousing 54 and is in selective fluid communication with thesample cell chamber 40. Similarly, awaste outlet 62 is positioned at adistal end 64 of thehousing 54 and is in selective fluid communication with thesample cell chamber 40. Illustratively, both thesample inlet 58 and thewaste outlet 62 may include aresilient septum septum 66 of thesample inlet 58 is configured to receive thetip 70 of aconventional syringe 72 including aplunger 74 slidably received within abarrel 76. Similarly, theseptum 68 of thewaste outlet 62 may receive thetip 78 oftubing 80 which is coupled to a collection device, such as a vial 82 (FIG. 6A ). - The sample
cell module housing 54 illustratively includes an outercylindrical side wall 84 extending between theproximal end 60 and thedistal end 64. A first orproximal end wall 90 is coupled to theproximal end 60 of theside wall 84, and a second ordistal end wall 92 is coupled to thedistal end 64 of theside wall 84. Theside wall 84 and theend walls inner surface 100 of thesample cell chamber 40 is illustratively darkened, illustratively by application of a dark coating and/or texturing. More particularly, theinner surface 100 may be defined by thesidewall 84 and theend walls - A
light entry port 96 is illustratively formed within theproximal end wall 90, while alight exit port 98 is illustratively formed within thedistal end wall 92. Illustratively, thelight entry port 96 and thelight exit port 98 are aligned along thelongitudinal axis 14, and each has an illustrative diameter of about 5 millimeters centimeters (0.20 inches). The samplecell module housing 54 is illustratively sealed from external light, except for thelight entry port 96 and thelight exit port 98. - The sample
cell module housing 54 illustratively defines a quartzsample cell chamber 40. Aninner surface 100 of the samplecell module housing 54 may be textured for self-cleaning. In an illustrative embodiment, theinside surface 100 of the samplecell module housing 54 is nano-textured using, for example, ultra-short pulsed laser (USPL) beams or other known techniques to render the inner surface super-hydrophobic (i.e., water repelling) and/or super-lipophobic (i.e., repelling organic solvents/fats). The quartzsample cell chamber 40, as opposed to plastic vials or cells, reduces the chances of reaction and degradation, and promotes resulting prolonged usage and duration when used with various bio-agents. The walls of the quartzsample cell chamber 40 allows the laser light (illustratively 275 nm wavelength) and the fluorescence radiation (illustratively 345 nm wavelength) to pass through. - With further reference to
FIGS. 3 and 4 , afluorescence detector 102 is illustratively supported adjacent afirst side 104 of the samplecell module housing 54. More particularly, thefluorescence detector 102 may comprise a strip detector coupled to theside wall 84 of the samplecell module housing 54. - Illustratively, the
fluorescence detector 102 is configured to detect electromagnetic radiation having a wavelength of interest, illustratively between 200 nm and 1000 nm. In one illustrative embodiment, thefluorescence detector 102 is configured to detect electromagnetic radiation having a wavelength of about 345 nm. In one illustrative embodiment, thefluorescence detector 102 is a high quantum-efficiency avalanche photodiode-array, such as 1.5 mm UV-VIS (200-1000 nm), Si APD, Stock No. 59-184, available from Edmund Optics Inc. of Barrington, N.J. - A
fluorescence filter 106 is illustratively supported internally of thefluorescence detector 102. More particularly, thefluorescence filter 106 is illustratively positioned between thesample cell chamber 40 and thefluorescence detector 102. Illustratively, thefluorescence filter 106 comprises a spectral filter, such as a narrow band-pass filter configured to allow only fluorescence light of a wavelength of interest to pass therethrough. In an illustrative universal embodiment of thebiosensor 10, thefluorescence filter 106 allows only radiation having a wavelength between about 295 nm and 420 nm, and more particularly about 345 nm, to pass therethrough. - A curved
