WO2008008557A1 - Allergy testing cartridge with coated allergens - Google Patents

Allergy testing cartridge with coated allergens Download PDF

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Publication number
WO2008008557A1
WO2008008557A1 PCT/US2007/061601 US2007061601W WO2008008557A1 WO 2008008557 A1 WO2008008557 A1 WO 2008008557A1 US 2007061601 W US2007061601 W US 2007061601W WO 2008008557 A1 WO2008008557 A1 WO 2008008557A1
Authority
WO
WIPO (PCT)
Prior art keywords
microneedle
microneedle array
replaceable cartridge
coated
allergens
Prior art date
Application number
PCT/US2007/061601
Other languages
French (fr)
Inventor
Jose Mir
Dennis Roland Zander
Original Assignee
Infotonics Technology Center, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to PCT/US2006/026774 priority Critical patent/WO2007008824A2/en
Priority to USPCT/US2006/26774 priority
Priority to USPCT/US2006/26734 priority
Priority to PCT/US2006/026734 priority patent/WO2007008800A2/en
Application filed by Infotonics Technology Center, Inc. filed Critical Infotonics Technology Center, Inc.
Publication of WO2008008557A1 publication Critical patent/WO2008008557A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/0059Detecting, measuring or recording for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/20Surgical instruments, devices or methods, e.g. tourniquets for vaccinating or cleaning the skin previous to the vaccination
    • A61B17/205Vaccinating by means of needles or other puncturing devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/41Detecting, measuring or recording for evaluating the immune or lymphatic systems
    • A61B5/411Detecting or monitoring allergy or intolerance reactions to an allergenic agent or substance
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/44Detecting, measuring or recording for evaluating the integumentary system, e.g. skin, hair or nails
    • A61B5/441Skin evaluation, e.g. for skin disorder diagnosis
    • A61B5/445Evaluating skin irritation or skin trauma, e.g. rash, eczema, wound, bed sore
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/685Microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/5302Apparatus specially adapted for immunological test procedures
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854Immunoglobulins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023Drug applicators using microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046Solid microneedles
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00Detection or diagnosis of diseases
    • G01N2800/24Immunology or allergic disorders

Abstract

A replaceable cartridge for use in an allergy testing system has a microneedle array comprising at least one microneedle. The replaceable cartridge also has at least one coated allergen coupled in alignment with the at least one microneedle. Another replaceable cartridge for use in an allergy testing system has a reusable microneedle array. The replaceable cartridge also has removable and recoatable coated allergens coupled to the microneedle array. A method of manufacturing a replaceable cartridge for use in an allergy testing system is disclosed. At least one orifice is formed in a cover to form a cover assembly. A microneedle array is formed having a substrate and at least one microneedle. At least one allergen is coated on the at least one microneedle. An energy storage device is coupled to the substrate to form a microneedle array assembly. The cover assembly is coupled with the microneedle array assembly.

Description

ALLERGY TESTING CARTRIDGE WITH COATED ALLERGENS

RELATED APPLICATIONS

[0001] This application claims priority to international application PCT/US2006/26774 filed on My 11, 2006 and to international application PCT/US2006/26734 also filed on July 1 1, 2006. In addition to containing some subject matter previously contained in those prior applications, this application also discloses new subject matter throughout the application.

FIELD

[0002] The claimed invention generally relates to systems and methods for testing medical conditions and, more particularly, to systems used to determine a degree of reaction to one or more allergens by a subject in a minimally invasive manner.

BACKGROUND

[0003] It is estimated that allergies affect over 50 million people in the United States and result in billions of dollars of medical costs and lost productivity in industrialized countries. On average, primary care physicians see one allergy patient per day. Some of these allergy patients get referred to allergy specialists but many more arc temporarily treated for their symptoms or misdiagnosed as having unrelated respiratory problems. Undiagnosed and untreated allergies potentially increase the patient's probability of increased sensitization or progressive stages of allergy known in Europe as the "allergic march". Adding to these concerns, industrialized countries such as Great Britain and the US are experiencing unprecedented growth in allergy sensitivity, doubling or tripling in the last three decades. Allergic rhinitis today ranks as the world's most prevalent immunological affliction and chronic health problem while asthma is the most common illness diagnosed during U. S. hospital admissions. Although allergic rhinitis has unpleasant symptoms such as rhinorrhea and . congestion, other more severe allergic reactions to insect stings, nut/foods, drugs, and occupational substances can result in serious medical conditions such as anaphylaxis and death.

[0004] The dangers that these allergies represent are undeniable. However, while the number of people actually tested for allergies is on the rise, far more people never get tested and run the risk that undiagnosed allergies are present. Unfortunately, many allergies are diagnosed only after serious symptoms are noticed and before precautions can be taken to avoid the allergen or prevent further sensitization, resulting in hospitalization, loss of productivity from sick days, and even death.

[0005] Physicians prescribe allergy testing because early diagnosis can help patients take preventive measures such as managing their environment, avoiding certain drugs or foods, availing themselves of medication, immunotherapy, or self- administered epinephrine. Allergy tests such as hypersensitivity skin testing have been used for decades because of their sensitivity, reliability, and relative immediacy of results. The widely-used Skin Prick (percutaneous) Test involves the manual application of as many as 40 standardized allergen extracts in a labeled array pattern on the patient's back or forearm, subsequently pricking the region with a needle to allow diffusion of allergens into the patient's epidermal tissue. The intradermal test (intracutaneous) is somewhat more invasive and labor intensive since it involves injecting small amounts of allergens into the patient's skin. The procedure, while more sensitive than percutaneous tests, has a somewhat lower predictive value. Intracutaneous testing is most often used to diagnose insect venom and drug allergies. Due to the nature of these processes, large areas of the subject's skin tend to be affected.

[0006] In both of these types of hypersensitivity skin testing, reactions to the allergens are assessed after a time period of approximately 20 minutes based on the area and coloration of wheals or erythemas produced by each allergen. Sensitivity is diagnosed and recorded using semi -quantitative guidelines and controls such as saline and histamine. Although the procedure is not highly painful and produces only temporary tenderness, itching, or swelling, it can lead to significant stress and anxiety in many patients, especially children. In addition to psychological effects the test may have on some patients, there may be other related problems: 1) Degree of invasiveness and skin surface area covered; 2) Time and manual labor needed to label, dispense, and prick regions with allergens; 3) Lack of an automated standardized protocol to capture the data and store as a digital record.

[0007] Blood testing provides an invasive, yet possibly more convenient method of allergy testing. Unfortunately, blood testing does not surpass the sensitivity, specificity, and predictive value of the skin test. Blood test results are often dependent upon the laboratory which is performing the test. Furthermore, blood testing for allergies is also a more expensive option.

[0008] The alarming prevalence of allergies and their rapid growth indicate that the demand for allergists and immunologists will increase in the years to come. Unfortunately, American Academy of Allergy, Asthma, & Immunology (AAAAI) surveys indicate that the number of graduating allergists may not be sufficient to address future health needs. Furthermore, demographic studies of the approximately 4000 allergists in the U. S. show that a disproportionately high number of core allergists will likely retire in the near future, further exacerbating the problem. These trends indicate not only that the number of allergists per capita will decline but, more importantly, that the number of allergists per allergy patient will decline at an even faster rate. Not surprisingly, allergy practices, especially those run by younger physicians, are experiencing rapid growth in the number of patient visits. [0009] These trends point to a compelling need for less invasive, more quantitatively productive allergy tests with shorter procedure times. Less invasive, shorter, lower cost procedures are also likely to reduce patient fear and reduce barriers associated with current procedures. Improved testing might also promote early or preventative allergy screening mitigating "allergic march", sensitization, or the cost and trauma of serious reactions.

