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Sanitary swab collection system, microfluidic assay device, and methods for diagnostic assays

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Sanitary swab collection system, microfluidic assay device, and methods for diagnostic assays


Biohazard specimen collection containers are provided with an external disposable skin, that is stripped away and discarded after the biohazardous specimen is collected, thus reducing or eliminating objectionable or dangerous residues on the outside surfaces of the container. Further, we teach that the sample collection container with external disposable skin may also serve as an integrated microfluidic biosample processing and analytical device, thereby providing a single entry, disposable assay unit, kit and system for “world-to-result” clinical diagnostic testing. These integrated assay devices are provided with synergic, multiple safe-handling features for protecting healthcare workers who handle them. The modified collection containers and analytical devices find application, for example, in PCR detection of infectious organisms or pathogenic markers collected on a swab.

Browse recent Micronics, Inc. patents - Redmond, WA, US
Inventors: C. Frederick Battrell, Jason Capodanno, John Clemmens, Joan Haab, John Gerdes
USPTO Applicaton #: #20120271127 - Class: 600309 (USPTO) - 10/25/12 - Class 600 
Surgery > Diagnostic Testing >Measuring Or Detecting Nonradioactive Constituent Of Body Liquid By Means Placed Against Or In Body Throughout Test



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The Patent Description & Claims data below is from USPTO Patent Application 20120271127, Sanitary swab collection system, microfluidic assay device, and methods for diagnostic assays.

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CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No. 12/695,487 filed Jan. 28, 2010, now allowed; which application is a continuation of International Patent Application No. PCT/US2008/071810 filed Jul. 31, 2008; which application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 60/953,045, filed Jul. 31, 2007; which applications are incorporated herein by reference in their entireties.

STATEMENT OF GOVERNMENT INTEREST

This invention was made with government support under Contract No. U01 AI070801 awarded by National Institutes of Health. The government has certain rights in this invention.

BACKGROUND

1. Technical Field

The invention relates to medical and veterinary sample collection devices and to medical and veterinary analytical devices of specialized form and function, and to integrated microfluidic devices for both sample collection and analysis. The invention further relates to a method for biohazard sample collection.

2. Description of the Related Art

The art relating to handling of swabs is well established, but remains in need of improvement, both to ensure the integrity of the clinical sample and its protection from contamination, but also to ensure that healthcare professionals are not unnecessarily or inadvertently exposed to biological material on the exterior surfaces of the swab container. Once the external surfaces are contaminated during sample collection, exposure readily occurs when a swab container is passed from hand to hand, and no on-board means is known to refresh or cleanse the outside surfaces of the sample container.

We have reviewed the patent literature, and found little or no teaching that comments on this problem. U.S. Pat. No. 4,803,998 to Kezes relates to a swab retaining vial cap and describes a combination containment vial with cap and with swab mounted inside the cap, the vial containing a medium for preserving a sample on the swab during shipment. The swab is removed from the cap to collect a sample and the swab tip can then be broken off when inserted into the vial so that the swab tip drops to the bottom of the vial without contamination by the user. The cap is then sealed. FIG. 4 shows a swab with frangible shaft. The patent is indicative of early efforts to protect a sample from contamination. This seems to accurately reflect the overall state of the art as it exists at this filing. We note that while the interior of the vial is carefully protected from contamination, the exterior is subject to contamination during handling, and becomes a fomite vector for infectious disease. Samples collected in this way are frequently removed for analysis at a separate location, and those who handle the sample container may inadvertently be exposed to material on the exterior surface of the sample container.

U.S. Pat. No. 6,991,898 to O'Connor (Jan. 31, 2006) describes a self-contained diagnostic test device for collection and detection of an analyte in a biological specimen. The device comprises a tubular swab and reagent dispensing cap. The reagent dispensing cap delivers one or more selected reagents to an assay chamber upon the rotation of the reagent chamber.

In U.S. Pat. No. 7,098,040 to Kaylor, a swab-based diagnostic test device is provided. The test device contains a reagent and a rupturable seal for adding the reagent to the sample after the swab is sealed inside the device.

U.S. Pat. No. 6,277,646 to Guirguis provides a device for both collecting and testing a fluid specimen. A fluid specimen is collected and an aliquot is transferred to an isolation chamber, from which a flow path to a test chamber is opened.

U.S. Pat. No. 6,565,808 to Hudak describes a fluid flow actuating device or structure, such as a valve, which separates the sample receiving chamber from the test platform. The test method involves collecting a sample, contacting the sample with the proprietary test device, and detecting the analyte in the sample.

U.S. Pat. No. 6,248,294 to Nason relates to a self-contained diagnostic test unit for use in the collection and analysis of a biological specimen. The test unit comprises is tubular housing for capturing a swab. A reagent dispenser cap delivers reagents to the specimen chamber and a diagnostic strip assembly is mounted on the housing so a portion of the specimen can flow by wick action through the test strip, producing a visible color change.

U.S. Pat. Nos. 5,266,266 and 5,879,635 to Nason relate to a reagent dispenser which includes a pair of reagent chambers with selected reagents therein, and a dual nib for hermetically sealing the reagent chambers. A portion of the dispenser is deformable to break or otherwise to displace the nib in a manner permitting the two reagents to flow together and mix within one of the reagent chambers. The deformable portion or the dispenser can then be squeezed to express the mixed reagents for delivery to contact the specimen to be analyzed. In a preferred form, the dispenser is a cap assembly on an open-ended tubular housing configured for receiving a swab.

Similarly, U.S. Pat. No. 6,890,484 to Bautista relates to in-line test device and describes a swab receiving port integrated into the body of a lateral flow strip. No means for protecting the exterior of the test apparatus is described. Goodfield, in Sampling and Assay Device (WO1997/23596), discloses a swab and swab container with liquid assay reagents accessible by rupture of foil liners, again with no outer disposable protective layer.

