WO2012064704A1 - Multi-function microfluidic test kit - Google Patents
Multi-function microfluidic test kit Download PDFInfo
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- WO2012064704A1 WO2012064704A1 PCT/US2011/059724 US2011059724W WO2012064704A1 WO 2012064704 A1 WO2012064704 A1 WO 2012064704A1 US 2011059724 W US2011059724 W US 2011059724W WO 2012064704 A1 WO2012064704 A1 WO 2012064704A1
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- microfluidic channels
- capturing
- capture molecule
- sample
- microfluidic
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54366—Apparatus specially adapted for solid-phase testing
- G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
- G01N33/5438—Electrodes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0627—Sensor or part of a sensor is integrated
- B01L2300/0645—Electrodes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
- B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
- B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
- B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/06—Valves, specific forms thereof
- B01L2400/0605—Valves, specific forms thereof check valves
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- This document relates to microfluidic systems for diagnosing multiple disease conditions.
- this document provides methods and materials that can be used to detect two or more disease conditions (e.g., HIV infections, syphilis infections, malaria infections, anemia, gestational diabetes, and/or pre-eclampsia) via a single multiplexed assay.
- two or more disease conditions e.g., HIV infections, syphilis infections, malaria infections, anemia, gestational diabetes, and/or pre-eclampsia
- This document provides methods and materials related to diagnosing multiple disease conditions.
- this document provides methods and materials that can be used to detect two or more disease conditions (e.g., HIV infections, syphilis infections, malaria infections, anemia, gestational diabetes, and/or pre-eclampsia) via a single multiplexed assay.
- a biological sample can be collected from a mammal and analyzed using a kit provided herein to determine whether or not the mammal has any of a group of different disease conditions (e.g., two, three, four, five, six, seven, eight, nine, or more different disease conditions).
- the analysis for each disease condition can be performed in parallel such that the results for each condition are provided at essentially the same time.
- the methods and materials provided herein can be used outside a clinical laboratory setting. For example, the methods and materials provided herein can be used in rural settings outside of a hospital or clinic.
- kits provided herein can allow medical personnel and nonmedical personnel to identify humans having any one or more of the disease conditions capable of being detected by a kit provided herein.
- medical volunteers can use the kits provided herein to identify pregnant women who are infected with HIV, syphilis, or malaria via a single assay process. Once identified, the pregnant women can be properly treated to help improve the health of the mother or her baby.
- one aspect of this document features a device for detecting the presence of one or more disease conditions in a pregnant woman.
- the device comprises, or consists essentially of, a substrate comprising three or more microfluidic channels and an inlet port for delivering a portion of a biological sample to each of the three or more microfluidic channels, wherein each of the three or more microfluidic channels comprises a sensor area having an electrode circuit, wherein each of the sensor areas is configured to include a different capture molecule for capturing a different target analyte, and wherein each electrode circuit of each sensor area is configured to detect the presence of a captured target analyte when present in the biological sample, thereby detecting the presence of the one or more conditions in the pregnant woman.
- the one of the three or more microfluidic channels can comprise a capture molecule for capturing an anti-HIV antibody.
- the one of the three or more microfluidic channels can comprise a capture molecule for capturing a CD4 + T cell.
- the one of the three or more microfluidic channels can comprise a capture molecule for capturing an anti-syphilis antibody.
- the one of the three or more microfluidic channels can comprise a capture molecule for capturing malaria-parasitized red blood cells.
- the biological sample can be a blood sample.
- this document features a method for detecting the presence of one or more disease conditions in a pregnant woman.
- the method comprises, or consists essentially of, delivering a biological sample collected from the woman into a device comprising a substrate comprising three or more microfluidic channels and an inlet port for delivering a portion of the biological sample to each of the three or more microfluidic channels, wherein each of the three or more microfluidic channels comprises a sensor area having an electrode circuit, wherein each of the sensor areas is configured to include a different capture molecule for capturing a different target analyte, and wherein each electrode circuit of each sensor area is configured to detect the presence of a captured target analyte when present in the biological sample, thereby providing a user with an indication of the presence of the one or more conditions in the pregnant woman.
- the one of the three or more microfluidic channels can comprise a capture molecule for capturing an anti-HIV antibody.
- the one of the three or more microfluidic channels can comprise a capture molecule for capturing a CD4 + T cell.
- the one of the three or more microfluidic channels can comprise a capture molecule for capturing an anti-syphilis antibody.
- the one of the three or more microfluidic channels can comprise a capture molecule for capturing malaria-parasitized red blood cells.
- the biological sample can be a blood sample.
- Figure 1 is a schematic diagram of a microfluidic system for multiplexed detection of medical conditions, in accordance with some embodiments.