[00010] Therefore, there is a need for a minimally invasive allergy testing system which does not need to cover large areas of a patient's skin, which can be automated to a large extent, which can be correlated to existing skin testing data, which offers more than a snapshot in time of an allergic reaction, which is economical, and which is easy to use and manufacture.

SUMMARY

[00011] An allergy testing system is disclosed. The allergy testing system has a microneedle array. The allergy testing system also has at least one coated allergen. The allergy testing system further has an activation system coupled to the microneedle array such that the at least one coated allergen is moved into contact with a subject as the microneedle array is moved from a resting position to a penetrating position. [00012] Another allergy testing system is disclosed. The allergy testing system has an attachment band having a test frame, wherein the test frame defines an opening in the attachment band. The allergy testing system also has a package, for interfacing with the test frame. The package has a microneedle array and coated allergens. The allergy testing system also has an imaging system for interfacing with the test frame. The allergy testing system further has an analyzer coupled to the imaging system. [00013] A method for determining a degree of reaction to one or more allergens by a patient in a minimally invasive manner is disclosed. One or more allergen coated microneedles is caused to penetrate into a skin of the patient. One or more images of at least one of the penetrations into the skin are captured. At least one of the captured images are analyzed to assess the degree of reaction to a specific allergen. Allergic reactivity data is output for at least one of the allergens.

[00014] Another method for determining a degree of reaction to one or more allergens by a patient in a minimally invasive manner is disclosed. One or more coated allergens on a sheet are wetted to dissolve the coated allergens. One or more microneedles are caused to penetrate into a skin of the patient. Each of the penetrations into the skin are exposed with dissolved coated allergens. One or more images of each of the penetrations into the skin arc captured. At least one of the captured images are analyzed to assess the degree of reaction to the specific allergen. Allergic reactivity data is output for at least one of the allergens. [00015] A replaceable cartridge for use in an allergy testing system is disclosed. The replaceable cartridge has a microneedle array comprising at least one microneedle. The replaceable cartridge also has at least one coated allergen coupled in alignment with the at least one microneedle.

[00016] Another replaceable cartridge for use in an allergy testing system is disclosed. The replaceable cartridge has a reusable microneedle array. The replaceable cartridge also has removable and recoatable coated allergens coupled to the microneedle array.

[00017] A method of manufacturing a replaceable cartridge for use in an allergy testing system is disclosed. At least one orifice is formed in a cover to form a cover assembly. A microneedle array is formed having a substrate and at least one microneedle. At least one allergen is coated on the at least one microneedle. An energy storage device is coupled to the substrate to form a microneedle array assembly. The cover assembly is coupled with the microneedle array assembly. [00018] The claimed invention provides a replaceable cartridge for use in an allergy testing system to minimize the invasiveness of allergy testing, degree and area of reaction, testing time, general discomfort, and risk of infection. Another advantage of the claimed invention is that it enables a much smaller test area footprint when compared to prior testing devices. The much smaller footprint also simplifies and expedites the allergy testing process for a medical staff. The claimed invention tises dried allergens that are used only once, hence avoiding contamination and aging compared to the current method of liquid storage. The allergen dispensing process may also be automated in some embodiments, allowing for automated and quantified allergy reactivity data readout, thereby reducing uncertainty and subjectivity. A further advantage possible with automated embodiments is the ability to capture continuous or nearly continuous visual images of an allergy test site. This allows scientist and medical personnel a chance to study the time rate of change for certain allergic reactions, and better understand a patient's reaction and sensitivity. Overall, the minimally-invasive allergy testing system enables a relatively fast allergy test cycle time, lowers the cost of such testing, and significantly reduces the chance for errors.

BRIEF DESCRIPTION OF THE DRAWINGS

[00019] FIGS. 1-2L schematically illustrate embodiments of an allergy testing system.

[00020] FIGS. 3A & 3B to FIGS. 8A & 8B schematically illustrate side views (A) and top views (B), respectively, of embodiments of microneedles for use in an allergy testing system.

[00021] FIG. 9 schematically illustrates a side view of a corrugated microneedle embodiment for use in an allergy testing system.

[00022] FIG. 1OA schematically illustrates an exploded perspective view of an embodiment of an allergy testing system.

[00023] FIG. 1OB schematically illustrates an assembled, cross-sectional view of the allergy testing system embodiment of FIG. 1OA.

[00024] FIG. 1 IA schematically illustrates an exploded perspective view of an embodiment of an allergy testing system.

[00025] FIG. 1 IB schematically illustrates an assembled, cross-sectional view of the allergy testing system embodiment of FIG. 1 IA.

[00026] FIGS. 12 A - 12C schematically illustrate one possible method of applying allergens to a subject using an embodiment of an allergy testing system. [00027] FIGS. 12Dl - 12D3 schematically illustrate different embodiments of gathering and analyzing allergy test data after the allergens have been applied by the allergy testing system in FIGS. 12A-12C.

[00028] FIG. 13 schematically illustrates an embodiment of an allergy testing system.

[00029] FIGS. 14A - 14B schematically illustrate a side view of an embodiment of an allergy testing system.

[00030] FIGS. 15A - 15B schematically illustrate a top view of an embodiment of an allergy testing system.

[00031] FIGS. 16A-16M schematically illustrate one embodiment of a process for manufacturing a replaceable allergen cartridge.

[00032] It will be appreciated that for purposes of clarity and where deemed appropriate, reference numerals have been repeated in the figures to indicate corresponding features, and that the various elements in the drawings have not necessarily been drawn to scale in order to better show the features.

DETAILED DESCRIPTION

[00033] FIG. 1 schematically illustrates an embodiment of a minimally invasive allergy testing system 20. The minimally invasive allergy testing system 20 has a microneedle array 22 and at least one coated allergen 24. The microneedle array 22 has at least one microneedle, and preferably a plurality of microneedles which may be spaced in a linear array, a two-dimensional array, or any other spacing desired. The microneedles may have a height of about 50-1000 microns and a tip dimension ranging from submicron to about 80 microns in order to penetrate a subject's skin, although other embodiments may have other dimensions. (Skin not illustrated in this view.) The microneedle 22 array may be manufactured out of a number of different substances, for example, silicon, glass, metal, quartz, or plastic. Due to its attractive micromachining properties, silicon may be etched using chemical and reactive ion etching processes to fabricate the microneedles, although other materials and manufacturing processes can be used.

[00034] The microneedle array 22 and the one or more coated allergens 24 may be aligned relative to each other by virtue of the coated allergens 24 being coated directly onto the microneedle array 22. or by virtue of the coated allergens 24 being coated on a another structure, such as a sheet, film, or label held in alignment relative to the microneedle array 22. The minimally invasive allergy testing system 20 also has an activation system 26 which may be directly or indirectly coupled to the microneedle array 22. The activation system 26 causes a skin of a test subject to be pricked, while allowing the coated allergens 24 to dissolve within the subject's skin to initiate a controlled allergic reaction. In some embodiments, as will be discussed further in this disclosure, the coated allergens 24 maybe dissolved prior to the pricking of the subject's skin by wetting the coated allergens 24 with a solvent. [00035] There is a great degree of flexibility in configuring the activation system 26. In some embodiments, the activation system 26 can be a mechanical plunger or other mechanical system, which is pressed by a medical professional, or even the test subject themselves. In other embodiments, the activation system 26 can be a spring- loaded release which allows a predictable force to be applied to the microneedle array 22 as it pricks the subject's skin. Further embodiments of an allergy testing system 20 may have an activation system 26 which is an electro-mechanical system, sueh as a solenoid, motor, or a micromcchanical actuator.