All the above devices and methods are deficient for the present purpose in that the operator is exposed to contamination of the external surfaces of the specimen collection container by contact with residues of specimen or unrelated patient-derived bodily material, which may be unhygienic and grossly objectionable. This problem is apparently not considered.

United States Patent Application 2005/0009200 to Guo relates to a sanitary and compact fecal occult blood collector kit. The swab tip in this case is covered “for hygienic purposes”. Also disclosed is a package for the swab and the cover. However, on closer study, the purpose of the cover is again to protect the sample, not the handle of the swab contacted by the operator or the external surfaces of the swab collection container, and the exterior of the package cannot be cleaned of contaminating matter that accumulates during sampling. Further, the swab must again be retrieved from the package. Thus while the sample is protected, the user is potentially exposed at multiple levels.

Miniaturizing some of the processes involved in clinical analyses, including nucleic acid, immunological and enzymatic analysis, or combinations thereof, has been achieved using microfluidic devices. Microfluidic techniques known in the art include electrophoretic detectors, for example those designed by ACLARA BioSciences Inc., or the LabChip™ by Caliper Technologies Inc, and hybridization detectors such as those manufactured by Nanogen of San Diego. Also indicative of the state of the art are PCT Publication WO1994/05414, U.S. Pat. Nos. 5,498,392, 5,304,487, 5,296,375, 5,856,174, 6,180,372, 5,939,312, 5,939,291, 5,863,502, 6,054,277, 6,261,431, 6,440,725, 5,587,128, 5,955,029, 5,498,392, 5,639,423, 5,786,182, 6,261,431, 6,126,804, 5,958,349, 6,303,343, 6,403,037, 6,429,007, 6,420,143, 6,572,830, 6,541,274, 6,544,734, 6,960,437, 6,762,049, 6,509,186, 6,432,695, 7,018,830, and 2001/0046701, 2003/0138941, and International Pat. Nos. WO 2003/004162, WO2002/18823, WO2001/041931, WO1998/50147, WO1997/27324, all of which describe apparatuses and methods incorporating various microfluidic processing and analytical operations involved in nucleic acid analysis, and are incorporated herein by reference.

Co-assigned to Micronics, Inc of Redmond Wash., and also incorporated herein in full by reference, are U.S. Pat. No. 6,743,399 (“Pumpless Microfluidics”), U.S. Pat. No. 6,488,896 (“Microfluidic Analysis Cartridge”), U.S. Pat. No. 5,726,404 (“Valveless Liquid Microswitch”), U.S. Pat. No. 5,932,100 (“Microfabricated Differential Extraction Device and Method”), (“Tangential Flow Planar Microfluidic Fluid Filter”), U.S. Pat. No. 5,872,710 (“Microfabricated Diffusion-Based Chemical Sensor”), U.S. Pat. No. 5,971,158 (“Absorption-Enhancing Differential Extraction Device”), U.S. Pat. No. 6,007,775 (“Multiple Analyte Diffusion-Based Chemical Sensor”), U.S. Pat. No. 6,581,899 (“Valve for Use in Microfluidic Structures”), U.S. Pat. No. 6,431,212 (“Valve for Use in Microfluidic Structures”), U.S. Pat. No. 7,223,371 (“Microfluidic Channel Network Device”), U.S. Pat. No. 6,541,213 (“Microscale Diffusion Immunoassay”), U.S. Pat. No. 7,226,562 (“Liquid Analysis Cartridge”), U.S. Pat. No. 5,747,349 (“Fluorescent Reporter Beads for Fluid Analysis”), US Patent Applications 2005/0106066 (“Microfluidic Devices for Fluid Manipulation and Analysis”), 2002/0160518 (“Microfluidic Sedimentation”), 2003/0124619 (“Microscale Diffusion Immunoassay”), 2003/0175990 (“Microfluidic Channel Network Device”), 2005/0013732 (“Method and system for Microfluidic Manipulation, Amplification and Analysis of Fluids”), 2007/0042427, “Microfluidic Laminar Flow Detection Strip”, 2005/0129582 (System and Method for Heating, Cooling and Heat Cycling on a Microfluidic Device); and unpublished US Patent documents titled, “Integrated Nucleic Acid Assays,” “Microfluidic Cell Capture and Mixing Circuit”, “Microfluidic Mixing and Analytical Apparatus,” “System and Method for Diagnosis of Infectious Diseases”, “Methods and Devices for Microfluidic Point of Care Assays”, “Integrated Microfluidic Assay Devices and Methods”, and “Microscale Diffusion Immunoassay Utilizing Multivalent Reactants”, all of which are hereby incorporated in full by reference. Also representative of microfluidic technologies that are co-assigned to Micronics are PCT Publications WO 2006/076567 and 2007/064635, all incorporated herein in full by reference for what they enable.