reflective surface 108 is illustratively supported adjacent asecond side 110 of the samplecell module housing 54, opposite thefluorescence detector 102 adjacent thefirst side 104 of the samplecell module housing 54. Illustratively, the curvedreflective surface 108 is defined by a polished surface or a mirror, illustratively a concave orspherical mirror 112 configured to curve-fit with the samplecell module housing 54. Themirror 112 is configured to collect and focus light or fluorescence emission 113 (FIG. 4 ) toward thefluorescence detector 102. Thereflective surface 108 is illustratively configured to collect and focus light 113 with a wavelength of about 345 nm. - In the illustrative embodiment
universal biosensor 10, thelaser beam 38 is an electromagnetic radiation of approximately 275 nm wavelength, which is used to uniquely excite amino-acids tryptophan (Trp) and tyrosine (Tyr) in the sample solution insample cell chamber 40. Fluorescence emission 113 (the 345 nm wavelength of light emitted from excited amino-acids tryptophan and tyrosine in this example) is collected withmirror 112 and reflected to the direction of thefluorescence detector 102. A blank solution within thesample cell chamber 40 generates no fluorescence detection, provides background from thefluorescence detector 102, and gives a background-subtracted zero fluorescence reading at afluorescence display 150. Any fluorescence signals above zero represents detection at thefluorescence detector 102 of the 345 nm wavelength of light, characteristically representing the presence of amino-acids tryptophan and/or tyrosine in the sample solution within thesample cell chamber 40 and symbolizing detection of biomolecules. - A first
releasable coupling 114 is positioned between theradiation emitting module 22 and thesample cell module 24. Illustratively,internal threads 116 on thedistal end 33 of theradiation emitting module 22 engageexternal threads 118 on theproximal end 60 of thesample cell module 24. Other releasable couplings may be substituted for cooperating threads, including, for example bayonet couplings, resilient fingers, lock washers, etc. - The
absorption detector module 26 illustratively includes an absorptiondetector module housing 120. The absorptiondetector module housing 120 illustratively includes acylindrical side wall 122 extending between aproximal end 124 and adistal end 126. Theside wall 122 is illustratively formed of a durable, light weight material, such as anodized aluminum or thermoplastic. - An
absorption detector 128 is received within the absorptiondetector module housing 120, and is configured to detect emission intensity/energy produced by electromagnetic radiation passing through a solution in thesample cell chamber 40. In response, thedetector 128 produces absorption spectral data. In an illustrative embodiment, theabsorption detector 128 is an absorption spot detector. As further detailed herein, theabsorption detector 128 in a universal embodiment of thebiosensor 10 may comprise a deep ultraviolet (DUV) photodiode. Since theabsorption detector 128 directly senses the laser beam, sensitivity is not an issue. In a selective embodiment of thebiosensor 10 that employs a longer wavelength, a wide variety of known diodes are readily available. - Illustratively, the
absorption detector 128 is configured to detect electromagnetic radiation having a wavelength of between about 200 nm and 980 nm, and more particularly a wavelength of about 275 nm. More particularly, theabsorption detector 128 may comprise a silicon photodiode, such as 5.7 mm2 DUV Photodiode with Ceramic Housing, Stock No. 84-982, available from Edmund Optics Inc. of Barrington, N.J. - A second
spectral filter 130 is supported internally or proximal of theabsorption detector 128. More particularly, the secondspectral filter 130 is positioned between thesample cell chamber 40 and theabsorption detector 128. Thespectral filter 130 may comprise a band-pass/interference filter that permits only radiation from thelaser diode 36 to pass therethrough. For example, thespectral filter 130 allows only radiation of the laser diode 36 (e.g., about 275 nm+/−15 nm in the illustrative universal embodiment of biosensor 10). - More particularly, the
illustrative absorption detector 128 senses the intensity of thelaser beam 38. In operation, the original intensity of the laser beam 38 (for example, 275 nm wavelength) passes through a blank solution in thesample cell chamber 40, is detected from theabsorption detector 128, is registered and showed as zero absorption signal at anabsorption display 152. An absorption signal higher than zero represents a partial absorption of thelaser beam 38. The approximately 275 nm wavelength in this example indicates the presence of the amino acids tryptophan (Trp) and/or tyrosine (Tyr) in the sample solution in thesample cell chamber 40, and therefore, the presence of biomolecules. - The