[00036] The microneedle array 22, the coated allergens 24, and/or the activation system 26 may be separate components of the allergy testing system 20. In various embodiments, the microneedle array 22 and the coated allergens 24 may be removeably packaged from the activation system 26. This removeability allows for designs and embodiments with simple replacement of the microneedles and coated allergens which are typically only used once.

[00037] FIG. 2A illustrates another embodiment of an allergy testing system 20. This allergy testing system 20 has the microneedle array 22 directly coupled to the activation system 26. The microneedle array 22 may still be removeably coupled to the activation system 26 in some embodiments. For simplicity, the microneedle array 22 is schematically illustrated in this and other embodiments as only having a single needle 28. It should be understood that any number of microneedles 28 may be present on the microneedle array 22, depending on size of the microneedle array 22 and the number of allergy test sites desired. The activation system 26 and the microneedle array 22 are moveably supported by a package 30. The package 30 defines at least one orifice 32 within which one or more of the microneedles 28 may be moved. In this embodiment, the coated allergen 24 is coated directly onto the microneedle 28 of the microneedle array 22. The coated allergen 24 may be coated onto the microneedle 28 as a pure extract, or can be dissolved into a solution containing film forming agents such as glycerol, biocompatible water soluble polymer, or other addenda. These film forming agents operate as binders which assist the coated allergen 24 in adhering to the microneedle 28. The film forming agents may also be used to improve coatability and wetting during manufacturing. In other embodiments, a binder layer can be coated directly onto the microneedle 28 prior to coating with allergens. In the orientation of FIG. 2A, the activation system 28 will engage downwards 34 to push the microneedles 28 of the microneedle array 22 into a subject's skin 36. The activation system 26 may allow the coated microneedles 28 to penetrate the skin 36 for a period of time sufficient for the coated allergen 24 to dissolve in the fluids found within the subject's skin 36 and/or on the subject's skin 36, thereby allowing the allergen to enter the skin 36. This time is variable and depends on the solubility of the allergen and any addenda. Useful times for some embodiments may be in the range of 0.3-5.0 seconds, however other embodiments may require shorter or longer times.

[00038] The allergy testing system embodied in FIG. 2A could also be pre-treated with a solvent, such as water, just prior to the administration of the allergy test to assist the coated allergens 24 in dissolving, or if it is simply desired to have the coated allergens 24 in dissolved form, prior to penetrating the siϊbject's skin. In this case, access for wetting the coated allergens 24 may be provided through the orifices 32 in the package 30.

[00039] FIG. 2B schematically illustrates another embodiment of an allergy testing system 20 which is similar to the allergy testing system 20 of FIG. 2 A, with the addition of a sealing film 38 to cover the microneedle array 22 and the coated allergens 24. The sealing film 38 may be employed over at least a portion of the package 30 to serve as a sterile layer protecting the sterile microneedles 28 and the coated allergens 24. The sealing film 38 may be removed before use or left on the patient's skin 36. If left behind on the skin 36, the sealing film 38 may have a human readable code or a machine readable code 40, such as a bar code, or other identification marks 40. These identifying marks 40 can also be used for orientation in the analysis stage to be discussed later in this specification. The identifying marks 40 can also identify the various allergens being used in one or more locations. [00040] FIG. 2C schematically illustrates another embodiment of an allergy testing system 20 which is similar to the embodiment of FIG. 2B. However, the embodiment of FIG. 2C has an access hole 42 defined by the package 30 which may be used to provide access for a solvent to be applied to the coated allergen 24 prior to administration of the allergy test. Depending on the embodiment, there could be one or more access holes 42. It may be desirable to assist the coated allergens 24 in dissolving, or it may simply be desired to have the coated allergens 24 in dissolved form prior to penetrating the subject's skin. A sealing flap 44 may be provided in some embodiments to cover the access hole 42 to allow a solvent to be agitated within the orifice 32 without leaking prior to administration of an allergy test or removal of the sealing film 38.

[00041] FIG. 2D schematically illustrates another embodiment of an allergy testing system 20. This allergy testing system 20 has the microneedle array 22 coupled to the activation system 26. The activation system 26 and the microneedle array 22 are moveably supported by a package 30. The package 30 defines at least one orifice 32 within which the microneedle 28 may be moved. In this embodiment, the coated allergen 24 is coated directly onto the microneedle array 22, but not in the area of the microneedle 28. The coated allergen 24 may be coated onto the microneedle array 22 as a pure extract, or can be dissolved into a solution containing film forming agents such as glycerol, biocompatible water soluble polymer, or other addenda. These film forming agents operate as binders which assist the coated allergen 24 in adhering to the microneedle array 22. In other embodiments, a binder layer can be coated directly onto the microneedle array 22 prior to coating with allergens.

[00042] Prior to activating the allergy testing system 20, the coated allergens 24 maybe wetted with a solvent via the orifice 32. These wetted allergens may then coat the microneedle 28. Once the coated allergens 24 have been wetted, the activation system 26 may be engaged downwards 34 to push the microneedles 28 of the microneedle array 22 into a subject's skin 36. The activation system 26 may allow the microneedles 28 with allergens 24 to penetrate the skin 36 for a desired period of time. Useful times for some embodiments may be in the range of 0.3-5.0 seconds, however other embodiments may require shorter or longer times. [00043] FIG. 2E schematically illustrates another embodiment of an allergy testing system 20. This allergy testing system 20 may be configured to have the microneedle array 22 coupled to the activation system 26, however, for simplicity, the activation system is illustrated in this embodiment separate from the microneedle array 22. The activation system 26 and the microneedle array 22 are moveably supported by a package 30. The package 30 defines at least one orifice 32 within which the microneedle 28 may be moved. In this embodiment, the coated allergen 24 is coated directly onto the microneedle array 22, but not on. the side of the microneedle array 22 having the microneedle 28. Instead, in this embodiment, the coated allergen 24 is coupled to a second side of the microneedle array 22. The coated allergen 24 may be coated onto the microneedle array 22 as a pure extract, or can be dissolved into a solution containing film forming agents such as glycerol, biocompatible water soluble polymer, or other addenda. These film forming agents operate as binders which assist the coated allergen 24 in adhering to the microneedle array 22. In other embodiments, a binder layer can be coated directly onto the microneedle array 22 prior to coating with allergens.