- Figure 2 is a schematic diagram of a microfluidic system for multiplexed detection of medical conditions, in accordance with alternative embodiments.
- Figure 3 depicts various sensors included in a microfluidic system for multiplexed detection of medical conditions, in accordance with some embodiments.
- This document provides methods and materials related to diagnosing multiple disease conditions. For example, this document provides methods and materials that can be used to detect two or more disease conditions (e.g., HIV infections, syphilis infections, malaria infections, anemia, gestational diabetes, and/or pre-eclampsia) via a single multiplexed assay.
- a biological sample can be collected from a mammal (e.g., pregnant woman) and analyzed using a kit provided herein to determine whether or not the mammal has any of a group of different disease conditions (e.g., two, three, four, five, six, seven, eight, nine, or more different disease conditions).
- the analysis for each disease condition can be performed in parallel such that the results for each condition are provided at essentially the same time.
- the methods and materials provided herein can be used outside a clinical laboratory setting.
- the methods and materials provided herein can be used in rural settings outside of a hospital or clinic.
- a multi-function microfluidic diagnostic kit can be used as a single, on-the-spot method to diagnose multiple conditions.
- the diagnostic kit can perform the diagnosis using small amounts of bodily fluids (e.g., one or more drops, about 1/30 mL, less than 0.1 mL, and the like) readily obtained from an individual.
- the fluid can be a drop of blood obtained from a heelstick, fingerstick, or other simple collection method from a finger tip or alternative collection site.
- Exemplary bodily fluids that can be used can include, without limitation, blood, plasma, urine, sputum, or other fluids that can be easily obtained from an individual.
- the diagnostic kit provided herein can be used to diagnose medical conditions of concern to pregnant women, such as HIV, HBV and HCV, sexually transmitted diseases, and the like.
- a diagnostic kit provided herein can be used to diagnose, in a multiplexed format, major contributors to maternal mortality such as HIV, syphilis, malaria, anemia, gestational diabetes, pre-eclampsia, HSV, CMV, toxoplasmosis, rubella, bacterial sepsis, and the like.
- a diagnostic kit provided herein can be configured to include electrochemical sensors, such that that the diagnostic kit can be relatively low-cost, be simple to use, and make multiple measurements substantially simultaneously from a small amount of bodily fluid (e.g., about 1 drop).
- a diagnostic kit provided herein can rapidly diagnose conditions of relevance to maternal health for a low cost and with limited training such that the diagnosis can be performed in places where maternal mortality is high and where financial resources and access to trained medical personnel is limited such as in developing countries.
- a multi-function microfluidic diagnostic kit 100 can include a microfluidic card 110 (e.g., a microfluidic chip) to which one or more microfluidic sensors are attached.
- microfluidic card 110 can include microfluidic structures such that a biological sample can be introduced to microfluidic card 110 which in turn can be positioned within a microfluidic diagnostic device (not shown) to facilitate testing of the biological sample for the presence of target analytes.
- Microfluidic card 110 can include a sample inlet 120, into which a sample can be added, and a sample outlet 130.
- sample inlet 120 can be fluidly connected to one or more electrochemical sensor areas (e.g., electrochemical sensor areas 140, 145, 150, and 155), each of which can measure one or more target analytes.
- electrochemical sensor areas e.g., electrochemical sensor areas 140, 145, 150, and 155
- Sample inlet 120 can be fluidly connected to other areas (not shown), such as storage chambers (e.g., containing materials used to process a sample added to sample inlet 120), reaction chambers (e.g., for processing a sample added to sample inlet 120), and the like either directly, or via sensor areas 140, 145, 150 and 155.
- micro fluidic card 110 can include a storage well (not shown), fluidly connected to sample inlet 120 and containing phosphate buffered saline (PBS) for use in diluting a sample added to sample inlet 120.
- the substrate can also include a plurality of microfluidic components such as reactors, pumps, check valves, reservoirs, channels, sensors, and heaters to enable diagnostic kit 100 to detect medical conditions from a biological sample.
- sensor areas 140, 145, 150, and 155 can be fluidly connected in parallel to sample inlet 120 such that a sample added to inlet 120 can be divided into portions, each of which can substantially simultaneously be moved to sensor areas 140, 145, 150, and 155.
- diagnostic kit 100 can substantially simultaneously diagnose a plurality of medical conditions using, for example, sensor areas 140, 145, 150, and 155.
- additional sensor areas can be included as part of microfluidic card 110 such that additional medical conditions can be diagnosed by diagnostic kit 100.
- additional sensor areas can be added that are in parallel with sensor areas 140, 145, 150, and 155.
- sensor areas can be fluidly connected in series with one or more of sensor areas 140, 145, 150, and 155.