The utility and breadth of microfluidic assays for nucleic acid assays is further demonstrated in the scientific literature, the teachings of which are incorporated by reference herein. These teachings include, for example, Nakano H et al. 1994. High speed polymerase chain reaction in constant flow. Biosci Biotechnol Biochem 58:349-52; Wilding, P et al. 1994. PCR in a silicon microstructure. Clin Chem 40(9):1815-18; Woolley A T et al. 1996. Functional integration of PCR amplification and capillary electrophoresis in a microfabricated DNA analysis device. Anal Chem 68:4081-86; Burke D T et al. 1997. Microfabrication technologies for integrated nucleic acid analysis. Genome Res 7:189-197; Kopp et al. 1998. Chemical amplification: continuous-flow PCR on a chip. Science 280:1046-48; Burns, M A. 1998. An Integrated Nanoliter DNA Analysis Device. Science 282:484-87; Belgrader P et al. 1999. PCR Detection of bacteria in seven minutes. Science 284:449-50; Lagally E T et al. 2001. Fully integrated PCR-capillary electrophoresis microsystem for DNA analysis. Lab Chip 1:102-07; Tudos A J et al. 2001. Trends in miniaturized total analysis systems for point-of-care testing in clinical chemistry. Lab Chip 1:83-95; Belgrader P et al. 2002. A battery-powered notebook thermocycler for rapid multiplex real-time PCR analysis. Anal Chem 73:286-89; Hupert L M et al. 2003. Polymer-Based Microfluidic Devices for Biomedical Applications. In, (H Becker and P Woias, eds) Microfluidics, BioMEMS, and Medical Microsystems, Proc SPIE Vol 4982:52-64; Chartier I et al. 2003. Fabrication of an hybrid plastic-silicon microfluidic device for high-throughput genotyping. In, (H Becker and P Woias, eds) Microfluidics, BioMEMS, and Medical Microsystems, Proc SPIE Vol 4982:208-219; Anderson R C et al. 2000. A miniature integrated device for automated multistep genetic assays. Nucl Acids Res 28(12):[e60,i-vi]; Yang, J et al. 2002. High sensitivity PCR assay in plastic micro reactors. Lab Chip 2:179-87; Giordano B C et al. 2001. Polymerase chain reaction in polymeric microchips: DNA amplification in less than 240 sec. Anal Biochem 291:124-132; Khandurina J et al. 2000. Integrated system for rapid PCR-based DNA analysis in microfluidic devices. Anal Chem 72:2995-3000; Chiou, J et al. 2001. A Closed-Cycle Capillary Polymerase Chain Reaction Machine. Anal Chem 73:2018-21; Yuen, P K et al. 2001. Microchip module for blood sample preparation and nucleic acid amplification reactions. Genome Res 11:405-412; Zhou X, et al. 2004. Determination of SARS-coronavirus by a microfluidic chip system. Electrophoresis. 25(17):3032-9; Liu Y et al. 2002. DNA amplification and hybridization assays in integrated plastic monolithic devices. Anal Chem 74(13):3063-70; Zou, Q et al. 2002. Micro-assembled multi-chamber thermal cycler for low-cost reaction chip thermal multiplexing. Sensors Actuators A 102:224-121; Zhang C et al. 2006. PCR Microfluidic devices for DNA amplification. Biotech Adv 24:243-84, and Zhang, C and Xing D. 2007. Miniaturized PCR chips for nucleic acid amplification and analysis: latest advances and future trends. Nucl Acids Res 35(13):4223-37.

Thus there is a clear and ongoing interest in microfluidic devices for clinical and veterinary diagnostic assays. As these commercial applications increase, the world-to-chip interface is receiving increasing attention, and we note that little has been done in the area of sample collection to both improve the validity of nucleic acid amplifications by preventing cross-sample contamination, and just as importantly, to prevent exposure of those persons handling the specimens to objectionable or potentially infectious materials. As has been noted, (Nelson, D. B. et al. 2003. “Self-Collected Versus Provider-Collected Vaginal Swabs for the Diagnosis of Bacterial Vaginosis: an Assessment of Validity and Reliability,” J Clin Epidemiol, 56:862-866), there is an increasing trend toward patient self-collection of samples, often with swabs or cups. Typically the patient is not provided with means to ensure that the external surfaces of the sample collection device does not become contaminated with the sample or related biological fluids during handling. These swabs or cups are typically then processed or handled by ungloved couriers and paraprofessionals and must then be transferred to the analytical device or further handled and processed by nursing and laboratory personnel. The sample collection device thus becomes a fomite potentially capable of spreading infectious disease to numerous persons, and a method or means for eliminating or at least reducing the exposure of health workers to the contaminated exterior of the sample collection vials, bottles, cups, tubes, and so forth, has been a longstanding and unmet need in the healthcare industry.

Furthermore, awareness of the dangers of unsafe handing of biological fluids and specimens has increased dramatically in the last two decades, and single-entry devices are increasingly needed that seamlessly integrate sample preparation, extraction, and analysis without unnecessary operator exposure. A further objective we have identified is the need to fully integrate the device into a disposable format, so that once a sample is collected, either by patient or by a health professional, all remaining steps of the analysis, up to and including display of the result, are performed without further personal exposure to the sample. A critical step in this process is thus the refreshing or disinfecting of the external surface sample collection container (whether it is also the analytical device or not), and to our knowledge, satisfactory solutions to this problem have not been recognized or brought forward prior to our disclosure herein.

BRIEF

SUMMARY

Swabs are extremely useful for collecting specimens. Following collection of a specimen on a swab, the swab must be generally protected during subsequent transport and processing for analysis. During initial handling, contamination of the external surfaces of the swab collection container by contact with residues of specimen or unrelated patient-derived bodily material, which may be unhygienic and grossly objectionable, is almost inevitable. Gloves are protective only to the hands on which they are worn, not to the swab collection container. We see a solution to this problem as an unrecognized and unmet need with significant potential benefits, particularly in reduction of nosocomial infections, for example, and more generally in reduction of disease transmission to health care workers, and also in improvement of sample quality, which is mandatory for tests such as PCR, where false positives due to cross-contamination will invalidate any testing system.

Cross-contamination by transmission on the surfaces of fomites is a longstanding problem. We find that this problem can be alleviated or significantly reduced by applying a disposable external skin to the collection device, and by removing the skin after the risk of exposure to further contamination is ended. Contamination risk is most great during the act of specimen collection itself, and decreases greatly after the specimen collection container is removed from the sampling site. Contamination of the external surfaces of an article passed from hand-to-hand, or hand-to-machine, with normal flora and normal squamous epithelial cells, is significantly less likely to result in false diagnostic positives for a pathogenic condition.

We disclose a biohazard swab collection device or container, comprising a body with external surfaces, an internal hollow volume, and a sealable closure for separating said external surfaces from said internal hollow volume, said external surface further comprising a disposable external skin layer, whereby after the biohazardous swab is enclosed and sealed within the internal hollow volume, any biohazardous residues accumulated on the external surfaces are removed by removing and disposing of the disposable external skin layer, and further optionally comprising a valve separating said internal hollow volume into a swab receiving chamber and a microfluidic assay circuit with a microfluidic channel and an on-board liquid reagent.