sample cell module 24 facilitates high sensitivity by providing a long absorption path length and a long emission (fluorescence) region. Absorption spectrophotometry is defined by Beer's Law according to the equation: A=a·b·c, where A is the absorbance signal (the remaining intensity of the source radiation detected), a is the unique spectral absorption of monochromatic source radiation (illustratively 275 nm laser light) for the example biomolecule at that wavelength, b is the absorption cell radiation path length, and c is the concentration of the sample solution. - As may be appreciated by Beer's Law, the absorbance signal (A) increases when the absorption cell radiation cell path length (b) increases. With reference to
FIG. 4 , the path length (b) of the sample cell in the illustrative biosensor is at least about 5 centimeters (1.96 inches). This path length provides improved signal strength of about five times over known biosensors having reduced path lengths (approximately 1 centimeter (0.39 inches)). - In fluorescence spectrophotometry, a molecule absorbs its unique excitation radiation and emits a red shifted characteristic radiation. The intensity of this emission is monitored by the
fluorescence detector 102. Illustratively, a biomolecule absorbslaser light 38 of wavelength 275 nm and emitfluorescence light 113 of wavelength 345 nm. - Typically, with a fluorescence spectrophotometer, the emission from a sample cell having a volume less than 1 cm3 (0.06 in3) generated with diffused-lamp-excitation, is collected right-angle to the source-radiation and focused onto a spot-detector. The
biosensor 10 of the present disclosure employs an intense, directional, laser-beam for optically-thin excitation of a relatively long (approximately 5 cm (1.96 inches)) sample path; and generates a long emission image that is collected at a right angle to the laser source by the concave reflective mirror (surface) 112 and focused onto thefluorescence strip detector 102. The detector and the emission image has an approximately overlapped dimension, resulting in high sensitivity. - As further detailed herein, the
biosensor 10 may be used as a universal sensor for detecting all biomolecules, and/or a selective sensor for detecting only particular biomolecules. All biomolecules and biological cells (e.g., spores, human and bacterial cells, etc.) have proteins with their constituents being amino acids. Amino acids bond together to form proteins. The amino acids phenylalanine (Phe), tryptophan (Trp) and tyrosine (Tyr) can be monitored for “native” (i.e., label-free) absorption and fluorescence in response to electromagnetic radiation. With respect to the amount of amino acid found in protein: Phe>Tyr>Trp. As for the extinction coefficient for the amino acids: Trp>Tyr>Phe. Thebiosensor 10 detects the amino acids specifically and defines as a universal sensor for all biomolecules and biological cells. - When configured as an illustrative embodiment
universal biosensor 10 for detecting both Trp and Tyr, thelaser diode 36 illustratively emits an electromagnetic radiation or light having a wavelength of between about 265 nm and about 285 nm for the absorption measurement by theabsorption detector 128. In one such illustrative embodiment, thelaser diode 36 emits light having a wavelength of about 275 nm. An illustrative laser diode has an 8 to 10 mW output power, emitting a wavelength of 270 to 280 nm, such as model UVCLEAN275SMD available from QPhotonics of Ann Arbor, Mich. - The fluorescence measurement may illustratively be set between 295 nm and 420 nm, primarily for Trp. In one such illustrative embodiment, this is set at 345 nm through the fluorescence band-
pass filter 106. - In the case for detecting Phe, the
laser diode 36 illustratively emits electromagnetic radiation of about 255 nm for the absorption measurement and excitation, while about 280 nm is used for the fluorescence measurement. - As further detailed herein, the
absorption detector 128 and thefluorescence detector 102 are illustratively deep ultraviolet (DUV) detectors. In alternative illustrative embodiments, theabsorption detector 128 and thefluorescence detector 102 may each be a charge-coupled device (CCD) as used in camera and imaging devices. - When the