- a sensor area can be fluidly connected with sensor area 140 such that a portion of a sample can be transitioned from sample inlet 120 to sensor area 140, to an additional sensor area (not shown), and then to sample outlet 130.
- a portion of a sample can pass from sample inlet 120, through a reaction chamber (not shown), and later divided wherein a first portion enters one sensor area (e.g., sensor area 140) and a second portion enters a different sensor area (e.g., sensor area 145).
- a sample added to inlet 120 can exit microfluidic card 110 through sample outlet 130.
- Materials exiting sample outlet 130 can be transfer to, for example, a self-contained waste area, one or more other assays, or one or more further processing areas on a microfluidic card (e.g., microfluidic card 110, another microfluidic substrate, and the like).
- diagnostic kit 100 can include sensor areas for target analytes of relevance to maternal health that may be combined in a single kit. Exemplary analytes that can be detected can include, without limitation, those relevant to HIV (e.g., CD4 cells), malaria, syphilis, anemia, pre-eclampsia, toxoplasmosis, rubella,
- diagnostic kit 100 can be configured such that sensor area 140 can measure anti-HIV antibodies, sensor area 145 can measure CD4 cells, sensor area 150 can detect syphilis, and sensor area 155 can detect malaria.
- diagnostic kit 100 can be configured to detect anti-HIV antibodies, CD4 cells, syphilis, and malaria, but using sensor areas 140, 145, 150, and 155 in a different configuration than just described.
- diagnostic kit 100 can be configured to diagnose other conditions relevant to the health of an individual, either in lieu of or in addition to those described.
- multi-function microfluidic diagnostic kit 100 can include a microfluidic substrate 210 (e.g., a microfluidic chip), similar to the microfluidic card 110 described in connection with Figure 1, to which one or more microfluidic sensors are attached.
- support substrate 210 can include sensor areas 140, 145, 150, and 155.
- support substrate 210 can include a sensor area 260 (e.g., an electrical sensor, an electrochemical sensor, and the like) that can count individual targets such as cells, platelets, bacteria, viruses, particles, and the like.
- sensor area 260 can include an electrical impedance particle size sensor of the Coulter type for counting white blood cells, red blood cells, and/or platelets.
- one or more of sensor areas 140, 145, 150, and 155 can include electrochemical sensors that use, for example, coulometry, amperometry, voltammetry, electrochemical impedance spectroscopy, cell lysate impedance
- diagnostic kit 100 for the specific detection of multiple target analytes in a parallel manner can include sensor areas 140, 145, 150, and 155 that can detect target analytes.
- sensor areas 140, 145, 150, and 155 detect target analytes such as cells, bacteria, viruses, nucleic acids, antibodies, antigens, and the like and can be used to diagnose medical conditions of concern to pregnant women.
- Exemplary medical conditions can include, without limitation, HIV, syphilis, malaria, anemia, gestational diabetes, pre-eclampsia, HSV, CMV, toxoplasmosis, rubella, and bacterial sepsis.
- sensor area 140 can be configured to detect the presence of anti-HIV antibodies 10
- sensor area 145 can be configured to detect the presence or amount of CD4 + T cells 12
- sensor area 150 can be configured to detect the presence of anti-syphilis antibodies 14
- sensor area 155 can be configured to detect the presence of one or more biomarkers of malaria infection (e.g., malaria-parasitized red blood cells 16).
- Sensor areas 140, 145, 150, and 155 can include support substrates 142, 147, 152, and 157, respectively, to which one or more electrodes 112 and primary capture molecules 170, 172, 174, and 176 are attached.
- substrates 142, 147, 152, and 157 can include one or a combination of polymers (e.g., polycarbonate, polymethyl methacrylate, and the like), glass, silicon, and any substrate which can include the microfluidic sensors and be used in a microfluidic diagnostic device (not shown).
- polymers e.g., polycarbonate, polymethyl methacrylate, and the like
- glass e.g., glass, silicon
- any substrate which can include the microfluidic sensors and be used in a microfluidic diagnostic device (not shown).
- Substrates 142, 147, 152, and 157 can each include one or more electrodes 112.
- diagnostic kit 100 can be configured such that one or more of substrates 142, 147, 152, and 157 include a single opposed pair of electrodes.
- some or all of the electrodes can be interdigitated electrodes.
- one or more of substrates 142, 147, 152, and 157 can include electrodes 112 that are part of an electrode array.
- one or more of the sets of electrodes 112 can be individually addressable and individually controlled, while some electrodes 112 can be linked.
- capture molecules 170, 172, 174, and 176 can be covalently attached to substrates 142, 147, 152, and 157, respectively.
- capture molecules can be attached through direct physical absorption or through avidin-biotin chemistry, Click chemistry, or other linker chemistry.
- capture molecules can be attached covalently or non-covalently.