We further disclose a method wherein the specimen is not limited to a swab and the specimen collection device is not limited to an analytical device. The general method comprises the steps of:

a) providing a sample and a specimen collection container with body and with sample receiving orifice, said body with external surface and internal hollow volume, said external surface with disposable skin or skins, said sample receiving orifice with sealable closure;

b) inserting said sample into said sample receiving orifice;

c) closing said sealable closure said sample receiving orifice; thereby capturing said sample; and,

d) removing said disposable skin or skins from said external surface; thereby renewing said external surface.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a perspective view of a representative specimen collection device with external skins and with integrated sample processing and analytical assay capability.

FIG. 2 is a perspective view of a sample swab with frangible handle.

FIG. 3A is a plan view of the upper surface of the device of FIG. 1, and shows section plane 3B. FIG. 3B is a section of the device of FIG. 1 on plane 3B, and shows the swab receiving chamber and inner workings of an embodiment of the integrated device. Representative inner workings are indicated schematically.

FIG. 4 is an exploded view of protective external disposable skins applied to a representative specimen collection device.

FIG. 5 is a conceptual illustration of the manufacture of a heat-shrink external disposable skin on a representative specimen collection device.

FIG. 6 is an illustration of the assembly of a disposable bag applied to a representative specimen collection device.

FIG. 7 is an exploded view of a Styrofoam or composite coverblock assembly applied to a representative specimen collection device.

FIG. 8 is a sketch of a device with composite cover formed in place over and around the device.

FIGS. 9A-E is a sequential view of the steps of a method in which a representative specimen collection device fitted with a disposable external sanitary skin is used to collect a specimen on a swab.

FIG. 10 is a block diagram of the steps of a method for collecting a biohazardous swab in a swab collection device fitted with a disposable external sanitary skin.

FIG. 11 is a block diagram of the more general steps of a method for collecting a biohazardous specimen in a specimen collection device fitted with a disposable external sanitary skin.

FIGS. 12A and B show a detail of a tab on the disposable external cover for use in removing the protective cover after the specimen is collected.

FIG. 13 is a second embodiment of a specimen collection device for a swab or tampon, and includes operator interface and real-time point-of-care data display that is hidden under the cap of a protective removable overlayer during specimen collection.

FIG. 14 is a section down the long axis of a third embodiment of a specimen collection device for a swab or tampon, and includes operator interface and real-time point-of-care data display that is hidden under a protective removable overlayer during specimen collection.

FIGS. 15A and B is a first embodiment of a specimen collection device for a swab where the specimen collection device has no analytical capacity.

DETAILED DESCRIPTION

Definitions:

The following definitions are provided as an aid in interpreting the claims and specification herein. Where works are cited or incorporated by reference, and any definition contained therein is inconsistent with that supplied here, the definition used therein shall not supersede or limit the definition supplied herein.

Fomite: An inanimate object or substance, such as a doorknob, utensil, soap bar, or specimen container, that is capable of transmitting infectious organisms (broadly bacterial and viral) from one individual to another, typically by hand-to-hand or hand-to-mouth exposure to a biological residue on the surface of the inanimate object or substance.

Test samples: Representative biosamples taken by swab include, for example: gingival, buccal, and mucosal epithelial materials, saliva, wound exudates, pus, surgical specimens, lung and other respiratory secretions, nasal secretions, sinus drainage, sputum, blood, urine, medial and inner ear contents, ocular secretions and mucosa, cyst contents, cerebral spinal fluid, stool, diarrhoeal fluid, tears, mammary secretions, ovarian contents, ascites fluid, mucous, gastric fluid, gastrointestinal contents, urethral discharge, vaginal discharge, vaginal mucosa, synovial fluid, peritoneal fluid, meconium, amniotic fluid, semen, penile discharge, or the like may be presented for testing on a swab. Assay from swabs representative of mucosal secretions and epithelia are acceptable, for example mucosal swabs of the throat, tonsils, gingival, nasal passages, vagina, urethra, rectum, lower colon, and eyes. Besides physiological fluids, samples of water, industrial discharges, food products, milk, air filtrates, and so forth are also likely test specimens. Particularly preferred as samples are biosamples collected on swabs or tampons, where a tampon is essentially a handleless swab that is sometimes worn internally before testing.

Biohazard: A biohazard is a material, either biologically active or inanimate, that poses a risk or threat to health. Also included in this category as biohazards, sensu lato, as defined here, are materials of likely biological origin that are visually, tangibly, or odorously objectionable or repulsive, and those materials which are not in fact a threat, but which potentially are a threat until tested negative. Biohazards include potentially infectious material of any kind, and may contain infectious agents from multiple biological categories, including but limited to, bacteria and viruses, either singly or in one or more combinations thereof, and microbial products such as toxins.

Bioassay Target Molecule: or “analyte of interest”, or “target molecule”, may include a nucleic acid, a protein, an antigen, an antibody, a carbohydrate, a cell component, a lipid, a receptor ligand, a small molecule such as a drug, and so forth. Target nucleic acids include genes, portions of genes, regulatory sequences of genes, mRNAs, rRNAs, tRNAs, siRNAs, cDNA and may be single stranded, double stranded or triple stranded. Some nucleic acid targets have polymorphisms, deletions and alternate splice sequences. Multiple target domains may exist in a single molecule, for example an immunogen may include multiple antigenic determinants. An antibody includes variable regions, constant regions, and the Fc region, which is of value in immobilizing antibodies. The microfluidic analytical devices of the present invention are configured to detect a bioassay target molecule of these sorts, singly or in combinations.

Such bioassay target molecules may be associated with a pathogenic condition: which is taken as a condition of a mammalian host characterized by the absence of health, i.e., a disease, infirmity, morbidity, or a genetic trait associated with potential morbidity.