100044] The package 30 defines a channel 46 which fluidically couples the microneedle 28 side of the microneedle array 22 to the side of the microneedle array 22 with the coated allergen 24. In other embodiments, the channel 46 may be provided by the microneedle array 22 or a combination of the microneedle array 22 and the package 30. Prior to activating the allergy testing system 20, the coated allergens 24 may be wetted with a solvent via the orifice 32 and the channel '46. After wetting, when the activation system 26 is engaged downwards 34 to push the microneedles 28 of the microneedle array 22 towards a subject's skin 36, the motion of the activation system 26 against the microneedle array 22 may squeeze the wetted allergens 24 out the channel 46 and onto the microneedle 28 as it penetrate the skin 36 for a desired period of time. Useful times for some embodiments may be in the range of 0.3-5.0 seconds, however other embodiments may require shorter or longer times. [00045] FIG. 2F schematically illustrates another embodiment of an allergy testing system 20. This allergy testing system 20 may be configured to have the microneedle array 22 coupled to the activation system 26, however, for simplicity, the activation system 26 is illustrated in this embodiment separate from the microneedle array 22. The activation system 26 and the microneedle array 22 are moveably supported by a package 30. The package 30 defines at least one orifice 32 within which the microneedle 28 may be moved. In this embodiment, the coated allergen 24 is coated directly onto the microneedle array 22, but not on the side of the microneedle array 22 having the microneedle 28. Instead, in this embodiment, the coated allergen 24 is coupled to a second side of the microneedle array 22. The coated allergen 24 may be coated onto the microneedle array 22 as a pure extract, or can be dissolved into a solution containing film forming agents such as glycerol, biocompatible water soluble polymer, or other addenda. These film forming agents operate as binders which assist the coated allergen 24 in adhering to the microneedle array 22. In other embodiments, a binder layer can be coated directly onto the microneedle array 22 prior to coating with allergens.

[00046] In this embodiment, the microneedle 28 defines a channel 48 which fluidically couples the microneedle 28 side of the microneedle array 22 to the side of the microneedle array with the coated allergen 24. Prior to activating the allergy testing system 20, the coated allergens 24 may be wetted with a solvent via an access hole 42. As mentioned above, the access hole 42 may be provided with a plug 44 for removeably sealing the access hole 42. After wetting, when the activation system 26 is engaged downwards 34 to push the microneedles 28 of the microneedle array 22 towards a subject's skin 36, the motion of the activation system 26 against the microneedle array 22 may squeeze the wetted allergens out the channel 48, through the microneedle 28, and into the skin 36 as the microneedle 28 penetrates the skin 36 for a desired period of time.. Useful times for some embodiments may be in the range of 0.3-5.0 seconds, however other embodiments may require shorter or longer times. [00047] FIG. 2G schematically illustrates another embodiment of an allergy testing system 20. This allergy testing system 20 may be configured to have the microneedle array 22 coupled to the activation system 26, however, for simplicity, the activation system 26 is illustrated in this embodiment separate from the microneedle array 22. The activation system 26 and the microneedle array 22 are moveably supported by a package 30. The package 30 defines at least one orifice 32 within which the microneedle 28 may be moved. Tn this embodiment, the coated allergen 24 is coated directly onto the microneedle array 22, but not on the side of the microneedle array 22 having the microneedle 28. Instead, in this embodiment, the coated allergen 24 is coupled to a second side of the microneedle array 22. The coated allergen 24 may be coated onto the microneedle array 22 as a pure extract, or can be dissolved into a solution containing firm forming agents such as glycerol, biocompatible water soluble polymer, or other addenda. These film forming agents operate as binders which assist the coated allergen 24 in adhering to the microneedle array 22. In other embodiments, a binder layer can be coated directly onto the microneedle array 22 prior to coating with allergens. [00048] In this embodiment, the microneedle 28 defines a channel 48 which fluidically couples the microneedle 28 side of the microneedle array 22 to the side of the microneedle array with the coated allergen 24. Prior to activating the allergy testing system 20, the coated allergens 24 may be wetted with a solvent via the orifice 32 and the channel 48. After wetting, when the activation system 26 is engaged downwards 34 to push the microneedles 28 of the microneedle array 22 towards a subject's skin 36, the motion of the activation system 26 against the microneedle array 22 may squeeze the wetted allergens out the channel 48, through the microneedle 28, and into the skin 36 as the microneedle 28 penetrates the skin 36 for a desired period of time. Useful times for some embodiments may be in the range of 0.3-5.0 seconds, however other embodiments may require shorter or longer times. [00049] FIG. 2H schematically illustrates another embodiment of an allergy testing system 20. This allergy testing system 20 has the microneedle array 22 coupled to the activation system 26. The activation system 26 and the microneedle array 22 are moveably supported by a package 30. The package 30 defines at least one orifice 32 within which the microneedle 28 may be moved. The allergy testing system 20 also has a sheet 50 coupled to the package 30. One side of the sheet 50 is disposed towards the microneedle array 22 and the other side of the sheet 50 is disposed away from the microneedle array 22. In this embodiment, the coated allergen 24 is coated directly onto the side of the sheet 50 facing away from the microneedle array 22. The coated allergen 24 may be coated onto the sheet 50 as a pure extract, or can be dissolved into a solution containing film forming agents such as glycerol, biocompatible water soluble polymer, or other addenda. These film forming agents operate as binders which assist the coated allergen 24 in adhering to the sheet 50. Sheet 50 may even be selected for its properties in allowing the allergens to coat properly thereon without the need for a binder. [00050] Prior to activating the allergy testing system 20, the coated allergens 24 may be wetted with a solvent via the orifice 32. The activation system 26 may then be engaged downwards 34 to push the microneedles 28 of the microneedle array 22 through the sheet 50, supporting the now dissolved allergens 24, and into a subject's skin 36. The activation system 26 may allow the microneedles 28 with allergens 24 to penetrate the skin 36 for a desired period of time. Useful times for some embodiments may be in the range of 0.3-5.0 seconds, however other embodiments may require shorter or longer times. [00051] FIG. 21 schematically illustrates another embodiment of an allergy testing system 20. This allergy testing system 20 has the microneedle array 22 coupled to the activation system 26. The activation system 26 and the microneedle array 22 are moveably supported by a package 30. The package 30 defines at least one orifice 32 within which the microneedle 28 maybe moved. The allergy testing system 20 also has a sealing film 38 coupled to the package 30 and covering at least a portion of the orifice 32. One side of the sealing film 38 is disposed towards the microneedle array 22 and the other side of the sealing film 38 is disposed away from the microneedle array 22. In this embodiment, the coated allergen 24 is coated directly onto the side of the sealing film 38 facing away from the microneedle array 22. The coated allergen 24 may be coated onto the sealing film 38 as a pure extract, or can be dissolved into a solution containing film forming agents such as glycerol, biocompatible water soluble polymer, or other addenda. These film forming agents operate as binders which assist the coated allergen 24 in adhering to the sealing film 38. Sealing film 38 may even be selected for its properties in allowing the allergens to coat properly thereon without the need for a binder.

[00052] Prior to activating the allergy testing system 20, the coated allergens 24 may be wetted with a solvent. The sealing film and wetted allergens may then be placed against the subject's skin 36, and the activation system 26 may then be engaged downwards 34 to push the microneedles 28 of the microneedle array 22 through the sealing film 38, supporting the now dissolved allergens 24, and into a subject's skin 36. The activation system 26 may allow the microneedles 28 with allergens 24 to penetrate the skin 36 for a desired period of time. Useful times for some embodiments maybe in the range of 0.3-5.0 seconds, however other embodiments may require shorter or longer times.