- Exemplary capture molecules 170, 172, 174, and 176 can include, without limitation, antibodies, aptamers, nucleic acid probes, and the like such that primary capture molecules 170, 172, 174, and 176 can each specifically bind to a target analyte.
- Diagnostic kit 100 can include one or more electrical measurement circuits 180 electrically coupled to electrodes 112 for measuring an electrical property such as current, impedance, and conductance.
- measurement circuits 180 can detect a change in the electrical properties of a solution before and after exposure to a sample.
- Diagnostic kit 100 can be configured such that primary capture molecules 170, 172, 174, and 176 can specifically bind to target analytes 10, 12, 14, and 16.
- Exemplary target analytes can include cells (e.g., CD4 + T cells, bacterial cells, fungal cells, and the like), viruses (e.g., human
- immunodeficiency viruses hepatitis viruses, and the like
- nucleic acids nucleic acids
- antibodies antigens, polypeptides, pharmaceuticals, and the like.
- a sample to be tested for the presence of a plurality of target analytes can be added to sample inlet 120.
- the sample can be divided into portions, each of which can substantially simultaneously be moved to sensor areas 140, 145, 150, and 155.
- diagnostic kit 100 can substantially simultaneously diagnose a plurality of medical conditions using, for example, sensor areas 140, 145, 150, and 155.
- a portion of the sample is transferred to sensor area 140 wherein anti-HIV antibodies 10 (if contained in the sample) specifically bind to the capture molecules 170, the presence or amount of which can be detected with one of measurement circuits 180.
- a portion of the sample can be transferred to sensor area 145 wherein CD4 + T cells 12 (if contained in the sample) can specifically bind to capture molecules 172, the presence or amount of which can be detected with one of measurement circuits 180.
- a portion of the sample can be transferred to sensor area 150 wherein anti-syphilis antibodies 14 (if contained in the sample) can specifically bind to capture molecules 174, the presence or amount of which can be detected with one of measurement circuits 180.
- a portion of the sample can be transferred to sensor area 155 wherein the malaria-parasitized red blood cells 16 (if contained in the sample) can specifically bind to capture molecules 176, the presence or amount of which can be detected with one of measurement circuits 180.
- additional steps can be performed to clear unbound species from sensor areas 140, 145, 150, and 155 without disrupting the binding of target analytes 10, 12, 14, and 16 to capture molecules 170, 172, 174, and 176.
- wash fluids can be flowed past one or more of sensor areas 140, 145, 150, and 155, shear stress can be applied, and the like.
- Substances that pass through sensor areas 140, 145, 150, and 155 can be transferred through outlet 130 to, for example, a self-contained waste area, one or more other assays, and/or one or more further processing areas on a micro fluidic card (e.g., micro fluidic card 110, another microfluidic substrate, and the like).
- a micro fluidic card e.g., micro fluidic card 110, another microfluidic substrate, and the like.
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Abstract
This document provides methods and materials related to diagnosing multiple disease conditions. For example, methods and materials that can be used to detect two or more disease conditions (e.g., HIV infections, syphilis infections, malaria infections, anemia, gestational diabetes, and/or pre-eclampsia) via a single multiplexed assay are provided.
Description
Multi- function Microf uidic Test Kit
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Serial No. 61/411,278, filed November 8, 2010. The disclosure of the prior application is considered part of (and is incorporated by reference in) the disclosure of this application.
TECHNICAL FIELD
This document relates to microfluidic systems for diagnosing multiple disease conditions. For example, this document provides methods and materials that can be used to detect two or more disease conditions (e.g., HIV infections, syphilis infections, malaria infections, anemia, gestational diabetes, and/or pre-eclampsia) via a single multiplexed assay.
BACKGROUND
In parts of the world, including nearly developing countries, diseases such as HIV infection (and its stage), syphilis infection, malaria infection, and anemia are common and debilitating to humans, particularly to pregnant women. For example, nearly 3.5 million pregnant women are HIV-infected, and nearly 700,000 babies contract HIV from their mothers each year. These infant HIV infections can be prevented with better case finding and HIV treatment. In addition, nearly 20% of pregnant women in developing countries are infected with syphilis, leading to more than 500,000 infant stillbirths and deaths each year. Nearly 10,000 women and 200,000 infants die each year due to malaria during pregnancy, and nearly 45% of pregnant women in developing countries suffer from anemia as a result of, for example, worm infections, parasites, and/or nutritional deficiencies. Anemia can adversely affect a pregnant woman's chance of surviving postpartum hemorrhage and stunt infant development. About 115,000 maternal deaths and 500,000 infant deaths have been associated with anemia in developing countries.