Microfluidic cartridge: a “device”, “card”, or “chip” with fluidic structures and internal channels having microfluidic dimensions. These fluidic structures may include chambers, valves, vents, vias, pumps, inlets, nipples, and detection means, for example. Generally, microfluidic channels are fluid passages having at least one internal cross-sectional dimension that is less than about 500 μm and typically between about 0.1 μm and about 500 μm, but we extend the upper limit of the range to 600 um because the macroscopic character of the bead suspensions sometimes used as analytical aids require it. Therefore, as defined herein, microfluidic channels are fluid passages having at least one internal cross-sectional dimension that is less than 600 um.

Microfluidic cartridges may be fabricated from various materials using techniques such as laser stenciling, embossing, stamping, injection molding, masking, etching, and three-dimensional soft lithography. Laminated microfluidic cartridges are further fabricated with adhesive interlayers or by adhesiveless bonding techniques, such by thermal or pressure treatment of oriented polypropylene or by ultrasonic welding. The microarchitecture of laminated and molded microfluidic cartridges can differ according to the limitations of their fabrication methods.

Microfluidic pumps: include for example, bulbs, bellows, diaphragms, or bubbles intended to force movement of fluids, where the substructures of the pump have a thicknesses or other dimension of less than 1 millimeter. Such pumps include the mechanically actuated recirculating pumps described in U.S. Pat. No. 6,743,399 to Weigl and US 2005/0106066 to Saltsman, commonly assigned to the applicant. Such pumps may be robotically operated or operated by hand. Electroosmotic pumps are also provided. Such pumps can be used in place of external drives to propulse the flow of solubilized reagents and sample in microfluidic device-based assays.

Blister pack: an on-board reagent pack or sachet under a deformable (or elastic) diaphragm. Used to deliver reagents by pressurizing the diaphragm and may appose a “sharp”, such as a metal chevron, so that pressure on the diaphragm ruptures the “pillow” (see pillow). These may be used with check valves or closable vents to produce directional fluid flow and reagent delivery. Elastic diaphragms are readily obtained from polyurethane, polysilicone and polybutadiene, and nitrile for example (see elastomer). Deformable, inelastic diaphragms are made with polyethylene terephthalate (PET), mylar, polypropylene, polycarbonate, or nylon, for example. Other suitable materials for the deformable film include parafilm, latex, foil, and polyethylene terephthalate Key factors in selecting a deformable film include the yield point and the deformation relaxation coefficient (elastic modulus).

Use of these devices permits delivery or acceptance of a fluid while isolating the contents of the microfluidic device from the external environment, and protecting the user from exposure to the fluid contents.

Single entry: refers to a microfluidic device, card or cartridge that requires, or permits, only a single introduction of sample, and the assay is then conducted within a self-contained, sealed system. Such devices optionally contain a device for sealing or locking the sample port and an on-board means for disinfecting the contents of the device and any waste following completion of the assay. In one embodiment, the device can be discarded after use without special precautions.

Waste chamber or “pack”: is a cavity or chamber that serves as a receptacle for sequestering discharged sample, rinse solution, and waste reagents. Typically also includes a wicking material (see wick). Waste packs may also be sealed under an elastic isolation membrane sealingly attached to the body of the microfluidic device. This inner membrane expands as the bibulous material expands, thus enclosing the waste material. The cavity outside the isolation membrane is vented to atmosphere so that the waste material is contained and isolated. Waste packs may optionally contain dried or liquid sterilants.

Vent: a pore intercommunicating between an internal cavity and the atmosphere. A “sanitary” or “isolation vent” also contains a filter element that is permeable to gas, but is hydrophobic and resists wetting. Optionally these filter elements have pore diameters of 0.45 microns or less. These filters function both in forward and reverse isolation. Filter elements of this type and construction may also be placed internally, for example to isolate a valve or bellows pump from the pneumatic manifold controlling it.

Herein, where a “means for a function” is described, it should be understood that the scope of the invention is not limited to the mode or modes illustrated in the drawings alone, but also encompasses all means for performing the function that are described in this specification, and all other means commonly known in the art at the time of filing. A “prior art means” encompasses all means for performing the function as are known to one skilled in the art at the time of filing, including the cumulative knowledge in the art cited herein by reference to a few examples.

Means for extracting: refers to various cited elements of a device, such as a solid substrate, filter, filter plug, bead bed, frit, or column, for capturing target nucleic acids from a biological sample, and includes the cumulative knowledge in the art cited herein. Extracting further comprises methods of solubilizing, and relates to the resuspension of cells and tissue from the tip of a swab. This includes methods, for example, for dissolution of mucous and protein as described in United States Patent Application 2004/0175695 to Debad. Generally, extraction means include a mechanical pumping component that promotes physical resuspension by turbulent or near turbulent flow. Such flow may be reciprocating flow, and may be pulsatile at varying frequencies to achieve the desired resuspension in a reasonable interval of time. Extraction means also include use of detergent-based buffers, sulfhydryl-reducing agents, proteolytics, chaotropes, passivators, and other solubilizing means.

A means for polymerizing, for example, may refer to various species of molecular machinery described as polymerases and their cofactors and substrates, for example reverse transcriptases and TAQ polymerase, and includes the cumulative knowledge of enzymology cited herein by reference to a few examples.

Means for Amplifying: The grandfather of this art is the “polymerase chain reaction” (referred to as PCR) which is described in detail in U.S. Pat. Nos. 4,683,195, 4,683,202 and 4,800,159, Ausubel et al. Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, Md. (1989), and in Innis et al., (“PCR Protocols”, Academic Press, Inc., San Diego Calif., 1990). Polymerase chain reaction methodologies require thermocycling and are well known in the art. Briefly, in PCR, two primer sequences are prepared that are complementary to regions on opposite complementary strands of a target sequence. An excess of deoxynucleoside triphosphates are added to a reaction mixture along with a DNA polymerase, e.g., Taq polymerase. If the target sequence is present in a sample, the primers will bind to the target and the polymerase will cause the primers to be extended along the marker sequence by adding on nucleotides. By raising and lowering the temperature of the reaction mixture, the extended primers will dissociate from the template to form reaction products, excess primers will bind to the template and to the reaction products and the process is repeated. By adding fluorescent intercalating agents, PCR products can be detected in real time.