illustrative biosensor 10 is configured as a selective sensor for only particular biomolecules, thelaser diode 36 is selected with a suitable emission wavelength for detecting that biomolecule of interest. More particularly, in such a configuration, thebiosensor 10 demonstrates increased selectivity and sensitivity for detection. As further detailed herein, the biomolecule of interest in the sample solution is dye-labeled prior to injection into thesample cell chamber 40. Certain organic-dyes or semi-conductor quantum dots preferentially bind to particular biomolecules/proteins. The dye-labeled or quantum dot-labeled protein has a characteristic absorption (excitation) and fluorescence (emission) wavelength profile. - In one illustrative embodiment of the
biosensor 10 configured as a selective sensor, thelaser diode 36 is configured to emit electromagnetic radiation having a wavelength of between about 400 nm and about 410 nm. The fluorescence measurement is 465 nm as defined by the fluorescence band-pass filter 106. The proper combination oflaser diode 36 andfilter 106 depends on the detection of the biomolecule(s) of interest. Modules or component sections are illustratively constructed for a particular application, for example, optimal wavelengths for excitation, and for absorption and fluorescence (detection) measurements. - A second
releasable coupling 140 is positioned between thesample cell module 24 and theabsorption detector module 26. Illustratively,internal threads 142 on thedistal end 64 of thesample cell module 24 engageexternal threads 144 on theproximal end 124 of theabsorption detector module 26. Other releasable couplings may be substituted for cooperating threads, including, for example bayonet couplings, resilient fingers, lock washers, etc. - A
controller 145, including aprocessor 146 and amemory 147, is illustratively in electrical communication with thefluorescence detector 102 and theabsorption detector 128. Thememory 147 may include software and/or firmware containing instructions executed byprocessor 146 for controlling theradiation emitting module 22, thefluorescence detector 102, theabsorption detector 128, thedisplays biosensor 10. Theprocessor 146 may convert the fluorescence signal from thefluorescence detector 102 into a fluorescence reading on thefluorescence display 150. Similarly, theprocessor 146 may convert the absorption signal from theabsorption detector 128 into an absorbance reading on theabsorption display 152. Thememory 147 may include a random-access memory configured to store information such as the date, locations, and the number of positive hits for particular biomolecules based upon the electromagnetic radiation wavelengths sensed by thedetectors controller 145 for providing electrical communication with theprocessor 146 to supply data to external devices, for example. - The
display module 28 is illustratively positioned distal of theabsorption detector module 26 and includes adisplay module housing 148.Fluorescence display 150 is supported within thedisplay module housing 148 and is configured to provide an indication of the fluorescence spectral data from theprocessor 146 as received from thefluorescence detector 102.Absorption display 152 is supported within thedisplay module housing 148 and is configured to provide an indication of the absorption spectral data from theprocessor 146 as received from theabsorption detector 128. Thefluorescence display 150 illustratively comprises a digital readout (e.g., a liquid crystal display (LCD)) configured to display fluorescence spectral data from theprocessor 146 as received from thefluorescence detector 102. Similarly, theabsorption display 152 illustratively comprises a digital readout (e.g., a liquid crystal display (LCD)) configured to display absorption data from theprocessor 146 as received from theabsorption detector 128. - Different colors displayed by the display screens 150 and 152 (e.g., backlighting) may indicate the detection result from the target sample solution in the
sample cell chamber 40. For example, green may represent no detectable signal (i.e., safe), yellow may represent a low detection signal (i.e., warning), and red may represent a significant detection signal (i.e., alarming). Illustratively, the intensity level of the display screens 150 and 152 are digital scales from 0 to 100, with threshold readings representing safe, warning, and alarming detection from the target sample. - Illustratively, the