SUMMARY
This document provides methods and materials related to diagnosing multiple disease conditions. For example, this document provides methods and materials that can
be used to detect two or more disease conditions (e.g., HIV infections, syphilis infections, malaria infections, anemia, gestational diabetes, and/or pre-eclampsia) via a single multiplexed assay. As described herein, a biological sample can be collected from a mammal and analyzed using a kit provided herein to determine whether or not the mammal has any of a group of different disease conditions (e.g., two, three, four, five, six, seven, eight, nine, or more different disease conditions). The analysis for each disease condition can be performed in parallel such that the results for each condition are provided at essentially the same time. In some cases, the methods and materials provided herein can be used outside a clinical laboratory setting. For example, the methods and materials provided herein can be used in rural settings outside of a hospital or clinic.
The methods and materials provided herein can allow medical personnel and nonmedical personnel to identify humans having any one or more of the disease conditions capable of being detected by a kit provided herein. For example, medical volunteers can use the kits provided herein to identify pregnant women who are infected with HIV, syphilis, or malaria via a single assay process. Once identified, the pregnant women can be properly treated to help improve the health of the mother or her baby.
In general, one aspect of this document features a device for detecting the presence of one or more disease conditions in a pregnant woman. The device comprises, or consists essentially of, a substrate comprising three or more microfluidic channels and an inlet port for delivering a portion of a biological sample to each of the three or more microfluidic channels, wherein each of the three or more microfluidic channels comprises a sensor area having an electrode circuit, wherein each of the sensor areas is configured to include a different capture molecule for capturing a different target analyte, and wherein each electrode circuit of each sensor area is configured to detect the presence of a captured target analyte when present in the biological sample, thereby detecting the presence of the one or more conditions in the pregnant woman. The one of the three or more microfluidic channels can comprise a capture molecule for capturing an anti-HIV antibody. The one of the three or more microfluidic channels can comprise a capture molecule for capturing a CD4+ T cell. The one of the three or more microfluidic channels can comprise a capture molecule for capturing an anti-syphilis antibody. The one of the three or more microfluidic channels can comprise a capture molecule for
capturing malaria-parasitized red blood cells. The biological sample can be a blood sample.
In another aspect, this document features a method for detecting the presence of one or more disease conditions in a pregnant woman. The method comprises, or consists essentially of, delivering a biological sample collected from the woman into a device comprising a substrate comprising three or more microfluidic channels and an inlet port for delivering a portion of the biological sample to each of the three or more microfluidic channels, wherein each of the three or more microfluidic channels comprises a sensor area having an electrode circuit, wherein each of the sensor areas is configured to include a different capture molecule for capturing a different target analyte, and wherein each electrode circuit of each sensor area is configured to detect the presence of a captured target analyte when present in the biological sample, thereby providing a user with an indication of the presence of the one or more conditions in the pregnant woman. The one of the three or more microfluidic channels can comprise a capture molecule for capturing an anti-HIV antibody. The one of the three or more microfluidic channels can comprise a capture molecule for capturing a CD4+ T cell. The one of the three or more microfluidic channels can comprise a capture molecule for capturing an anti-syphilis antibody. The one of the three or more microfluidic channels can comprise a capture molecule for capturing malaria-parasitized red blood cells. The biological sample can be a blood sample.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and
advantages of the invention will be apparent from the description and drawings, and from the claims.
DESCRIPTION OF DRAWINGS
Figure 1 is a schematic diagram of a microfluidic system for multiplexed detection of medical conditions, in accordance with some embodiments.
Figure 2 is a schematic diagram of a microfluidic system for multiplexed detection of medical conditions, in accordance with alternative embodiments.
Figure 3 depicts various sensors included in a microfluidic system for multiplexed detection of medical conditions, in accordance with some embodiments.
Like reference symbols in the various drawings indicate like elements.
DETAILED DESCRIPTION
This document provides methods and materials related to diagnosing multiple disease conditions. For example, this document provides methods and materials that can be used to detect two or more disease conditions (e.g., HIV infections, syphilis infections, malaria infections, anemia, gestational diabetes, and/or pre-eclampsia) via a single multiplexed assay. As described herein, a biological sample can be collected from a mammal (e.g., pregnant woman) and analyzed using a kit provided herein to determine whether or not the mammal has any of a group of different disease conditions (e.g., two, three, four, five, six, seven, eight, nine, or more different disease conditions). The analysis for each disease condition can be performed in parallel such that the results for each condition are provided at essentially the same time. In some cases, the methods and materials provided herein can be used outside a clinical laboratory setting. For example, the methods and materials provided herein can be used in rural settings outside of a hospital or clinic.