Other amplification protocols include LAMP (loop-mediated isothermal amplification of DNA) reverse transcription polymerase chain reaction (RT-PCR), ligase chain reaction (“LCR”), transcription-based amplification systems (TAS), including nucleic acid sequence based amplification (NASBA), “Rolling Circle”, “RACE” and “one-sided PCR”.

These various non-PCR amplification protocols have various advantages in diagnostic assays, but PCR remains the workhorse in the molecular biology laboratory and in clinical diagnostics. Embodiments disclosed here for microfluidic PCR should be considered representative and exemplary of a general class of microfluidic devices capable of executing one or various amplification protocols.

Means for detecting: as used herein, refers to an apparatus for displaying an endpoint, i.e., the result of an assay, and may include a detection channel and test pads, and a means for evaluation of a detection endpoint. Detection endpoints are evaluated by an observer visually in a test field, or by a machine equipped with a spectrophotometer, fluorometer, luminometer, photomultiplier tube, photodiode, nephlometer, photon counter, voltmeter, ammeter, pH meter, capacitative sensor, radio-frequency transmitter, magnetoresistometer, or Hall-effect device. Magnetic particles, beads and microspheres haing or impregnated color or having a higher diffraction index may be used to facilitate visual or machine-enhanced detection of an assay endpoint. Magnifying lenses in the cover plate, optical filters, colored fluids and labeling may be used to improve detection and interpretation of assay results. Means for detection of magnetic particles, beads and microspheres may also include embedded or coated “labels” or “tags” such as, but not limited to, dyes such as chromophores and fluorophores; radio frequency tags, plasmon resonance, spintronic, radiolabel, Raman scattering, chemoluminescence, or inductive moment as are known in the prior art. Colloidal particles with unique chromogenic signatures depending on their self-association are also anticipated to provide detectable endpoints. QDots, such as CdSe coated with ZnS, decorated on magnetic beads, or amalgamations of QDots and paramagnetic Fe304 microparticles, optionally in a sol gel microparticulate matrix or prepared in a reverse emulsion, are a convenient method of improving the sensitivity of an assay of the present invention, thereby permitting smaller test pads and larger arrays. Fluorescence quenching detection endpoints are also anticipated. A variety of substrate and product chromophores associated with enzyme-linked immunoassays are also well known in the art and provide a means for amplifying a detection signal so as to improve the sensitivity of the assay, for example “up-converting” fluorophores. Detection systems are optionally qualitative, quantitative or semi-quantitative. Visual detection is preferred for its simplicity, however detection means can involve visual detection, machine detection, manual detection or automated detection.

Means for isolation include impermeable cartridge body, gas permeable hydrophobic venting, bibulous padding in waste chamber, disinfectant in waste chamber, elastomeric membrane separating pneumatic actuator from blister pack, valve with elastomeric membrane actuated by suction pressure, suction pressure in said sample entry port, on-board reagent pack, self-locking single-entry sample port, gasketed closure, and disposable external skin or skins Isolation refers both to the protection of the user from potentially biohazardous specimens, and to the protection of the specimen from contamination by the user or by foreign environmental materials. Closure means, or “means for sealingly closing”, include caps, lids, threaded closures, “ziplock” closures, ball valves, gasketed closures, gaskets, seals, snap caps of all sorts, bungs, corks, stoppers, lip seals, press seals, adhesive seals, waterproof seals, single-entry seals, tamper-proof seals, locking seals, track-slidable sealable covers, compression seals, one-way valves, spring-loaded valves, spring-loaded lids, septa, tee-valves, snap-locking closures in general, piston-valves, double-reed valves, diaphragm closures, hinged closures, folding closures, Luer lock closures, and so forth.

Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to”.

“Conventional” is a term designating that which is known in the prior art to which this invention relates.

“About” and “generally” are broadening expressions of inexactitude, describing a condition of being “more or less”, “approximately”, or “almost” in the sense of “just about”, where variation would be insignificant, obvious, or of equivalent utility or function, and further indicating the existence of obvious minor exceptions to a norm, rule or limit.

Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Turning now to the figures, FIG. 1 is a conceptual view of a microfluidic analytical device (1) with integrated sanitary swab collection features. The device, which is hand sized, is provided with upper and lower disposable external skins (2, lower not shown). Tabs (4,5) assist in peeling off the skins. These skins are removed after the specimen collection process is completed. Also shown is the swab receiving orifice (6) and sliding closure (7) in the open position for receiving a swab. The closure is provided with a seal and track guide (8) whereby the closure is slid into position sealingly covering the swab receiving orifice. The closure is textured with ribs (9) to aid the thumb in moving from left to right (as shown here) in order to effectuate swab capture within the device. The card body (10) is bounded by external surfaces (11).

FIG. 2 is a representation of a swab (20) as would be used in an embodiment of the invention. The swab comprises a shaft (21) with handle portion (22), neck portion (23), frangible breakaway notch (24), and tip (25) mounted at the distal end of the shaft. The shaft may be of various shapes or materials. Shaft materials include polypropylene, polyurethane, polycarbonate, polyethylene terephthalate, and other polyesters. Also conceived are polyimides such as nylon and natural fibers such as pine, bamboo, compressed paper, and so forth.

The tip may be of various shapes or materials. Preferred swab shapes include a pipe-cleaner shape of bristles, a spade shape with sponge pad, and a “bud” shape with fiber bat. Non-limiting examples of synthetic fiber materials useful in forming swabs include acetate fibers, aramide fibers, polyamide fibers, e.g. nylons, polyester fibers, e.g. polyethylene terephthalate fibers (PET), polyolefin fibers, e.g. polypropylene and polyethylene fibers, polyvinyl alcohol fibers, polyurethane fibers or foams, and mixtures thereof. Further suitable synthetic fibers include bi- or tricomponent fibers such as PE/PET- or PP/PE fibers. These fibers can for example be so-called core-sheath-, side-by-side- or island-in-the-sea type fibers, as may be useful in selected applications. Lyocell fibers are also useful. Non-synthetic materials include woven paper or cotton. Fiber chemistry is generally chosen to be compatible with extraction or analytical chemistries.