[00053] FIG. 2 J schematically illustrates another embodiment of an allergy testing system 20. This allergy testing system 20 has the microneedle array 22 coupled to the activation system 26. The activation system 26 and the microneedle array 22 are moveably supported by a package 30. The allergy testing system 20 also has a sheet 50 coupled to the package 30. One side of the sheet 50 is disposed towards the microneedle array 22 and the other side of the sheet 50 is disposed away from the microneedle array 22. In this embodiment, the coated allergen 24 is coated directly onto the side of the sheet 50 facing towards the microneedle array 22. The coated allergen 24 may be coated onto the sheet 50 as a pure extract, or can be dissolved into a solution containing film forming agents such as glycerol, biocompatible water soluble polymer, or other addenda. These film forming agents operate as binders which assist the coated allergen 24 in adhering to the sheet 50. Sheet 50 may even be selected for its properties in allowing the allergens to coat properly thereon without the need for a binder.

[00054] Prior to activating the allergy testing system 20, the coated allergens 24 may be wetted with a solvent via an access hole 42 defined by the package 30. A plug 44 may be provided to removeably seal the access hole 42. The activation system 26 may then be engaged downwards 34 to push the microneedles 28 of the microneedle array 22 through the dissolved allergens 24, supported by the sheet 50, and into a subject's skin 36. The activation system 26 may allow the microneedles 28 with allergens 24 to penetrate the skin 36 for a desired period of time. Useful times for some embodiments may be in the range of 0.3-5.0 seconds, however other embodiments may require shorter or longer times.

[00055] FIG. 2K schematically illustrates another embodiment of an allergy testing system 20. This allergy testing system 20 has the microneedle array 22 coupled to the activation system 26. The activation system 26 and the microneedle array 22 are moveably supported by a package 30. The package 30 defines at least one orifice 32 within which the microneedle 28 may be moved. The allergy testing system 20 also has a sealing film 38 coupled to the package 30 and covering at least a portion of the orifice 32. One side of the sealing film 38 is disposed towards the microneedle array 22 and the other side of the sealing film 38 is disposed away from the microneedle array 22. In this embodiment, the coated allergen 24 is coated directly onto the side of the sealing film 38 facing towards the microneedle array 22. The coated allergen 24 may be coated onto the sealing film 38 as a pure extract, or can be dissolved into a solution containing film forming agents such as glycerol, biocompatible water soluble polymer, or other addenda. These film forming agents operate as binders which assist the coated allergen 24 in adhering to the sealing film 38. Sealing film 38 may even be selected for its properties in allowing the allergens to coat properly thereon without the need for a binder.

[00056] Prior to activating the allergy testing system 20, the coated allergens 24 may be wetted with a solvent via an access hole 42 defined by the package 30. A plug 44 may also be provided to removeably seal the access hole 42. The sealing film may then be placed against the subject's skin 36, and the activation system 26 may then be engaged downwards 34 to push the microneedles 28 of the microneedle array 22 through the dissolved allergens 24 supported by the sealing film 38, and into a subject's skin 36. The activation system 26 may allow the microneedles 28 with allergens 24 to penetrate the skin 36 for a desired period of time. Useful times for some embodiments may be in the range of 0.3-5.0 seconds, however other embodiments may require shorter or longer times.

[00057] FIG. 2L schematically illustrates another embodiment of an allergy testing system 20. This allergy testing system 20 has the microneedle array 22 coupled to the activation system 26. The activation system 26 and the microneedle array 22 are moveably supported by a package 30. The allergy testing system 20 also has a sheet 52 coupled to the microneedle array 22. One side of the sheet 52 is disposed towards the microneedle array 22 and the other side of the sheet 52 is disposed away from the microneedle array 22. In this embodiment, the coated allergen 24 is coated directly onto the side of the sheet 52 facing away from the microneedle array 22. The coated allergen 24 may be coated onto the sheet 52 as a pure extract, or can be dissolved into a solution containing film forming agents such as glycerol, biocompatible water soluble polymer, or other addenda. These film forming agents operate as binders which assist the coated allergen 24 in adhering to the sheet 52. Sheet 52 may even be selected for its properties in allowing the allergens to coat properly thereon without the need for a binder. [00058] Prior to activating the allergy testing system 20, the coated allergens 24 maybe wetted with a solvent via the orifice 32. The activation system 26 may then be engaged downwards 34 to push the microneedles 28 and the sheet 50, supporting the now dissolved allergens 24, and into contact with a subject's skin 36. When the sheet 52 reaches the skin 36, the microneedle 28 will be able to exert pressure on the sheet 52, piercing it, and penetrating the skin along with the dissolved allergens 24 which were on the sheet. The activation system 26 may allow the microneedles 28 with allergens 24 to penetrate the skin 36 for a desired period of time. Useful times for some embodiments maybe in the range of 0.3-5.0 seconds, however other embodiments may require shorter or longer times.

[00059] The microneedles in the microneedle array 22 may have a variety of geometries. FIGS. 3 A and 3B schematically illustrate an embodiment of a microneedle 54 with a substantially square or rectangular cross-section in a side view and a corresponding top view, respectively. [00060] FIGS. 4A and 4B schematically illustrate an embodiment of a microneedle 56 with a substantially circular cross-section in a side view and a corresponding top view, respectively. The microneedle embodiment shown in FIG. 4 A illustrates another variation possible with microneedle design. The microneedle 56 has a wedged top. Although other embodiments are not shown wedged, they could be modified in further embodiments to have a wedge-shaped top. [00061] FIGS. 5A and 5B schematically illustrate an embodiment of a microneedle 58 with a substantially triangular cross-section in a side view and a corresponding top view, respectively.

[00062] FIGS. 6 A and 6B schematically illustrate an embodiment of a microneedle 60 with a substantially square or rectangular cross-section in a side view and a corresponding top view, respectively. This microneedle, however, is a hollow microneedle, having a channel formed within the needle for the passage of allergens. [00063] FIGS. 7 A and 7B schematically illustrate an embodiment of a microneedle 62 with a substantially square or rectangular cross-section in a side view and a corresponding top view, respectively. This microneedle, however, is a grooved microneedle, having a channel formed on the side of the needle for the passage of allergens.

[00064] FIGS. 8A and 8B schematically illustrate an embodiment of a microneedle 64 with a changing cross-sectional area that tapers to a point. [00065] Any of the features of the microneedles in the embodiments of FIGS. 3A- 8B maybe combined with one another, and cross-sectional shapes may be varied. For example, a microneedle could be both hollowed and grooved at the same time. As mentioned before, the microneedles may have a height of about 50-1000 microns and a tip dimension from submicron to about 80 microns in order to penetrate a subject's skin, although other embodiments may have other dimensions. (Skin not illustrated in this view.) The microneedle array may be manufactured out of a number of different substances, for example, silicon, glass, metal, or plastic. Due to its attractive micromachining properties, silicon may be anisotropically etched using chemical and reactive ion etching processes to fabricate the microneedles, although other materials and manufacturing processes can be used.

[00066] A further embodiment of a microneedle 66 is schematically illustrated in FIG. 9. In this embodiment, the microneedle is corrugated around a generally pointed microneedle structure. Corrugated needle designs like this one may facilitate the entry and exit of the microneedle from the test subject 36 with a reduced amount of force. The corrugations may also provide channels for the allergens to enter a puncture site. Furthermore, the corrugations can also provide higher surface area to enhance the amount of material diffusing.