In some cases, a multi-function microfluidic diagnostic kit provided herein can be used as a single, on-the-spot method to diagnose multiple conditions. The diagnostic kit can perform the diagnosis using small amounts of bodily fluids (e.g., one or more drops, about 1/30 mL, less than 0.1 mL, and the like) readily obtained from an individual. In some cases, the fluid can be a drop of blood obtained from a heelstick, fingerstick, or
other simple collection method from a finger tip or alternative collection site. Exemplary bodily fluids that can be used can include, without limitation, blood, plasma, urine, sputum, or other fluids that can be easily obtained from an individual. For example, the diagnostic kit provided herein can be used to diagnose medical conditions of concern to pregnant women, such as HIV, HBV and HCV, sexually transmitted diseases, and the like. In some cases, a diagnostic kit provided herein can be used to diagnose, in a multiplexed format, major contributors to maternal mortality such as HIV, syphilis, malaria, anemia, gestational diabetes, pre-eclampsia, HSV, CMV, toxoplasmosis, rubella, bacterial sepsis, and the like. In some cases, a diagnostic kit provided herein can be configured to include electrochemical sensors, such that that the diagnostic kit can be relatively low-cost, be simple to use, and make multiple measurements substantially simultaneously from a small amount of bodily fluid (e.g., about 1 drop). In some cases, a diagnostic kit provided herein can rapidly diagnose conditions of relevance to maternal health for a low cost and with limited training such that the diagnosis can be performed in places where maternal mortality is high and where financial resources and access to trained medical personnel is limited such as in developing countries.
Referring now to Figure 1, in some embodiments, a multi-function microfluidic diagnostic kit 100 can include a microfluidic card 110 (e.g., a microfluidic chip) to which one or more microfluidic sensors are attached. For example, microfluidic card 110 can include microfluidic structures such that a biological sample can be introduced to microfluidic card 110 which in turn can be positioned within a microfluidic diagnostic device (not shown) to facilitate testing of the biological sample for the presence of target analytes. Microfluidic card 110 can include a sample inlet 120, into which a sample can be added, and a sample outlet 130. For example, a processed or unprocessed sample (e.g., blood, plasma, urine, sputum, or other biological fluid) can be introduced into sample inlet 120 for processing by diagnostic kit 100. In some embodiments, sample inlet 120 can be fluidly connected to one or more electrochemical sensor areas (e.g., electrochemical sensor areas 140, 145, 150, and 155), each of which can measure one or more target analytes. Sample inlet 120 can be fluidly connected to other areas (not shown), such as storage chambers (e.g., containing materials used to process a sample added to sample inlet 120), reaction chambers (e.g., for processing a sample added to
sample inlet 120), and the like either directly, or via sensor areas 140, 145, 150 and 155. For example, micro fluidic card 110 can include a storage well (not shown), fluidly connected to sample inlet 120 and containing phosphate buffered saline (PBS) for use in diluting a sample added to sample inlet 120. The substrate can also include a plurality of microfluidic components such as reactors, pumps, check valves, reservoirs, channels, sensors, and heaters to enable diagnostic kit 100 to detect medical conditions from a biological sample.
As depicted in Figure 1, sensor areas 140, 145, 150, and 155 can be fluidly connected in parallel to sample inlet 120 such that a sample added to inlet 120 can be divided into portions, each of which can substantially simultaneously be moved to sensor areas 140, 145, 150, and 155. In this manner, diagnostic kit 100 can substantially simultaneously diagnose a plurality of medical conditions using, for example, sensor areas 140, 145, 150, and 155. In some embodiments, additional sensor areas (not shown) can be included as part of microfluidic card 110 such that additional medical conditions can be diagnosed by diagnostic kit 100. For example, additional sensor areas can be added that are in parallel with sensor areas 140, 145, 150, and 155. In another example, sensor areas (not shown) can be fluidly connected in series with one or more of sensor areas 140, 145, 150, and 155. A sensor area can be fluidly connected with sensor area 140 such that a portion of a sample can be transitioned from sample inlet 120 to sensor area 140, to an additional sensor area (not shown), and then to sample outlet 130. In yet another example, a portion of a sample can pass from sample inlet 120, through a reaction chamber (not shown), and later divided wherein a first portion enters one sensor area (e.g., sensor area 140) and a second portion enters a different sensor area (e.g., sensor area 145). In some embodiments, after the sample has passed through one or more of sensor areas 140, 145, 150, and 155, a sample added to inlet 120, including any additional materials added during processing by diagnostic kit 100 can exit microfluidic card 110 through sample outlet 130. Materials exiting sample outlet 130 can be transfer to, for example, a self-contained waste area, one or more other assays, or one or more further processing areas on a microfluidic card (e.g., microfluidic card 110, another microfluidic substrate, and the like).