display module housing 148 includes acylindrical side wall 154 extending between aproximal end 156 and adistal end 158. Illustratively, anend cap 160 is threadably coupled to theproximal end 156 of theside wall 154.Openings side wall 154 and are aligned with thedisplays display module 28 is in electrical communication with theprocessor 146. Thedisplays processor 146 are illustratively coupled to a support, such as a printed circuit board (pcb) 166. - The
display module 28 illustratively further includes a second ordistal power source 168 in electrical communication with theprocessor 146, thedisplays absorption detector 128, and thefluorescence detector 102. Thesecond power source 168 illustratively comprises adistal battery 169 releasably supported within theend cap 160. Thedistal battery 169 is illustratively a rechargeable button cell battery. In one illustrative embodiment, a military grade 3.0 Volt Saft BA5367U Lithium Sulfur Dioxide (1 inch×1 inch×0.075 inch) battery produced by Saft SA in France may be used. Another illustrative battery is the BA5367U battery together with a DC/DC High Voltage DBC-Series (0.83 inch×0.83 inch×0.32 inch) Module available from Laser Components USA) for raising the voltage output. - A second or
distal power switch 170 is illustratively in electrical communication with thedistal battery 169 and is supported by theend cap 160 proximate thedistal end 18 of theouter casing 12. Thedistal power switch 170 may be a toggle push button that is configured to be depressed by a user. - A third
releasable coupling 172 is illustratively positioned between thedisplay module 28 and theabsorption detector module 26. Illustratively,internal threads 174 on thedistal end 126 of theabsorption detector module 26 engageexternal threads 176 on theproximal end 156 of thedisplay module 28. Other releasable couplings may be substituted for cooperating threads, including, for example bayonet couplings, resilient fingers, lock washers, etc. - Wires may electrically couple the fluorescence detector, the processor 146 (and thereby the fluorescence display), and the distal battery. In certain illustrative embodiments, the
releasable couplings radiation emitting module 22, thesample cell module 24, theabsorption detector module 26, and thedisplay module 28. - The
modules biosensor 10. More particularly, in theillustrative embodiment biosensor 10, the radiation emittingmodule housing 30, thesample cell chamber 40, the samplecell module housing 54, the absorptiondetection module housing 120 and thedisplay module housing 148 cooperate to define the cylindricalouter casing 12. Thereleasable couplings modules - With reference to
FIGS. 6A-6C , an illustrative method of operating thebiosensor 10 of the present disclosure is disclosed. Initially, thebiosensor 10 is oriented in an upright position with thelongitudinal axis 14 extending in a vertical direction with theproximal end 16 positioned below thedistal end 18. A wasteadapter including tubing 80 and waste collection chamber orvial 82 is fluidly coupled to thesample cell chamber 40. More particularly, an end of thetubing 80 is fluidly coupled to thewaste outlet 62. - Next, a cleansing solution (e.g., an alcohol-water mixture) of volume excess to (i.e., greater than) the volume of the
sample cell chamber 40 is received within thebarrel 76 of thesyringe 72. Thetip 70 of thesyringe 72 is received within theseptum 66 of thesample inlet 58 and the cleansing solution is injected into thesample cell chamber 40 by depressing theplunger 74 of thesyringe 72. The excess cleansing solution flows out through thewaste outlet 62 and into thecollection vial 82. - The method continues by inverting the
biosensor 10 to an inverted position such that thelongitudinal axis 14 extends in a vertical direction with thedistal end 18 positioned below theproximal end 16. Air is received within thebarrel 76 by pulling theplunger 74 of thesyringe 72 with thetip 70 engaged. Afilter 178 is then attached between thesyringe 72 and thetip 70. Thetip 70 of thesyringe 72 is received within theseptum 66 of thesample inlet 58. Next, theplunger 74 is depressed thereby injecting filtered air into thesample cell chamber 40. Thesample cell chamber 40 is evacuated by air forcing the residual cleansing solution out through thewaste outlet 62 and into thewaste vial 82, thereby helping to dry the inside surface of thesample cell chamber 40. - In the next step of the method, the