[00067] Referring to FIGS. 1OA and 10B3 another embodiment of a minimally invasive allergy testing system 68 is schematically illustrated in an exploded perspective view and an assembled side cross-sectional view, respectively. The allergy testing system includes a microneedle substrate 70 that supports an array of microneedles 72 with integral mesas 74. The mesas 74 are not absolutely necessary, but in some embodiments, they can provide stability for the microneedles 72 as the microneedles are engaged. (This will be explained in more detail later.) A linear array of microneedles 72 having mesas 74 are illustrated in this embodiment, but other embodiments may have other numbers and types of components in other shapes and configurations. The substrate 70, microneedles 72, and mesas 74 may be manufactured from a number of different materials, such as silicon, glass, metal, or plastic. The microsystem allergy testing device 68 also includes a package assembly 76 which houses the substrate 70, microneedles 72, and mesas 74 such that the lop surface of substrate 70 rests against a compressible stop 78 along an inner surface of the package 76. The compressible stop 78 may be permanently compressible, or may be an energy storage device such as a spring. The microneedles 72 are mounted for movement within the package 76 from a position where the upper tips of the . microneedles 72 lie within orifices 80, such that they do not protrude significantly outside of the package assembly 76, to a position protruding outside of the package assembly 76.

100068] This embodiment also has a thin sealing film 82 employed over a surface of the package assembly 76. A set of coated allergens 84 associated with each microneedle 72 is coated on the sealing film 82. Prior to testing, the coated allergens 84 may be wet with a solvent so that the coated allergens 84 may be dissolved. In some embodiments, the sealing film. 82 may have hydrophobic areas between coated allergens 84 to help prevent intermixing of the dissolved allergens. Such hydrophobic areas may also allow the applied water to selectively wet the allergens 84. The sealing film 82 may also have human readable, barcode, or other identifying marks 86. Such identifying marks have been discussed above with regard to previous embodiments. [00069] This embodiment of an allergy testing system 68 also has a plunger 88. The plunger 88 may be activated by an activation system (not shown), such as manual pressure, mechanical systems, electromechanical systems, piezoelectric, or a micromechanical actuator. Pressure applied to the plunger 88 causes substrate 70 to compress resting stop 78, allowing the microneedles 72 to protrude out of the package assembly 76, pierce through the sealing film 82 and the coated allergens 84 towards the patient's skin (not shown in this figure, but in this embodiment, the test subject would be above the allergy testing system 68 as oriented.) When the plunger 88 is depressed far enough, the microneedles 72 pierce the patient's skin while mesas 74 fit into orifices 80 in package 76 to help increase travel and positional stability of the microneedles 72.

[00070J Referring to FIGS. 1 IA and 1 IB, another embodiment of a minimally invasive allergy testing system 90 is schematically illustrated in an exploded perspective view and an assembled side cross-sectional view, respectively. The allergy testing system 90 includes a microneedle substrate 70 that supports an array of microneedles 72 with integral mesas 74. The mesas 74 are not absolutely necessary, but in some embodiments, they can provide stability for the microneedles 72 as the microneedles are engaged. A linear array of microneedles having mesas are illustrated in this embodiment, but other embodiments may have other numbers and types of components in other shapes and configurations. The substrate 70, microneedles 72, and mesas 74 may be manufactured from a number of different materials, such as silicon, glass, metal, or plastic. The microneedles 72 are coated with allergens 92, similar to the coated microneedles of FIG. 2A. The microsystem allergy testing device 90 of FIGS. HA and HB also includes a package assembly 76 which houses the substrate 70, microneedles 72, and mesas 74 such that the top surface of substrate 70 rests against a compressible stop 78 along an inner surface of the package 76. The compressible stop 78 may be pennanentϊy compressible, or may be an energy storage device such as a spring. The microneedles 72 are mounted for movement within the package 76 from a position where the upper tips of the microneedles 72 lie within orifices 80, such that they do not protrude significantly outside of the package assembly 76, to a position protruding outside of the package assembly 76.

[00071 J This embodiment of an allergy testing system 90 also has a plunger 88. The plunger 88 may be activated by an activation system (not shown), such as manual pressure, mechanical systems, electromechanical systems, piezoelectric, or a micromechanical actuator. Pressure applied to the plunger 88 causes substrate 70 to compress resting stop 78, allowing the microneedles 72 to protrude out of the package assembly 76 towards the patient's skin (not shown in this figure, but in this embodiment, the test subject would be above the allergy testing system 90 as oriented.) When the plunger 88 is depressed far enough, the allergen coated microneedles 72 pierce the patient's skin while mesas 74 fit into orifices 80 in package 76 to help increase travel and positional stability of the microneedles 72. The microneedles 72 may then remain in the skin long enough for the coated allergens 92 to dissolve into the fluids found in the skin, for example, interstitial fluid. [00072] FIGS. 12 A - 12C schematically illustrate one possible method of applying allergens to a subject using an embodiment of an allergy testing system. In a first step, FIG. 12 A, the minimally invasive allergy testing system 90 is placed in contact with a subject's skin 36. Since this embodiment of an allergy testing system 90 does not have a sealing film, the package assembly 76 is the portion of the test system initially in contact with the skin 36. In other systems, the portion initially in contact with the sldn 36 might be a sealing film. In FIG. 12 A, the microneedle array is in a resting position. In a second step, FIG. 12B, the plunger 88 is activated, in the orientation of FiG. 12B, in a downward direction, causing the substrate 70 to compress the compressible stop 78. This causes the microneedles 72 with coated allergens 92 to puncture the skin 36. In FIG. 12B, the microneedle array is in a penetrating position. After a time sufficient for the allergens 92 to dissolve into the patient's skin 36, the force on the plunger 88 is released, causing it to return to the resting position shown in FIG. 12C. After this procedure, the allergens 92 originally carried by the microneedles 72 are able to diffuse into the subject through the pricked regions 94, thereby potentially initiating allergic reactions.

[00073] Examples of various possible needle shapes and geometries have been discussed earlier, and the microneedle shapes illustrated in this example are not intended to be limiting. Furthermore, microneedles of differing lengths on the same substrate 70 maybe used. A benefit of providing different length microneedles may be to allow different allergens to reach a targeted skin depth, or to test the same allergen at different depths for studied comparisons.

[00074] FIGS. 12Dl - 12D3 schematically illustrate different embodiments of gathering and analyzing allergy test data after the allergens have been applied by the allergy testing system in FIGS. 12A-12C. FIG. 12Dl schematically illustrates a test subject's skin 36 which has been pricked and injected with allergens 92 by the microneedles 72 of a minimally invasive allergy testing system 90. Here, a schematic human eye 96 is looking for a reaction 98 to a particular allergen 92. A template may be included that matches the applied allergens so as to help identify the corresponding reactions. While the allergy test results may be evaluated using a manual approach such as this, other methods may make it easier to distinguish results given the close spacing between allergy test points possible with microneedles. [00075] FIG. 12D2 schematically illustrates an embodiment of an allergy analysis system 100 which can optionally be used in place of or in conjunction with manual evaluation methods. The allergy analysis system 100 includes an imaging module 102 with imaging optics 104. The imaging optics 104 focuses images of the tested skin area on an image sensor 106. The image sensor 106 is coupled to an image analyzer or processor 108. The image analyzer 108 can analyze the captured images for color, shape, dimension, and location in the test field. Based on this analysis and correlation with what allergen was tested in which location, the analyzer 108 determines reactivity data for each allergen. The reactivity data, as well as the captured images may be stored, displayed, transmitted, and/or printed by the analyzer 108. Optionally, the analyzer may output this data to another processor for storage, display, further analysis, transmission, and/or printing. In the embodiment of FIG. 12D2, the analyzer 108 is directly coupled to the allergy analysis system 100. In other embodiments, the analyzer 108 maybe remotely coupled to the analysis system 100 via a wireless or cabled link.