In some embodiments, diagnostic kit 100 can include sensor areas for target analytes of relevance to maternal health that may be combined in a single kit. Exemplary analytes that can be detected can include, without limitation, those relevant to HIV (e.g., CD4 cells), malaria, syphilis, anemia, pre-eclampsia, toxoplasmosis, rubella,
cytomegalovirus (CMV), herpes simplex virus (HSV), bacterial sepsis, and other conditions that contribute to maternal and perinatal mortality. For example, diagnostic kit 100 can be configured such that sensor area 140 can measure anti-HIV antibodies, sensor area 145 can measure CD4 cells, sensor area 150 can detect syphilis, and sensor area 155 can detect malaria. In some embodiments, diagnostic kit 100 can be configured to detect anti-HIV antibodies, CD4 cells, syphilis, and malaria, but using sensor areas 140, 145, 150, and 155 in a different configuration than just described. In yet other embodiments, diagnostic kit 100 can be configured to diagnose other conditions relevant to the health of an individual, either in lieu of or in addition to those described.
Referring now to Figure 2, in some embodiments, multi-function microfluidic diagnostic kit 100 can include a microfluidic substrate 210 (e.g., a microfluidic chip), similar to the microfluidic card 110 described in connection with Figure 1, to which one or more microfluidic sensors are attached. For example, support substrate 210 can include sensor areas 140, 145, 150, and 155. Furthermore, support substrate 210 can include a sensor area 260 (e.g., an electrical sensor, an electrochemical sensor, and the like) that can count individual targets such as cells, platelets, bacteria, viruses, particles, and the like. For example, sensor area 260 can include an electrical impedance particle size sensor of the Coulter type for counting white blood cells, red blood cells, and/or platelets. In some embodiments, one or more of sensor areas 140, 145, 150, and 155 can include electrochemical sensors that use, for example, coulometry, amperometry, voltammetry, electrochemical impedance spectroscopy, cell lysate impedance
spectroscopy, and other electrochemical sensing methods.
Referring now to Figure 3, diagnostic kit 100 for the specific detection of multiple target analytes in a parallel manner can include sensor areas 140, 145, 150, and 155 that can detect target analytes. In some embodiments, sensor areas 140, 145, 150, and 155 detect target analytes such as cells, bacteria, viruses, nucleic acids, antibodies, antigens, and the like and can be used to diagnose medical conditions of concern to pregnant
women. Exemplary medical conditions can include, without limitation, HIV, syphilis, malaria, anemia, gestational diabetes, pre-eclampsia, HSV, CMV, toxoplasmosis, rubella, and bacterial sepsis. For example, sensor area 140 can be configured to detect the presence of anti-HIV antibodies 10, sensor area 145 can be configured to detect the presence or amount of CD4+ T cells 12, sensor area 150 can be configured to detect the presence of anti-syphilis antibodies 14, and sensor area 155 can be configured to detect the presence of one or more biomarkers of malaria infection (e.g., malaria-parasitized red blood cells 16). Sensor areas 140, 145, 150, and 155 can include support substrates 142, 147, 152, and 157, respectively, to which one or more electrodes 112 and primary capture molecules 170, 172, 174, and 176 are attached. For example, substrates 142, 147, 152, and 157 can include one or a combination of polymers (e.g., polycarbonate, polymethyl methacrylate, and the like), glass, silicon, and any substrate which can include the microfluidic sensors and be used in a microfluidic diagnostic device (not shown).
Substrates 142, 147, 152, and 157 can each include one or more electrodes 112. For example, diagnostic kit 100 can be configured such that one or more of substrates 142, 147, 152, and 157 include a single opposed pair of electrodes. In other examples, some or all of the electrodes can be interdigitated electrodes. In yet other examples, one or more of substrates 142, 147, 152, and 157 can include electrodes 112 that are part of an electrode array. In some embodiments, one or more of the sets of electrodes 112 can be individually addressable and individually controlled, while some electrodes 112 can be linked.
In some embodiments, capture molecules 170, 172, 174, and 176 can be covalently attached to substrates 142, 147, 152, and 157, respectively. In some embodiments, capture molecules can be attached through direct physical absorption or through avidin-biotin chemistry, Click chemistry, or other linker chemistry. In some cases, capture molecules can be attached covalently or non-covalently. Exemplary capture molecules 170, 172, 174, and 176 can include, without limitation, antibodies, aptamers, nucleic acid probes, and the like such that primary capture molecules 170, 172, 174, and 176 can each specifically bind to a target analyte. Diagnostic kit 100 can include one or more electrical measurement circuits 180 electrically coupled to electrodes 112 for measuring an electrical property such as current, impedance, and conductance.
For example, measurement circuits 180 can detect a change in the electrical properties of a solution before and after exposure to a sample. Diagnostic kit 100 can be configured such that primary capture molecules 170, 172, 174, and 176 can specifically bind to target analytes 10, 12, 14, and 16. Exemplary target analytes can include cells (e.g., CD4+ T cells, bacterial cells, fungal cells, and the like), viruses (e.g., human
immunodeficiency viruses, hepatitis viruses, and the like), nucleic acids, antibodies, antigens, polypeptides, pharmaceuticals, and the like.