Swab fibers may be interlaid, either knitted or randomly entwined. Interlaid webs or fabrics have been formed from many processes, such as, for example, meltblowing processes, spunbonding processes, and bonded carded web processes. In particular embodiments, interlaid swab materials as utilized in the present invention are produced from polymers, such as, for example, polyethylene or polypropylene. The swab fibers optionally may be made from interbonded fibers, for example as of thermoplastic fibers. The term “fibers” as used herein refers to a broad range of thermoplastic members that can be used to form a nonwoven fabric, including members having defined lengths like staple fibers, meltblown fibers that show a beginning and an end, filaments having endless or continuous lengths, and the like. For example, and without limiting the generality of the foregoing, thermoplastic polymers such as polyolefins including polyethylene, polypropylene as well as polystyrene can be used as may be polyesters including polyethylene terephthalate, and polyamides including nylons. Also useful are other thermoplastic polymers such as those which are elastomeric including elastomeric polyurethanes and block copolymers. Compatible blends of any of the foregoing may also be used. In addition, additives such as wax, fillers, and the like may be incorporated in amounts consistent with the fiber forming process used to achieve desired results. Other fiber or filament forming materials will suggest themselves to those skilled in the art. Bicomponent fibers may be also used. The fibers may also be formed from solution, and examples include viscose. It is only essential that the composition be capable of spinning into filaments or fibers of some form that can be deposited onto a forming surface and thermally formed or interbonded in a manner dependent upon the forming surface. The swab tip may comprise a sponge element.

FIG. 3 shows a representative device for swab capture and analysis. FIG. 3A is a plan view of the top surface of the device, showing plane of section 3B and the location of the swab receiving orifice and sealing closure. In FIG. 3A, the device body 10 and exterior surfaces 11 are again shown.

FIG. 3B is a view of the internal workings of a representative device (30), showing a section through the device solid body interior (31), with captive swab tip (32) in swab receiving chamber (33), also termed herein an “internal hollow volume”. In this view, closure (34) and gasket (35) form a liquid-tight seal over the swab receiving chamber 33. Also shown in schematic form are the elements of an on-board nucleic acid assay. Generally, at least one valve (37) will separate the internal hollow volume of the device body into at least two compartments, one for the sample receiving chamber and the other the analytical microfluidics compartment or circuit (dotted lines with arrows, 42). Other valves (38) may also be used to add functionality to the microfluidic circuit. Any valve known in the art may be used. On-board microfluidic elements for a nucleic acid assay include at least one microfluidic channel (39), and optionally provision for reagent packs such as for lysis reagent and extract reagents (40,41), and an optional microfluidic nucleic acid assay circuit (42), shown schematically. In this embodiment, the internal hollow volume comprises a first compartment for receiving the swab (33) and a second compartment (42, dotted lines) for performing a fluidic operation on the sample, such as a sample preparation step or a sample analysis such as PCR. Generally, the first and second compartments are joined by a valved (37) microfluidic channel (39). This channel provides for fluidic connection between the compartments so that reagent and sample may be interechanged. Other compartments such as waste compartment (36) may also be provided. Variants of the illustrated microfluidic circuit for joining the compartments and exchanging fluids between the compartments are readily within the scope of the invention. Sample processing steps could include extraction of the biological material and lysis of cells of interest, followed by filtration and entry of the filtrate into a nucleic acid capture and elution module. Steps of capture, elution, amplification and detection are indicated without detail. Mesoscale devices for amplification and detection of a nucleic acid in a sample were first described in 1992 (U.S. Pat. No. 5,498,392 to Wilding, “Mesoscale Polynucleotide Amplification Device and Method”) and conventional mechanisms are known to those skilled in the art. These devices include various filters, pumps, vents, microfluidic channels, valves, and so forth. The device also optionally includes a display capability, although this function could be a simple visual indicator, or could be a complex interaction between the device and a docking site on an instrument that examines fluorescence of an array or a lateral flow strip, and so forth. Therefore, both stand-alone manual diagnostic applications and automated or semi-automated applications are envisaged. The inner workings of these devices are defined in various embodiments of the prior art. It should be noted that the claimed invention is not limited to a particular embodiment of the inner workings, and that applications for devices used in performing chemical or immunoassays are also anticipated. Devices may be built to assay for bioassay target molecules indicative of pathological conditions and biological threats of any kind

Sealing closure 34 comprises a gasket or gasket layer 35. In this embodiment, the guide track 8 serves also to force a tight seal between the gasket material and the swab receiving orifice 6, thus forming a fluid-tight seal over swab capture chamber 33. Following capture, the swab is treated by flowing extraction reagent or buffer in and out of the swab receiving chamber. The extraction buffer may include detergents, solvents such as water, and water in combination with DMSO, NMP, DMF, Formamide, THF, and detergents, co-detergents, cosolvents, proteolytics, sulfhydryl-reducing agents such as n-acetyl-cysteine and dithiothreitol, selective nucleases, mucopolysaccharidases, cellulases, proteases, and the like. A discussion of mucolytics is provided in United States Patent Application 2004/0175695 to Debad. Mechanical agitation is important, and may be enhanced by sonication, such as with piezoelectric transducers. For reciprocal flow, air in the chamber can be vented through the waste sequestration chamber or at a secondary vent site. Optionally, the swab receiving chamber may contain active pump elements in tandem pairs, operating in alternation by positive and negative displacement, so that venting is not required. The structure of these paired pump elements consists of elastomeric or flexible diaphragms and the operation requires merely that as the diaphragm of one pump element is compressed, the other diaphragm is distended, so that the fluid is forced back and forth between the two pump elements. The diaphragms may be operated manually, hydraulically, electrostatically, magnetically, or pneumatically as is known in the art.