[00076] The image analyzer 108 may comprise a central processing unit (CPU) or processor and a memory which are coupled together by a bus or other link, although other numbers and types of components in other configurations and other types of systems, such as an application specific integrated circuit (ASIC) could be used. The processor may execute a program of stored instructions for one or more aspects of the claimed invention, including the method for determining a degree of reaction to one or more allergens as described and illustrated herein. The memory stores these programmed instructions for execution by the processor. A variety of different types of memory storage devices, such as random access memory (RAM) or a read only memory (ROM) in the system or a floppy disk, hard disk, CD ROM, or other computer readable medium which is read from and/or written to by a magnetic, optical, or other reading and/or writing system that is coupled to the processor, can be used for the memory to store these programmed instructions. The image analyzer 108 can be in situ (as illustrated) or remote (for example, separate electronics or a separate computing device) linked by a wired or wireless connection.

[00077] In the example of FIG. 12D2, the skin puncture site 110 shows a positive allergy reaction 98, while skin puncture sites 112, 114 show negative allergy reactions. The imaging module 102 should be placed, in alignment with the original allergy testing device 90 (from FIGS. 12A - 12C) such that the imaging optics 104 creates images of test sites 110, 112, and 114. These test sites 110, 112, 114 are associated with each allergen in correlated locations on image sensor 106. Image patterns associated with each allergen, as imaged by sensor 106, are captured and transmitted to image analyzer 108 for analysis as described above in order to identify color, shape, dimension, allergic reaction, and/or a time rate of change of the allergic response. The determination of a time rate of change in the allergic response may be a great benefit to medical professionals who often do not have the time to personally/physically observe a reaction on a continuous or substantially continuous basis that would let them see how allergic reactions vary over time. [00078] In other embodiments of an allergy testing system which have as allergy imaging analysis system 100, it maybe important to determine topographic information when assessing reactivity to an allergen. In such embodiments, an extra set of imaging optics and an extra image sensor may be displaced laterally from the other optical system to obtain stereoscopic, parallax information about a given test location. Parallax information may in turn be used to calculate topographic profiles of test regions.

[00079] FIG. 12D3 schematically illustrates an embodiment of a minimally invasive allergy testing system 116 with an integrated imaging and analysis module 102. The microneedle array 118 and plunger 120 operate in similar fashion to the corresponding elements in FIG. 12A, except as described herein. In this embodiment, the array of microneedles 118 and plunger 120 are made of glass or some other transparent material, such as transparent hard plastic, such that imaging module 102 may image the tested regions with the needles in-situ, or even slightly or completely retracted. Preferably, the width of the microneedles 122 relative to their spacing should be fine enough to allow enough imaging area for an adequate diagnosis of the allergic reaction. [00080] FIG. 13 schematically illustrates a further embodiment of a minimally invasive allergy testing system 124. The allergy testing system 124 is coupled to a band 126 which may be wrapped around a portion of a person's body. In this example, the part of the body illustrated is an arm 128. Of course, it would be apparent to those skilled in the art that attachment band 126 could be compatible with or modified to attach to other portions of the body. Attachment band 126 need not circle completely around and back to itself, although preferred embodiments may have Velcro ® attachments which wrap around the body and then connect to themselves. The purpose of the attachment band 126 is to hold a test frame 130 in substantially the same position during a minimally invasive allergy test. The test frame 130 defines an opening in the band 126 through which the skin may be accessed. The test frame 130 also has a first alignment coupling, such as a hinge 132 onto which a package 134 containing a microneedle array having coated allergens may be placed for aligned engagement with the skin in the test frame 130. The test frame 130 has a second alignment coupling, such as a hinge 136 onto which an allergy imaging system 138 may be placed for aligned engagement with the skin in the test frame 130. In some embodiments, the allergen and microneedle package 134 will be engaged with the test frame at different times from the imaging system 138. In other embodiments, such as the transparent embodiments described above, both the allergen and microneedle package 134 and the imaging system 138 may be engaged at the same time. In various embodiments, the alignment coupling does not have to be a hinged connection. It may, instead, be a temporary guide for the manual placement of an otherwise loose portion of the testing system, such as the allergen package 134, or the imaging system 138. Lithe embodiment of FIG. 13, the analyzer 140 is illustrated as being remotely coupled to the imaging system 138. This remote link may be a physical wire or a radio frequency (RF) or optical wireless link. [00081] The imaging system 138 from the previous embodiment may be constructed to align- with and/or hold the microneedle package 134 in different ways, depending on the embodiment. For example, FIG. 14A schematically illustrates a side view of an imaging system 142 which holds a replaceable microneedle allergen package 144. The microneedle package 144 may be held in position by guides on the imaging system 142. FTG. 14B schematically illustrates the microneedle allergen package 144 being removed from the imaging system 142 in a substantially' linear 146 direction. A microneedle allergen package 144 could be installed by reversing the action illustrated in FIG. 14B. After inserting an allergen package 144, the microneedles may be engaged by the activation system as described in previous embodiments. Then, once the microneedles are allowed to retract from the test- subject's skin 36, the allergen package 144 can be removed from the optical path of the imaging sensor within the imaging system 142 as illustrated in FIG: 14B. In this case, non- transparent or non-optical materials can be used for the microneedle array, such as silicon, metal, opaque plastic, and others. In some cases, it may even be desirable to remove transparent materials away from the optical path in order to reduce requirements for optical flatness, transparency, and cost. [00082] FIG. 15 A schematically illustrates a top view of another embodiment of an imaging system 148 which holds a replaceable microneedle allergen package 150. In this embodiment, the microneedle package 150 is held in place by a pivot point 152 and may also be held in position by guides on the imaging system 148. FIG. 15B schematically illustrates the microneedle allergen package 150 being removed from the imaging system 148 in a substantially arcuate 154 direction. A microneedle allergen package 150 could be installed by reversing the action illustrated in FIG. 15B. After inserting an allergen package 150, the microneedles may be engaged by the activation system as described in previous embodiments. Then, once the microneedles are allowed to retract, the allergen package 150 can be removed from the optical path of the imaging sensor within the imaging system 148 as illustrated in FIG. 15B. In this case, non-transparent or non-optical materials can be used for the microneedle array, such as silicon, metal, opaque plastic, and others. In some cases, it may even be desirable to remove transparent materials away from the optical path in order to reduce requirements for optical flatness, transparency, and cost. [00083] All of the allergy testing systems embodied herein, and their equivalents, are intended to be used with replaceable cartridges having the coated microneedle array. FIGS. 16A - 16M schematically illustrate an embodiment of a process for manufacturing a replaceable allergen cartridge for use in an allergy testing system. [00084] The process begins, FIG. 16A, with a cover 160 which may be made from a variety of materials* such as, but not limited to plastics, metals, and glass. The cover 160 in FIG. 16A is schematically illustrated in a side cross-sectional view. Next, FIG. 16B, orifices 162 are formed in the cover 160 by a variety of machining and or micromachining techniques, such as laser cutting, die cutting, stamping, or etching, hi other embodiments, the cover 160 with orifices 162 may be formed by an injection molding process, or some other molding process. FIG. 16C illustrates the cover 160 with orifices 162 in a top view. It should be understood that the nine orifices 162 illustrated in FTG. 16C are only for the sake of an example, and that other embodiments may have one or more orifices 162. Similarly, in other embodiments, the orifices 162 may be of a different size and/or shape and/or distribution and/or layout.