biosensor 10 is returned to the upright position with thelongitudinal axis 14 extending in a vertical direction with theproximal end 16 positioned below thedistal end 18. A blank solution (e.g., water solution) is received within thebarrel 76 of thesyringe 72. Thetip 70 of thesyringe 72 is received within theseptum 66 of thesample inlet 58. Next, theplunger 74 is depressed thereby injecting the blank into thesample cell chamber 40. Theprocessor 146 will electronically generate zero absorbance at theabsorption display 152 and zero signal at thefluorescence display 150. In one illustrative method, a sample solution is next received within thebarrel 76 of thesyringe 72. Thetip 70 of thesyringe 72 is received within theseptum 66 of thesample inlet 58. Next, theplunger 74 is depressed thereby injecting the sample solution into thesample cell chamber 40. - In another illustrative method, a filtered sample solution is received within the
barrel 76 by pulling theplunger 74 with afilter 178 attached between thesyringe 72 and thetip 70 received in the sample solution. Thefilter 178 is then detached. Thetip 70 of thesyringe 72 is received within theseptum 66 of thesample inlet 58. Next, theplunger 74 is depressed thereby injecting the filtered sample solution into thesample cell chamber 40. - The blank solution or the sample solution is illustratively injected into the
sample cell chamber 40 within thesample inlet 58 to a volume level such that an excess volume of the sample solution comes out ofwaste outlet 62. - The method continues by the user depressing the
power buttons radiation emitting module 22, thedisplay module 28, thefluorescence detector 102 and theabsorption detector 128. Thelaser diode 36 emits electromagnetic radiation, illustratively light (e.g., laser beam 38), through theentry port 96 and thesample chamber 40. The light passes through the sample solution in thesample cell chamber 40, where the absorption portion of the light (i.e., intensity of thelaser beam 38 absorbed by the sample solution) is directed to theexit port 98 and to theabsorption detector 128, and the fluorescence portion of the light (i.e., intensity of excited or fluorescence emissions from the sample solution as a result of the laser beam 38) is reflected by thereflective surface 108 at a right angle to the electromagnetic radiation laser beam 38 (i.e., the longitudinal axis 14) to thefluorescence detector 102. - Absorption values from the absorption detector are transmitted to the
processor 146 and then displayed on theabsorption display 152. Fluorescence values from the fluorescence detector are transmitted to theprocessor 146 and then displayed on thefluorescence display 150. A baseline value can be set with the blank solution, where the display readings can be adjusted to zero values for background subtraction via theprocessor 146. Positive reading valves above zero indicate presence of biomolecules. The process may then continue by returning to the step of injecting the cleansing solution via thesyringe 72. - As detailed above the outer dimensions of the
biosensor 10 are relatively small. More particularly, thebiosensor 10 is of a small size and is light weight, similar to those of a pen/laser pointer. Thebiosensor 10 also includes the capability to provide both absorption and fluorescence measurements simultaneously in of a field acquired sample solution. Thebiosensor 10 may find utility in a variety of applications, including in the military, food and health industries, and with first responders. - As further detailed herein, the
biosensor 10 of the present disclosure facilitates portability by having a small size, being light weight, being durable, having low power requirements and being pocket wearable. Thebiosensor 10 includes modular components thereby allowing choices of integration into a variety of different purpose specific biosensors. - The
biosensor 10 of the present disclosure provides for improved selectivity. More particularly, thebiosensor 10 provides for selective detection based on combined molecular absorption spectrophotometry (MAS) and molecular fluorescence spectrophotometry (MFS). A higher signal reading is obtainable, due in part to the long path of laser beam-sample interactive, either from absorption detection or fluorescence detection, compared to “solo” operation (i.e., absorption detection or fluorescence detection alone). Some molecules favor the absorption process and other molecules favor the fluorescence process, due to either spectral or fundamental interactions, generating a higher combined signal. - The