An important capacity of any such device is the sequestration of medical waste. The device will typically contain buffer and bioactive reagents for sample processing and analysis and all such material is best viewed as biohazardous. Ideally, all such waste is retained in the sealed body of the device and can be disposed of without hazard by autoclaving or incinerating the device itself. Shown here is a waste chamber (36) that would in operation be vented. Such vents as are permeable to air but not to liquid are well known. Added isolation is possible using a flexible diaphragm as described in co-assigned US Patent Document “Integrated Nucleic Acid Assays”, where fully operative details of assay systems of this sort are disclosed, and which is herein incorporated in full by reference. Also useful are absorbent bats.

Preferably, the devices are self-contained and contain at least on-board reagent for conducting the analysis. In some cases the reagent is a fluid, for example an extraction buffer or a lysis reagent, but in other cases the reagent is a dried biological, for example a primer mix, an antibody, a polymerase, a divalent cation, or a dried weak acid and its salt. By designing the device to be self-contained, single entry use at the point-of-care is enabled. Liquid reagent storage may be achieved by supplying the reagents in sachets, which are ruptured when needed, by methods known in the art. These methods typically supply a sharp upon which the sachet is compressed so that it ruptures. Compression of the sachet may be by manual means or by pneumatic means.

FIG. 4 shows an exploded view of disposable external skins (2,3) applied to a device body (45). Here, both the upper skin (2) and lower skin (3) are shown. A ribbed surface (44) is provided for gripping the device. These skins may be applied as decals. The upper and lower skins may be made from a flexible plastic film or sheet, such as polyethylene, vinyl, polyvinyl chloride, PET or polyurethane, and are typically applied to the device with a removable, pressure sensitive adhesive that can be removed without residue. Candidate commercially available films include 3M™ Scotchcal™ Graphic Film Series 3470 or 3M™ Scotchcal™ Graphic Film Series 8000 available from 3M (St. Paul. Minn.) and adhesives include ROBOND™ PS-8211 latexes available from Rohm And Haas (Philadephia, Pa.). Other suitable decal materials include paper sheet, waxed paper sheet, and fiber/plastic or plastic/plastic composite sheets or films, such as polyethylene film bonded over cloth scrim. These sheets or films are typically printed with graphics and written instructions for the user. Optionally the instructions are printed onto the device body and the film cover is transparent. The adhesive is typically an acrylate derivative. Examples of repositionable and removable adhesives are emulsified polymers made from “soft” monomers such as n-butyl acrylate, isooctyl acrylate, or the like, or ionomeric copolymers made from a soft component, such as isobutylene, n-butyl acrylate, isooctyl acrylate, ethyl hexyl acrylate, or the like; in combination with a polar monomer such as acrylic acid, acrylonitrile, acrylamide, methacrylic acid, methyl methacrylate, trimethylamine methacrylimide, trimethylamine p-vinyl benzimide, ammonium acrylate, sodium acrylate, N,N-dimethyl-N-(.beta.-methacryloxyethyl)ammonium propionate betaine, 1,1-dimethyl-1-(2-hydroxypropyl)amine methacrylimide, 4,4,9-trimethyl-4-azonia-7-oxo-8-oxa-9-decene-1-sulphonate, 1,1-dimethyl-1-(2,3-dihydroxypropyl)amine methacrylimide, and maleic anhydride or the like. Non-spherical polyacrylate adhesives are commercially available, for example, as the Rohm and Haas Rhoplex™ line of adhesives. The adhesive applied to the film is typically repositionable or removable without residue, the adhesive may be selected from any adhesive that may be repeatably adhered to and removed from a substrate without substantial loss of adhesion capability. An example of such an adhesive is disclosed in U.S. Pat. No. 3,691,140 to Silver, which relates to solid tacky microspheres. Preferred adhesives are water resistant when dry. Repositionable adhesives are also known in which microspheres contained in the adhesive are non-tacky. A disclosure of this type of adhesive is provided in U.S. Pat. No. 4,735,837 to Miyasaka, which describes removable adhesives containing elastic micro-balls with the desired properties. The decal to be applied to the device is typically supplied on a release liner and has good moisture and chemical resistance and the adhesive has a working life of greater than 6 months. The decal may be a composite multilayered sheet to achieve these objectives. Multilayered decals variously fabricated from overlayer, liquid crystalline polymer, plastic, silicone, rubber, thermoplastic, paper, interlaid fiber, underlayer, microporous plastic, backing, scrim, cloth, and adhesive are anticipated for this use.

FIG. 5 shows a representation of how a disposable protective cover can be applied using tubestock of heatshrink plastic (50), as is readily commercially available. Once the device is inside a suitable length of the heatshrink material, heat is applied to form the coverlayer to the shape of the device. The swab receiving orifice can be provided with an adhesive-backed decal or appliqué that would be removed immediately before use, exposing the orifice, and also serves as a tamper-evident seal. A tearstrip may similarly be applied to the heatshrink wrapping so that the entire skin can be removed with a single motion. Candidate heat shrinkable thermoplastic films include those polyethylene composites described in U.S. Pat. No. 7,235,607, the polyethylene terephthalate esters of U.S. Pat. No. 6,623,821, and the thermoplastics of U.S. Pat. No. 3,655,503, for example.

FIG. 6 describes a similar protective cover, but made out of a soft plastic bag such as a polyethylene or polyolefin, or out of paper. The paper may be impregnated with a water repellent material or may be absorbent. The plastic or paper bag (60) is formed to include a male sealing rib (61) that mates with a corresponding female locking groove (62) on the exterior circumference of the device body. A tearstrip is provided for ease of removal. The swab receiving orifice 6 can be configured to a variety of swab dimensions and shapes. When the swab is safely captured within the device, closure 7 is pushed across the opening to seal the device.



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stats Patent Info
Application #
US 20120271127 A1
Publish Date
10/25/2012
Document #
13491009
File Date
06/07/2012
USPTO Class
600309
Other USPTO Classes
600572, 600580
International Class
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Drawings
15


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