[00085] In a parallel, preceding, or subsequent step, FIG. 16D, a substrate 164 is provided for formation into a microneedle array. The substrate 164 may be made from a variety of materials, such as, but not limited to, glass, plastic, metal, silicon, and quartz. In FIG. 16D, the substrate 164 is schematically illustrated in a side cross- sectional view.

[00086] In FIG. 16E, a mask 166 is formed on the substrate 164. In FIG 16F, microneedles 168 may be formed in the substrate 164 using a variety of techniques. A variety of suitable techniques, such as anisotropic etching, isotropic etching, and chemical etching, have been discussed above. In FIG. 16G5 the mask 166 is removed, leaving the microneedle 168 formed on the substrate 164.

[00087] In FIGS. 16H and 161, the microneedles 168 may be placed into contact with one or more allergens 170, resulting in a coating of allergens 172 on the microneedles 168. hi some embodiments, the liquid allergens maybe coated onto the microneedles using a pipette array or "arrayer" or "spotter". Similarly, an inkjet style device could be used to coat the allergens onto the microneedles. If the allergens are coated onto the microneedles using an arrayer or printhcad, then, in some embodiments, it may also be desirable to turn the microxieedle array needles-down for drying. FIG. 16J illustrates the substrate 164 in a top view with the coated 172 microneedles 168. It should be understood that the nine microneedles 168 illustrated in FIG. 16J are only for the sake of an example, and that other embodiments may have one or more microneedles 168. Similarly, in other embodiments, the microneedles 168 maybe of a different size and/or shape and/or distribution and/or layout. [00088] Next, in FIG. 16K, elastomer springs 174 are coupled to the substrate 164. FIG. 16K also shows the assembly in a top view. FIG. 16L shows the assembly in a side view. The elastomer springs 174 in this embodiment are just one type of energy storage device which may be coupled to the substrate 164. Other embodiments may have energy storage devices which include metal springs or plastic springs. [00089] Next, the cover assembly 160 from FIG. 16B and the substrate assembly from FIG. 16L are coupled together as in FIG. 16M to form a replaceable allergen cartridge 176.

[00090] Although the descriptions and figures of some of the embodiments described above show single needle arrays or one dimensional array systems, the claimed invention is easily extendible to two dimensions.

[00091] In various embodiments, sheets, thin-films, films, and labels have been described as being used on some embodiments of allergy testing systems and/or on the replaceable allergy testing cartridges, depending on where they were located. AU are considered to be equivalents of each other, and for the purposes of the claims, the terms are interchangeable.

[00092] Having thus described several embodiments of the claimed invention, it will be rather apparent to those skilled in the art that the foregoing detailed disclosure is intended to be presented by way of example only, and is not limiting. Various alterations, improvements, and modifications will occur and are intended to those skilled in the art, though not expressly stated herein. These alterations, improvements, and modifications are intended to be suggested hereby, and are within the spirit and the scope of the claimed invention. Additionally, the recited order of the processing elements or sequences, or the use of numbers, letters, or other designations therefore, is not intended to limit the claimed processes to any order except as may be specified in the claims. Accordingly, the claimed invention is limited only by the following claims and equivalents thereto.

Claims

What is claimed is:
1. A replaceable cartridge for use in an allergy testing system, comprising: a microneedle array comprising at least one microneedle; at least one coated allergen coupled in alignment with the at least one microneedle.
2. The replaceable cartridge of claim 1, wherein the at least one coated allergen is coupled in alignment with the at least one microneedle by being coupled onto the at least one microneedle.
3. The replaceable cartridge of claim 1, further comprising a sheet coupled in alignment with the at least one microneedle, wherein the at least one coated allergen is coupled in alignment with the at least one microneedle by being coupled to the sheet in alignment with the at least one microneedle.
4. The replaceable cartridge of claim 1, further comprising a compressible stop coupled to the microneedle array.
5. The replaceable cartridge of claim 1, wherein the at least one microneedle further comprises a hollow needle.
6. The replaceable cartridge of claim 1, wherein the at least one microneedle further comprises a grooved needle.
7. The replaceable cartridge of claim 1 , wherein the at least one microneedle further comprises a solid needle.
8. The replaceable cartridge of claim 1, wherein the at least one microneedle further comprises a corrugated needle.
9. The replaceable cartridge of claim 1, wherein the microneedle array comprises at least one needle of a first penetration depth and at least one needle of a second penetration depth which is different from the first penetration depth.
10. The replaceable cartridge of claim 1, wherein the microneedle array comprises at least one microneedle with a cross-section that is selected from the group consisting of square, rectangular, triangular, and circular.
11. The replaceable cartridge of claim 1, wherein the microneedle array comprises at least one needle with a varying cross-section.
12. The replaceable cartridge of claim 1, wherein the microneedle array comprises a transparent material.
13. The replaceable cartridge of claim 1, further comprising a cover which defines at least one orifice.
14. The replaceable cartridge of claim 13, wherein the microneedle array further comprises at least one mesa which is aligned to slideably engage with the at least one orifice.
15. The replaceable cartridge of claim 1, further comprising a sealing layer which prevents contaminants from reaching the microneedle array.
16. The replaceable cartridge of claim 15, wherein the sealing layer further comprises identifying marks.
17. The replacement cartridge of claim 16, wherein the identifying marks are selected from the group consisting of bar codes, graphics, and alphanumeric characters.
18. The replacement cartridge of claim 17, wherein the identifying marks are used for identification of the allergens being tested.
19. The replacement cartridge of claim 17, wherein the identifying marks are used for identification of a patient.
20. A replaceable cartridge for use in an allergy testing system, comprising: a reusable microneedle array; and removable and recoatable coated allergens coupled to the microneedle array.
21. A method of manufacturing a replaceable cartridge for use in an allergy testing system, comprising: forming at least one orifice in a cover to form a cover assembly; forming a microneedle array having a substrate and at least one microneedle; coating at least one allergen on the at least one microneedle; coupling an energy storage device to the substrate to form a microneedle array assembly; and coupling the cover assembly with the microneedle array assembly. .•
22. The method of claim 21, wherein the cover comprises a material selected from the group consisting of metal, plastic, glass, quartz, and silicon.
23. The method of claim 21, wherein the microneedle array is formed of glass, plastic, metal, quartz, or silicon.
24. The method of claim 21, wherein the energy storage device is selected from the group consisting of an elastomer spring, a metal spring, and a plastic spring.
25. The method of claim 21, wherein forming a microneedle array comprises anisotropically etching the at least one microneedle.
26. A replaceable cartridge for use in an allergy testing system formed by the process of claim 21 .
PCT/US2007/061601 2005-07-11 2007-02-05 Allergy testing cartridge with coated allergens WO2008008557A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
PCT/US2006/026774 WO2007008824A2 (en) 2005-07-11 2006-07-11 Minimally invasive allergy testing system
USPCT/US2006/26774 2006-07-11
USPCT/US2006/26734 2006-07-11
PCT/US2006/026734 WO2007008800A2 (en) 2005-07-11 2006-07-11 Replaceable cartridge for allergy testing system

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PCT/US2007/061604 WO2008008558A1 (en) 2005-07-11 2007-02-05 Minimally invasive allergy testing system with coated allergens

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