biosensor 10 of the present disclosure also provides for improved sensitivity. More particularly, thebiosensor 10 provides for high sensitivity from the sample cell including a long absorption path length and a long emission (fluorescence) region. Additionally, thebiosensor 10 operates with a laser beam, sample cell, and detectors enclosed in a light sealed assembly to prevent the detectors receiving interference from external light sources. Further, the sample cell of the biosensor may be recalibrated (i.e., zeroed) by using a blank solution or empty sample cell chamber, resulting in a higher signal-to-noise ratio, thereby increasing the sensitivity of thebiosensor 10. - Further, the
biosensor 10 is easy to operate with minimal or no sample preparation required. Simply inject an excess volume of a sample, and activate the power buttons to operate thebiosensor 10. - The
biosensor 10 demonstrates reliability by providing simple to read displays, providing repeatable performance with no operator interpretation required in reading results. Additionally, the occurrence of false or incorrect results is easily identifiable. In addition to potential molecular spectral interference, the absorption measurement may receive interference by beam-blockage from opaque particles and the fluorescence (emission) measurement may receive interference by beam-scattering from reflective particles. Receiving an absorption reading but not a fluorescence reading, or vice versa, may be an indication of a possible false/incorrect result. Therefore, having both an absorption reading and a fluorescence reading works as a double-assurance, thereby increasing the confidence on each result of the biosensor. - Native absorption and fluorescence provides a major advantage for biomolecule detection because all biomolecules contain amino acids (e.g., phenylalanine, tryptophan, and tyrosine) and, therefore, by laser or appropriate light exposure directly on the sample solution followed by simultaneous positive absorption detection and positive fluorescence detection indicate the presence of biomolecules (e.g., phenylalanine, tryptophan, and tyrosine). That is, tryptophan and tyrosine characteristically absorb the laser or light wavelength of 275 nm and, when excited, emit their fluorescence radiation at 345 nm.
- Additionally, operation of the
biosensor 10 of the present disclosure provides for improved assay time. Simply activate the power buttons and read the displays which provide instance results in the field. The components of the biosensor are relatively inexpensive, thereby providing for a cost low enough for wide distribution. - The modular design of the
biosensor 10 provides component choices. Assembling particular modules making thebiosensor 10 functions as a universal biosensor for all biomolecules (based on native molecular absorption spectrophotometry and native fluorescence spectrophotometry) or as a selective biosensor (based on specific-tagging of selective biomolecules followed by characteristic absorption and fluorescence from the tagged biomolecules). - As detailed herein, theoretically, all biomolecules are composed an amount of amino acids tryptophan and tyrosine. Spectrally, tryptophan and tyrosine uniquely absorb light energy of approximately 275 nm wavelength, get excited and subsequently emit their characteristic fluorescence of approximately 345 nm wavelength. Operatively as a biosensor, the
laser diode 36 emits an electromagnetic radiation (e.g., laser beam 38) of approximately 275 nm wavelength that is directed to pass through a sample in thesample cell chamber 40. Theabsorption detector 128 senses the intensity of the laser beam 38 (275 nm wavelength) absorbed, and thefluorescence detector 102 detects the collected light intensity, specifically of approximately 345 nm wavelength, emitted from the sample solution. A positive detection (signal above background from a blank solution) from thedetectors - Although the invention has been described in detail with reference to certain preferred embodiments, variations and modifications exist within the spirit and scope of the invention as described and defined in the following claims.
Claims (46)
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KR102604781B1 (en) * | 2020-05-20 | 2023-11-22 | 와이에스아이 인코포레이티드 | Spatial gradient-based fluorometer |
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