In some embodiments, a sample to be tested for the presence of a plurality of target analytes (e.g., anti-HIV antibodies 10, CD4+ T cells 12, anti-syphilis antibodies 14, the malaria-parasitized red blood cells 16, and the like) can be added to sample inlet 120. The sample can be divided into portions, each of which can substantially simultaneously be moved to sensor areas 140, 145, 150, and 155. In this manner, diagnostic kit 100 can substantially simultaneously diagnose a plurality of medical conditions using, for example, sensor areas 140, 145, 150, and 155. In one example, a portion of the sample is transferred to sensor area 140 wherein anti-HIV antibodies 10 (if contained in the sample) specifically bind to the capture molecules 170, the presence or amount of which can be detected with one of measurement circuits 180. In a similar manner, a portion of the sample can be transferred to sensor area 145 wherein CD4+ T cells 12 (if contained in the sample) can specifically bind to capture molecules 172, the presence or amount of which can be detected with one of measurement circuits 180. In yet another example, a portion of the sample can be transferred to sensor area 150 wherein anti-syphilis antibodies 14 (if contained in the sample) can specifically bind to capture molecules 174, the presence or amount of which can be detected with one of measurement circuits 180. A portion of the sample can be transferred to sensor area 155 wherein the malaria-parasitized red blood cells 16 (if contained in the sample) can specifically bind to capture molecules 176, the presence or amount of which can be detected with one of measurement circuits 180. Optionally, additional steps can be performed to clear unbound species from sensor areas 140, 145, 150, and 155 without disrupting the binding of target analytes 10, 12, 14, and 16 to capture molecules 170, 172, 174, and 176. For example, after transferring portions of the sample to sensor areas 140, 145, 150, and 155, wash fluids can be flowed past one or more of sensor areas 140, 145, 150, and 155, shear stress can be applied, and the like.
Substances that pass through sensor areas 140, 145, 150, and 155 can be transferred through outlet 130 to, for example, a self-contained waste area, one or more other assays, and/or one or more further processing areas on a micro fluidic card (e.g., micro fluidic card 110, another microfluidic substrate, and the like).
A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.
Claims
1. A device for detecting the presence of one or more disease conditions in a pregnant woman, wherein said device comprises a substrate comprising three or more micro fluidic channels and an inlet port for delivering a portion of a biological sample to each of said three or more microfluidic channels, wherein each of said three or more microfluidic channels comprises a sensor area having an electrode circuit, wherein each of said sensor areas is configured to include a different capture molecule for capturing a different target analyte, and wherein each electrode circuit of each sensor area is configured to detect the presence of a captured target analyte when present in said biological sample, thereby detecting the presence of said one or more conditions in said pregnant woman.
2. The device of claim 1, wherein said one of said three or more microfluidic channels comprises a capture molecule for capturing an anti-HIV antibody.
3. The device of claim 1, wherein said one of said three or more microfluidic channels comprises a capture molecule for capturing a CD4+ T cell.
4. The device of claim 1, wherein said one of said three or more microfluidic channels comprises a capture molecule for capturing an anti-syphilis antibody.
5. The device of claim 1, wherein said one of said three or more microfluidic channels comprises a capture molecule for capturing malaria-parasitized red blood cells.
6. The device of claim 1, wherein said biological sample is a blood sample.
7. A method for detecting the presence of one or more disease conditions in a pregnant woman, wherein said method comprises delivering a biological sample collected from said woman into a device comprising a substrate comprising three or more microfluidic channels and an inlet port for delivering a portion of said biological sample to each of said three or more microfluidic channels, wherein each of said three or more microfluidic channels comprises a sensor area having an electrode circuit, wherein each of said sensor areas is configured to include a different capture molecule for capturing a different target analyte, and wherein each electrode circuit of each sensor area is configured to detect the presence of a captured target analyte when present in said biological sample, thereby providing a user with an indication of the presence of said one or more conditions in said pregnant woman.
8. The method of claim 7, wherein said one of said three or more microfluidic channels comprises a capture molecule for capturing an anti-HIV antibody.
9. The method of claim 7, wherein said one of said three or more microfluidic channels comprises a capture molecule for capturing a CD4+ T cell.
10. The method of claim 7, wherein said one of said three or more microfluidic channels comprises a capture molecule for capturing an anti-syphilis antibody.
11. The method of claim 7, wherein said one of said three or more microfluidic channels comprises a capture molecule for capturing malaria-parasitized red blood cells.
12. The method of claim 7, wherein said biological sample is a blood sample.
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